3 vi: Brecesscesnenn eeestonaaces ponaesecipropsenteenscastcs See CaSO SRTA ES ERTEROROU RAEN OAS enema cer PICEE PRE IROELE SEO MIRAE POPPI EC IREELFSAERE ITER LOPE LTO OL TECTIA PRR LALO EIN LED LS OER no ' 20t3 Sen SEE PLE LATO CLs LAL GT RRES ELLIE LAS ELLIE ES ananatntncarntnernrcmnmtereneene” mancreeneer menns nares e: p Pe seoatann eee Pree tartrate isetoetertegrtcenthernnnnershoamapnerarstzerreane’ cs Pe EPIL ELS ITLN IE Le ELLIE fe LITERATE ELE BET oe ri oe SSCP OTP RARRAEEE PERPRNOR OEP RADNOR L LT NOCLE MEDD nan Pen seer Lo - -: 7 " ra ebteesteancerce crore hz basnnnetsstenenpeosenveepenerer sccarsnesas tor geen spepenrnenteser nap son mae noeaee sonore aes ne een : mae CM SELLERS shnannatenegecmrtacmasnehnnn stan srenne spon none rinnens ANee ty Pip Toenr hp emereinns RemenneRannesiy ~aas ree g re 3 OCCA NI CAN EEPERANAA SE NNRRRRT SNORE ARmn A neAhhd Ps norimnnninn me nnsereRaecrerreet cone, PES ESSELSSERCESTENE “ mpanases: Perel CP EP erm es PIES a z Mees os PEEL IIS I LISTE SEIT SSSSE SSIES COPEL Sostt ‘a - eeeess A ‘ LE LOR EP CPEEEE are spore ronmeecenerer cient sa nan ayaaeatne ae PORTE AREY : x: Soe tad speesoegpe neers COL. GEORGE WASHINGTON FLOWERS MEMORIAL COLLECTION TRINITY COLLEGE LIBRARY DURHAM, N.C. ruin Pau we Locsera) Date TZ) \ttedy Big LGB et ee | A gi HOA bs alge i Toys Ua , f ‘f Fy 3 uy eu) ret ,\ f , . , ee » - ‘ i DOK Eee SONG Moe RIS LE Ve PU BLTCAT LON S PERNICIOUS ANEMIA Lonpon: CAMBRIDGE UNIVERSITY PRESS New York: G. E. STECHERT & CO. Toxyo: MARUZEN COMPANY, LTD. SHANGHAI: EDWARD EVANS & SONS, LTD. PERNICIOUS ANEMIA BY BEAUMONT S. CORNELL, M.B. (Tor.) Fellow in Duke University 124380 DURHAM + NORTH CAROLINA DUKE UNIVERSITY PRESS OT i7, COPYRIGHT 1927 BY DUKE UNIVERSITY PRESS THE SEEMAN PRESS DURHAM, N. C. Printed in the United States of America Yur f ben £ 3 ‘ Peep Op) of Flowers : / ny * j 7 rt e / ~ , 20 bet. FOR NON-MEDICAL READERS For seventy years pernicious anemia has remained a mysterious and fatal disease. Even persons outside the medical profession have become unpleasantly familiar with the symptoms,—how it begins with weakness and pallor, improves for a time, only to end in death. Within the last two or three years, the medical profession has been astonished by the discovery of a very satisfactory means of treating this hitherto unyielding disease. The public is interested in pernicious anemia, and it is with the purpose of trying to give lay readers as accurate an idea as possible of the disease and its treatment, that this chapter is presented. We believe that better understand- ing will lead the readers to make sure, by being suitably examined, that they themselves are not candidates. The most uncontested fact about pernicious anemia has always been its invariably fatal termination. Most people have seen a case or two occurring perhaps in a relative or some associate, and are familiar with the yellowish skin and corpse-like pallor and with the extreme weakness so pitiable to behold. The word “Anemia” would come to the mind of the most inexpert observer and the adjective “pernicious”, though quite unscientific, would seem very apt indeed. Practically every patient died, usually within a period of two or three years, some after four or five years and a very few after the lapse of ten years. Once in a long while a patient appeared to get well and thus, by exception, to prove the rule. A very intelligent clergyman once volunteered to the writer a remarkable characterization of pernicious ane- mia. ““This disease,” he said, “is a type of physical degen- eracy which reminds me of the rotting of a hemlock knot.” Degeneration: this word has been used over and Cv] 124380 vi PERNICIOUS ANEMIA over again, in many connections, to describe the impres- sions of scientific observers. It has not proved to be very useful except as a side-track for several train loads of ignorance. You may, if you wish, say that the blood of these patients degenerates, but you must not overlook the fact that certain immutable laws of nature govern even the rotting of a hemlock knot. The exact process of dis- ease which causes pernicious anemia is just about as obscure today as it was in 1822 when a doctor in Scotland described the first recorded case. The lack of blood is just one of the features. The diges- tive organs and the spinal cord are also affected. In normal persons the stomach is not only a churn for mixing the food, but also a factory for manufacturing a juice which has a definite chemical influence on the food. The gastric juice is a colorless transparent liquid containing hydro- chloric acid and pepsin. In people suffering from perni- cious anemia the acid is lacking. It might be surmised, for that reason, that the food is not properly digested. One might even be led to think that this was the cause of the disease. Such an easy solution of the problem is at once rendered impossible by the fact that many perfectly healthy people go through life without acid in their stom- achs. It is apparently true, however, that cases of perni- cious anemia are all recruited from among persons having no acid in their stomachs. In other words, in order to be able to qualify for this most undesirable malady you must lack acid in your stomach. Of all persons with achlor- hydria (as this lack is named) probably one in ten devel- ops pernicious anemia. What causes achlorhydria? We do not know, but we think that the condition is hereditary. In a few families pernicious anemia runs like a scourge among blood relatives all of whom have achlorhydria. The spinal cord undergoes degeneration, quite exten- sive in many cases. Many of the paths which conduct nervous impulses are interrupted and consequently abnor- FOR NON-MEDICAL READERS vii mal sensations appear in the skin. The chief one is numb- ness of the hands and feet. The legs become partly para- lyzed and weak. Occasionally the brain is affected in such a way that reason departs and the patient becomes mod- erately insane. It is quite evident therefore that pernicious anemia is not merely a disease of the blood. It is a process, rather, which involves a great portion of the different organs of the body. Even the heart, liver and kidneys are appreci- ably affected. The first inkling which the patient has of any trouble is usually weakness, and weakness alone. A business man begins to notice that he tires out in the middle of the day, and when he tells his wife, she remarks that he has been looking pale or perhaps jaundiced for a few weeks. The doctor examines him and finds that he actually has only two-fifths of the normal amount of blood. If any indi- vidual were suddenly to lose three-fifths of his blood from hemorrhage he would be a bed case at once. But where the anemia has come on gradually over a number of months, his weakness has also developed so slowly that he has not at first noticed it. You will at once wonder why this man has only two-fifths of his blood. What has hap- pened to the rest of it? No matter how closely you ques- tion him you will not discover any reason, for he has had no hemorrhage at any time. Here, then, is a mystery —no pain, no bleeding, no illness, no signs of ill-health— but just weakness and lack of blood. If the reader will pause to reflect, he will realize that either the blood has been destroyed within the body, or else the organs which produce blood have become remiss in their function. To decide between these alternatives is really the major prob- lem of science in connection with this disease. Normally blood cells are being constantly formed by the marrow of the bones and turned out into the circula- tion. Also, blood cells are being constantly disposed of, Vili PERNICIOUS ANEMIA or destroyed by various organs, when their usefulness is at an end. The life of one red blood cell is probably about a month. Now the rate of blood production and the rate of blood destruction are exactly equal, because the num- ber of cells in circulation remains constant. Presented with an anemia not caused by hemorrhage, one logically concludes that either the rate of blood destruction has increased or the rate of blood production has been re- duced. We know for sure that the rate of destruction is somewhat increased, but we doubt if it has been suffi- ciently increased to account for such an anemia. We rather believe that a greatly reduced rate of production is responsible. The red blood cells are very tiny bi-concave discs of microscopic dimensions which carry oxygen to all tissues of the body. In health they are all practically of the same size and shape. In anemias due to hemorrhage they may show some degree of variation both in size and shape. In pernicious anemia, however, they show most remarkable variations in size and shape. Some of the cells are twice as wide as normal while others have only half the width they should have. Some of the smaller cells, instead of preserving their disc-like shape, resemble frying pans, dumbells, Indian clubs, Grecian urns, water bottles, Indian arrow-heads, carrots, etc. It is quite evident that the factory which turned out such products as these was in a state of dis- organization. Such faulty blood formation is one of the best arguments for blaming this anemia upon the bone marrow. Why, then, does the bone-marrow produce such irregu- lar cells and why does it produce fewer cells than it should ? That is the fundamental problem of the disease, but it is no more fundamental than the question,—why does the spinal cord degenerate? There have been at least several FOR NON-MEDICAL READERS ix dozens of theories advanced in the attempt to explain these phenomena. The commonest theory was that some toxin or poison arising in the body was simply poisoning the spinal cord and the bone-marrow. This “Toxin Theory” has held ‘the floor for the past forty years, although nobody was able to identify any poison in the body which could be responsible, and no one was able to produce true pernicious anemia in animals by injecting various poisons. Those who held the toxin theory usually supposed that the toxin arose from the intestines, but nowadays we are beginning to think that our bowels are not quite so harm- ful and dispensable as some of our associates would have us believe. The commanding position so long held by many diseases on toxins, because we know that the poi- sons of bacteria are responsible for many diseases. Bacte- riology has failed to help solve the problem of pernicious anemia, as it has failed in the case of cancer. Some scientists believe that bacteriology has ‘done its bit” for medicine and everyone is conscious of the grow- ing importance of a practically new science,—the study of food. Dietetics, or rather nutritional therapy, has caused a great change in our attitude toward pernicious anemia. Every treatment that has ever been tried,—drugs to no end, blood transfusions, surgery,—has failed to alter very much the course of the disease. Periods of improvement occur without any treatment, and therefore it is difficult to judge the effect of any special treatment. The fact which we now must take into consideration is this,—if a patient with pernicious anemia will eat one- half pound of lightly cooked calve’s liver a day, this patient will regain such a degree of health that he will, in all probability, be able to work and enjoy life. This sounds very simple indeed, and yet the story of this discovery is not simple, for it required a great volume of tedious work and observation upon many patients. x PERNICIOUS ANEMIA We cannot say positively that eating liver is a cure for pernicious anemia, since continuous observation on pa- tients has not, as yet, exceeded three years. But it is a fact that those patients who have persisted in the diet have not only greatly improved but have remained com- paratively well. No such statement can be made regarding the efficacy of any other treatment ever tried. We justly regard this “liver treatment’? as the most startling dis- covery that has been made in connection with this disease, and as anextremely satisfactory means of treatment. As yet, this treatment has shed no definite light on the cause of the disease, but it has placed pernicious anemia in the same category as rickets in that it can now be con- trolled, although its nature is obscure. INTRODUCTION That the author has done me the great honor of invit- ing me to write an introduction to his monograph on PERNICIOUS ANAEMIA is due largely, if not entirely, to my interest in this disease. Since my three happy years (1902-1905) at the Johns Hopkins Hospital, as assistant resident physician in the medical service of the late Sir William Osler, I have tried to keep abreast of the litera- ture in this particular field. Then when in 1910 I moved to Iowa and directed a clinic of my own, I was delighted to find there a rich collection of anaemia cases available for study. With such a staff of well trained laboratory workers as Drs. L. Baumann, R. H. Gibson, R. L. Fen- lon, F. S. Stevens, G. H. Hansmann, and the co-operation of Miss Margaret Sawyer of the Home Economics De- partment of the State University and later of Dr. Ruth Wheeler, the professor of Dietetics of the Medical School, much intensive work was carried on over a period of years. Clinical, biochemical, and therapeutic problems were undertaken. While, with the possible exception of the clinical use of Whipple’s high iron diet for pernicious anaemia cases, nothing fundamental was contributed by us, we nevertheless were of necessity constantly in touch with the literature on this fascinating subject. As the reader will soon learn this was no light task, as both in Europe and in America a great many workers were striv- ing to determine the etiology of this disease, or failing in this to develop at least some more successful line of therapy than that in vogue at the beginning of the present century. From a more or less intimate knowledge of the enormous literature I think the author, Dr. B. S. Cornell, is to be sincerely congratulated on his clear, concise, and unprejudiced presentation of our knowledge, or possibly I should say our lack of knowledge, of the fundamental [xi ] xii PERNICIOUS ANEMIA phenomena underlying Pernicious Anaemia. This mono- graph will, I feel certain, prove of great assistance to the present and future students of haematology and will occupy a well-deserved place on the book shelves of every medical school as well as of many physicians’ libraries. C. P. Howarp, B.A., M.D. Professor of Medicine, McGill University Physician to the Montreal General Hospital AUTHOR’S PREFACE In a disease of unknown etiology every clinician ulti- mately develops his own peculiar view-point, expands it, arranges all the phenomena of the disease in some rela- tion to it, and may therefore find, in any treatise on the subject, other arrangements and other points of emphasis seemingly at variance with his own. Pernicious anemia lends itself well to such diversified conceptions on account of the broad symptomatology and wide tissue involvement which it presents. In the etiological field, theories have blossomed by the score through the decades since 1820, indicating the strong imaginative appeal which the disease has made to medical men. Few of these hypotheses are ridiculous, yet some enunciated most dogmatically are least convincing, and even those most supported by fact have proved inadequate. Experimentally, no blood picture of a convincing character has yet been produced, nor have the cord lesions, the glossitis, or the remissions been imi- tated. Diagnosis is the one well-cultivated field, yet differ- entiation from certain other anemias is at times ex- tremely difficult. If time has taught one inescapable lesson, it is that from 1820 to 1926 no cure existed, and yet writers, deceived by the occurrence of spontaneous remis- sions, have continued to fill the journals with descriptions of innumerable forms of treatment. These must be re- garded with great caution and deductions made gradu- ally over years of time, not months. In the literature of few diseases has there been so marked a tendency to mix fact with fiction. This is to be largely explained by the striking challenge to hypothesis which the disease characteristically makes. An average journal contribution contains a small amount of informa- tion and a large amount of speculation. Not infrequently the two become badly confused. This unpleasant state of [ xiii ] xiv PERNICIOUS ANEMIA the literature in general is increased by a tangle of nomen- clature inherited from the last century. A great many investigators, however, have had very clear motives, and their contributions are pleasant to read. The Surgeon-General’s Library in Washington con- tains about two thousand references to this subject. The fact that almost half of these have accumulated during the past decade, whereas the disease has been before the profession more than seven decades, indicates not only an increasing habit of publication, but a greater recent inter- est in pernicious anemia. It might be possible to build the entire story of our knowledge of the disease on the one hundred most important papers which have appeared. The omission of others, however, would rob one of an array of theoretical exposition—the psychology of the subject—which, in itself, affords considerable fascina- tion. Northern Europe, the British Isles, the United States, and Canada are at once the regions of highest incidence of the disease and of greatest investigation and publica- tion. The Atlantic Ocean has always divided pernicious anemia into two or three ill-defined schools of thought. On the continent, the characteristic attitude remains, as it has always been, one permitting a wide definition of the disease; with a tendency during the past twenty years to regard the idiopathic (or true) pernicious anemia as due to chronic intestinal intoxication. In Eng- land the disease is strictly Addisonian—limited to idio- pathic cases—and is usually regarded as due to sepsis of the digestive tract. In North America the term “perni- cious anemia’”’ is reserved for the idiopathic or Addison- ian complex, and the general etiological attitude is more confessedly one of rather complete agnosticism. Animal experimentation has contributed in a relatively minor capacity to our knowledge. The disease seems to be a specific possession of man, and the investigations of AUTHOR’S PREFACE XV greatest importance have been those conducted on patients with the disease. The most enlightening contri- butions have been those made possible by newly discov- ered methods of examination. Anilin blood stains, the hemocytometer, the stomach tube, the metabolimeter, ac- curate methods in the chemistry of the blood, the advance of dietary studies—these have all added valuable infor- mation. The newly discovered value of a diet rich in liver is unquestionably the most striking fact which has yet been presented. Among the comparatively few books which have been devoted specially to pernicious anemia may be mentioned those of Miller (1877), Eichhorst (1878), William Hunter (1901) (1909), and Evans (1926). Among the comprehensive monographs may be mentioned those of Cabot, Minot, French, Vogel, Moffit, Squier, and Schauman and Saltzman. To these works the author gratefully acknowledges his indebtedness. The present volume attempts to afford a critical review of the literature, to give a picture of the disease in the light of present knowledge, to increase the interest of the general practitioner in a subject which has received too little interest in the past, and, finally, to recommend earlier diagnosis and such form of prophylaxis as may be em- ployed. With these ideals in mind, this book has been prepared and is offered to the profession with the sincere hope that it may be found useful. Royal Victoria Hospital, BS. ce Montreal, Canada, May 24, 1927. 5 a an ey i gu i Ny ad ‘th, A Mba ; Me i CONTENTS PAGE FOR NON-MEDICAL READERS v INTRODUCTION xi AUTHOR’S PREFACE xiii CHAPTER I DEFINITION—CLASSIFICATION— DISTRIBUTION 3 CHAPTER II HISTORICAL OUTLINE 16 CHAPTER III ETIOLOGY 31 CHAPTER IV GENERAL SYMPTOMATOLOGY 79 CHAPTER V THE DIGESTIVE SYSTEM 88 CHAPTER VI THE BLOOD SYSTEM 113 CHAPTER VII METABOLIC OBSERVATIONS 183 CHAPTER VIII THE NERVOUS SYSTEM 195 CHAPTER IX CARDIOVASCULAR, RESPIRATORY, GENITO-URINARY, AND OTHER SYSTEMS 207 CHAPTER X DIAGNOSIS AND PROGNOSIS 215 CHAPTER XI PROPHYLAXIS AND TREATMENT 228 AUTHOR-SUBJECT INDEX OF BIBLIOGRAPHY CONSIDERED 242 INDEX 299 PERNICIOUS ANEMIA CHAPTER I DEFINITION—CLASSIFICATION— DISTRIBUTION DEFINITION Pernicious anemia is a disease of unknown etiology, showing a characteristic triad of changes in the digestive, blood and nervous systems and progressing, usually by remissions, to a fatal termination. CLASSIFICATION The disease as a whole, considered from the stand- point of its common involvement of various systems, bears no very great resemblance to any other disease. Eventually it may be classified among the metabolic, or possibly the infectious, diseases. The anemia, which at- tends it so obtrusively as to have given it its name, re- quires classification. Any anemia is the result of one or more of the following factors—hemorrhage, blood de- struction, and depression of hemopoietic function. The anemia under consideration is believed to be due to a combination of the two latter causes, with an added fac- tor, namely, that the blood-forming function is not only depressed quantitatively but is also qualitatively per- verted. Otherwise expressed, blood corpuscles are being destroyed, they are being produced in insufficient num- bers, and those which are produced bear evidence of abnormal manufacture. The relative influence of blood destruction, on the one hand, and of hemopoietic depres- sion, on the other, in producing the anemia, is by no means clearly defined, although both phenomena defi- nitely occur. The term “hemolysis” should be restricted to indicate a physiological process by which a red blood corpuscle releases hemoglobin, and may be used in con- nection with many known in vitro phenomena. It is not [3] 4 PERNICIOUS ANEMIA perfectly correct to speak of this anemia as “hemolytic,” as the loss of hemoglobin is not the striking feature. The striking feature is cellular phagocytosis, and this is the only known mechanism of blood destruction in this disease. Nevertheless, the term “hemolytic” is used fre- quently as synonymous with “blood-destructive”, and it has crept into the nomenclature to such an extent as to be often unavoidable. The bone-marrow shows enormous erythroregenera- tive activity in the form of an early embryonic type of blood formation. Similar pictures may be found in a few other instances, e.g., the chronic hemolytic anemia of pregnancy, some cases of fish tape-worm infection, some cases of cancer of the stomach, some cases of sprue, as well as certain other conditions to be mentioned presently. Waugh (637) in referring to these anemias, states: “The bone-marrow becomes brick red and often erythrogenesis is taken up by the spleen and liver . . . the color-index is high . . . such a condition may be termed therefore, hyperchromic. We find this type of anemia in certain cases of lues, sometimes associated with pregnancy, in the intoxication resulting from the fish tape-worm, also from the hook-worm, and especially in pernicious ane- mia.’’ He would therefore group these together as hyper- chromic, hemomyelotoxic anemias, and regard the anemia of pernicious anemia merely as the idiopathic member of the group. The position can be seen from Table I, show- ing Waugh’s classification of the anemias. TABLE 1 Outline of classification of the anaemias (Waugh). A. Hemopathic (blood). 1. Hemorrhagic (loss of blood). 2. Hemotoxic (destruction of blood). B. Myelopathic (bone-marrow). 1. Hemomyelotoxic (blood and bone-marrow). (a) Aplastic. (b) Erythroplastic (hypochromic). CLASSIFICATION—DISTRIBUTION 5 (c) Erythrohyperplastic (hyperchromic). 2. Myelotoxic (wasting away). 3. Dyscrasic (dysharmonic, dysformative, dystrophic). This classification of the anemias and this characteriza- tion of pernicious anemia as an idiopathic member of the group of hyperchromic, hemomyelotoxic anemias, are as satsfactory as any offered. The very attempt to fit pernicious anemia into any group emphasizes its essen- tial dissimilarity, and it is felt that too great stress should not be placed upon classification. On the contrary, the disease should be studied first as a distinct phenomenon of nature, and comparisons left until later. THE NAME OF THE DISEASE The following names are among those which have been used, at various times, and by different writers, to designate the disease—idiopathic anemia, essential ane- mia, lethal anemia, pernicious anemia, primary progress- ive pernicious anemia, Biermer anemia, Biermer disease, Biermer-Erlich anemia, Addisonian anemia, Addison’s anemia, Addison-Hunterian anemia, idiopathic glossitic anemia. Any discussion of the relative merits of these names shows that objections can be raised to each one. In Ger- many and Switzerland, Biermer anemia is the choice. In England during the past ten years Addison’s anemia has been the common designation. In the United States and Canada, pernicious anemia has remained the sim- plest, the time honored, and perhaps the fairest, title. The term “primary” reflects a scholastic era in that it is the grammatical opposite of “secondary”, but modern intelli- gence cares to attach the adjective “uncaused” to but few phenomena. In retaining “pernicious anemia’, it is nec- essary to exclude all cases of anemia in which a cause can be noted and to use the term, therefore, in a much more restricted sense than that in which it was first pro- 6 PERNICIOUS ANEMIA posed. So far from being discarded because of its depress- ing effect on the patient, it should be preserved because it impels the patient earlier to seek advice. Even when the etiology is finally elucidated, it is questionable whether even better knowledge will discard this familiar name. GEOGRAPHIC DISTRIBUTION It has been recognized for fifty years that the disease is commoner in Northern Europe, the British Isles, and North America than elsewhere. Evans (177) quotes Klotz to the effect that it is very uncommon in Brazil. Cheng (109) stated that he had never seen a case among the natives in China. It is apparent from the experience of Longcope at Baltimore, and of others, that the disease seldom if ever occurs in a full-blooded negro. Jews are said to be uncommonly affected. Specific information is lacking from many quarters of the globe, but the writer sent out letters in November 1925 to many countries seeking mortality statistics. In Germany the hospitals have the only records. In Australia the Bertillon classi- fication groups pernicious anemia with certain other forms of anemia. The same grouping is used in Sweden, but Gram kindly produced the required information from special sources. In England the Statistical Reviews of the Registrar General contain figures for pernicious anemia (H. M. Stationery Office, Adastral House, Kingsway, London, W. C., 2, at 15/- each). South Africa collects no morbidity statistics; however, the number of European deaths from it, registered in the Union during the years 1914-1924 averaged 43 per year, although the European population is not stated. In Newfoundland for 1924 the deaths from pernicious anemia combined with other anemias and leukemias were 6 per 100,000 of population. The Surgeon General of the United States reported from the registration areas for 1921 and 1922 as follows: CLASSIFICATION—DISTRIBUTION vs TABLE 2 Deaths from pernicious anemia in the United States 1921 1922 itemanenmetndeatiosy 2 corso Ae ade 4377 4979 Death rate per 100,000 of population...................... 49 aes Additional details may be found in the annual volumes of mortality statistics issued by the Bureau of Census. Since the average duration of the disease, up until now, has averaged 2.2 years, it is safe to state that in the United States at any time there are 10,000 cases, at the lowest estimate. In Denmark, the deaths for 4 years, outside Copen- hagen, are shown by the statistics in Table 3. TABLE 3 Deaths in Denmark outside Copenhagen No. of deaths National Deaths per from pernicious population 100,000 anemia outside Copen. population 1OZO May nei yh 63 2,524,650 225 GAM ee Bee ce La 68 2,721,500 2.5 O22 Mie eee ee at 85 2,752,700 Sul SDV es coe aie Se 83 2,767,500 3.0 LOZ Aver ee 123 2,788,150 44 Separated statistics for the urban and rural sections outside Copenhagen are shown in Table 4. TABLE 4 Deaths in Urban and Rural Denmark outside Copenhagen No. of deaths Total urban Deaths per from pernicious population 100,000 anemia outside Copen. population 1 Ge? Se Ps 765,700 23 Soe ee 30 825,250 3.6 1/27 ao See ZA 835,900 Bd. 613 Se aes 31 840,100 3:7 IS 74 ee a ee 46 839,200 Df 8 PERNICIOUS ANEMIA Deaths per 100,000 population 2a 2.0 3.0 Zed 3.8 Deaths per 100,000 population 25 Sy 25 0.9 £5 3.6 4.0 48 6.0 No. of deaths Total from pernicious rural anemia population 1920 eee 42 1,758,950 11277 BE Sl 38 1,896,250 1977 Nate eee 62 1,916,800 OZS sae sees 52 1,927,400 NODA tl Beene 77 1,948,950 Figures for the City of Copenhagen are found in Table 5. TABLE 5 Deaths in Copenhagen Deaths from Population pernicious of Copen- anemia hagen BO OD a2 et ses Ae eee 10 416,540 [Est.] POG acess Ba ee 13 426,540 [ Act. ] TSO 7 Soe Reeth ee 11 434,540 [Est.] ROOS 2 eye ees 4 442,540 [Est.] NOOO eee Eee ai 450,540 [ Est. ] (SS ae ee 18 491,161 [Est.] HIS (ICR Peete state 20 506,390 [ Act. ] SR ee ae 28 573,295 [Act.] 1O24 a eee 5) 581,295 [Est.] Examination of these tables indicates a slight increase in reported cases especially in the period 1921-1924, and particularly in the urban population. Such increase is really small and may justly be attributed to better diag- nostic facilities in the cities. The investigation recently undertaken in Germany by Schilling at Magnus-Levy’s suggestion showed, however, a 3- to 4-fold increase of the disease at German clinics (521). Gram Sweden the following figures (Table 6). TABLE 6 Deaths in Sweden Deaths from pernicious Population anemia of Sweden DS ea Ds BA ee 82 2.5M LONG ee Re calle 2d. 87 2.5M reports for Deaths per 100,000 population BE 3.4 CLASSIFICATION—DISTRIBUTION 9 DO ee eens 8 aS ‘ 87 2.5M 3.4 MOS eee ete dh 76 2.5M 3.0 CIN ps hs Meee Nee Ame 86 2.5M 3.4 Oe Soe oe oe ts 88 2.5M a5 POS nee is 95 2.5M 3.8 IND |G ee ee oe cme 68 2.9M Zh SZ ers eens 79 2.5M 3.1 LING PAL Salle DA Re ene 96 2.9M 3.8 Nova Scotia in 1923 showed an incidence of 4.8 deaths per 100,000 of population. Saskatchewan showed a com- bined rate for anemias and chlorosis of 9.2 per 100,000, for 1923. New Brunswick in 1924 showed a death rate from pernicious anemia of 9.0 per 100,000 of population . but somewhat lower rates for the preceding four years. Quebec Province showed the following rates: Year No. of Deaths Rate per 100,000 population 1921 71 3.0 1922 69 2.8 1923 66 2.8 1924 73 25 British Columbia showed the following figures: Year No. of Deaths Rate per 100,000 population 1921 34 6.0 1922 41 8.0 1923 4] 8.0 1924 50 10.0 Alberta in 1923 showed 26 deaths in a population of 588,000 or a rate of 4.3 per 100,000 among the white population, exclusive of Indians. Ontario shows a very high incidence of the disease, as the following figures will indicate: Meat Population Deaths Rate per 100,000 population 1922 2,981,182 437 14.6 1923 3,028,907 454 15.0 1924 3,062,150 433 14.1 So high a figure has not been noted from any other regis- tration area from which statistics have been received. 10 PERNICIOUS ANEMIA As the deaths from all causes total 33,000 to 35,000, those from pernicious anemia form from 1.28 to 1.31 per cent of the total deaths! The reasons for this exception- ally high incidence in Ontario are not apparent, but that it is a reality has been impressed upon the writer during several tours of Ontario. Whereas in most regions of the world a general practitioner may see from three to five cases during twenty years’ practice, nearly all physicians in Ontario will treat a case every two or three years, and it is not uncommon to find a physician with two or three cases at a time, and two physicians with small- town practices have at present four and five cases on hand, respectively. Even without statistical studies it has been recognized for some time that Michigan, Ontario, New Brunswick, and the Eastern Townships of Quebec present high rates of incidence. While no detailed study of the incidence in Ontario by counties has been made, an apparent accentu- ation seems to occur annually in the counties bordering the first reaches of the St. Lawrence River, especially Leeds and Grenville, and the centre of the Western Peninsula from Woodstock to London and thereabouts. Ontario shows as well a high incidence of simple goitre, and in recently studying 85 cases of pernicious anemia at their homes in Ontario, the writer noted the occurrence of simple goitre in 3 of these patients. Whether further study might establish a relationship between pernicious anemia distribution and geological structure is uncer- tain, but it is of interest to note that Montgomery (452) in investigating the distribution of the disease in Western Canada found that areas of highest incidence were those in which the drinking water was the most highly saline. Moreover, he observed that in these areas the individuals acquiring the disease were the Anglo-Saxon, lifelong inhabitants and seldom, if ever, the more recently settled Scandinavian immigrants. A similar study ought to be CLASSIFICATION—DISTRIBUTION Is made in Ontario. Furthermore, the diets of Ontario should be investigated, as there is some reason to believe that the rural inhabitants, particularly in winter, tend to consume an ill-balanced diet and one deficient in the “protective” food-stuffs. SEX INCIDENCE Levine and Ladd (369) found the proportion of males to females as 2 and 3 in 150 consecutive cases. It is gen- erally considered that the incidence is slightly higher in men than in women. Eason (158) found this true only after the age of 50, before which the conditions were reversed. Sex statistics are very variable. From the mor- bidity statistics from various sources the following infor- mation is assembled. (Table 7). TABLE 7 Sex incidence figures from various sources Source Total Male Female leva Scotia wee ee ee 34 17, 17 PANT betters eau Pie wie 26 14 12 British Columbia .............- 166 101 65 New Brunswick .............. 36 18 18 Copenhagen’ 00006 os 146 58 88 Sombie Atirical eas eee 474 226 248 Sweat eee ine 844 385 459 PRG EAIS 2220 ete 1,726 819 907 In most computations differences of much significance seldom occur. AGE INCIDENCE Pernicious anemia is a disease of senescence, showing the highest incidence between 45 and 55. It is not uncom- mon to meet cases in the late twenties. Davison told the writer that in ten years experience at the Harriet Lane Home, where only children under 15 are admittd, no case had been encountered. Cases reported among children would require very careful confirmation. Of the 29 cases in children reported We PERNICIOUS ANEMIA by Mensi it is practically certain that the majority if not all were either severe aplastic anemias or splenic syn- dromes, due to causes apparent or obscure. The remark- ably interesting case of severe anemia in a boy of 8 years, reported by Morse and Wolbach, would, from their de- scription, probably have received a diagnosis of perni- cious anemia without question, although they do not men- tion the state of the gastric secretion. Barr (26) records the case of a boy of 16, dying of severe anemia, in which the insidious onset, lemon-yellow pallor, blood picture, and state of the gastric secretion (achlorhydria) were all con- sistent with a diagnosis of pernicious anemia, although neither cord symptoms nor glossitis were noted. Naegeli admits only 3 real cases of pernicious anemia in children. These have been fully described by Hotz (277). The out- standing one of the three is the now famous case of Mar- grith Ritter, aged 4 years, who died with every sign required to confirm the diagnosis of cryptogenic perni- cious anemia. The second case, that of Anna Koch, aged 11 years, began with pallor, weakness, anorexia, diar- rhoea, abdominal pain, occasional fever, and a gradual in- tensification of the anemia. Following iron and blood in- jections, a good remission occurred, the tongue which had been gelatinous-looking became normal, and the reflexes and blood picture returned to normal. After some months the anemia recurred, treatment proved futile, and she died of broncho-pneumonia. The third case, that of M.W., a 9 1-2 year old girl, was, on admission, a typical example of Herter’s intestinal infantalism, with pyelitis and simple anemia. In the course of a few months the emaciation and weakness grew worse, periods of fever occurred, and a pernicious-like anemia developed. After some further months a sudden improvement was noted, the signs of Herter’s disease disappeared as well as the pyelitis, and the anemia became of simple type. CLASSIFICATION—DISTRIBUTION 13 Vischer (629) has intelligently considered these perni- cious-like anemias of children. He shows that in the se- vere anemias of children a greater uncertainty exists than in adults, because the reaction of the youthful erythro- myeloid tissues deviates from the reaction of those of the adult. He agrees with Morawitz that the course of many anemias in children is characterized by a very high capa- city for regeneration, abundance of embryonic types of cells in the blood stream, a speedy development of extra- medullary foci of blood formation, and a generally fa- vourable course, with the result that a complete cure may occur in a condition which would be diagnosed as pernicious anemia in an adult. Evans and Happ (178) have noted the unjustifiable tendency to diagnose infan- tile pseudoleukemic anemia on the basis of splenic en- largement which means, in children, often nothing more than a characteristic infantile response to anemias of va- rious types. Evans (177) states that among the first 36,000 non-surgical patients under fourteen years of age treated in the Harriet Lane Home, no case of pernicious anemia was encountered, and that Howland developed a decided skepticism toward the possibility of the diagnosis in children, believing that some so diagnosed were pur- puras or lymphoid leukemias. Bass (30) and his associ- ates found no increased urobilin excretion in a series of infantile anemias, thus emphasizing the non-hemolytic and moderately aplastic tendency which usually obtains. Tecon’s (609) case in a child of six was frankly aplastic. Agnew (6) viewed his case as definitely aplastic with no suggestion of pernicious anemia. The purpuric tendency noted by Agnew is common in these severe aplastic ane- mias of children and causes them at times to merge with the purpuras (see McElroy 416). Sufficient has been written to make it appear questionable whether pernicious anemia ever occurs in children. 14 PERNICIOUS ANEMIA The opposite extreme of age is likewise not entirely free of difficulty, inasmuch as a superficial resemblance to pernicious anemia is constituted at times by old age it- self. Gilford (226) in his somewhat dogmatic claim for premature senescence of the erythropoietic tissues as the cause of Addison’s anemia, states that he has seen the blood of the aged simulate the picture of this disease, but omits giving detailed examples. Evans sums up this diffi- culty in his book and shows how superficial such resem- blances really are: “The cachexia of old age may simulate pernicious anemia. Here the complexion is often sallow, one frequently encounters an achylia, and there may be anemia. The sallowness of the elderly is not, however, the same as that seen in pernicious anemia, although it may resemble it closely. In the former it is usually an absence of color, or a grayish tint, differing from the peculiar yellow color of the latter. Furthermore, a discoloration of the skin in the elderly, which may lead one to suspect per- nicious anemia is usually only seen in them when there is emaciation and the resultant wrinkles. In pernicious anemia emaciation is most uncommon, and the com- plexion is usually smooth. The achylia gastrica should not confuse, as it is a common finding in advanced age. The anemia in these patients is dependent on a general lower- ing of the hemopoietic, together with other functional activities, and is usually readily differentiated from that of pernicious anemia. Poikilocytosis, anisocytosis and polychromasia may be present, but are usually of mini- mal grade even when the anemia is severe.”” He empha- sizes, as well, a normal ratio of polymorphonuclear leuko- cytes even when, in old age, a leukopenia is present. Ward (634) has shown, however, that the disease may occur in very old people. Including Templeton’s (611) cases, seven have been reported in persons at 70 or older. Hunter has always claimed a high seasonal incidence in the summer months. An isolated confirmation of this ob- CLASSIFICATION—DISTRIBUTION 5 servation comes from Bartlett (29) who noted in a cer- tain section of Pennsylvania, not only a great deal of per- nicious anemia, characterized by initial glossitis and oral tenderness, but a quite definite incidence in the spring. Owing to the coincidence of the maple-sugar industry at this period of the year, a superstition had gained ground, in this neighborhood, that the sore tongue and the anemia were due to eating maple sugar. In Ontario, in several districts a similar suspicion has been directed towards rhubark, possibly for the same reason. Further observa- tions on seasonal incidence would prove of considerable interest. CHAPTER II HISTORICAL OUTLINE Combe (128) described the first recorded case in May, 1822. Previous to that date, the disease was confused with other severe anemias such as those of ankylostomia- sis, sepsis, and chlorosis. Since modern mortality statistics do not indicate any more increase than might be due to improved diagnostic knowledge, it cannot be assumed that it is a disease of modern civilization. The absence of reports before Combe’s may well be due to confusion and the lesser glibness of our medical predecessors. “T was much struck by his peculiar appearance,” Combe wrote. “His lips, face and the whole surface were of a deadly pale colour; the whites of the eyes bluish; his motions and speech languid; he complained much of weak- ness; his respirations, free when at rest, became hurried on the slightest exertion; pulse 80 and feeble; inner parts of the lips and fauces nearly as colourless as the surface; bowels very irregular, generally lax, his stools very dark and foetid; urine reported to be copious and very pale; appetite unimpaired, of late his stomach had rejected almost every kind of food; constant thirst; he had no pain referable to any part and a minute examination could not detect structural derangement of any organ. “Post mortem. The subcutaneous fat was scanty, of a pale yellow colour and semi-fluid. Not a drop of blood escaped on dividing the scalp. The heart when cut into was of a pale colour, and did not tinge linen when rubbed upon it; it appeared like flesh macerated many days in water. The right ventricle contained a pale coagulum. The left side was wholly empty. There was a considerable moisture bedewing the viscera of the abdomen. The liver was of its proper size and structure but of a light brown colour; the spleen was the only organ which retained its [ 16] HISTORICAL OUTLINE 17 normal red colour; it was very soft, and its contents on pressure being applied, turned out like a sac.” Combe could find nothing in the history, the environ- ment, or habits of this patient to explain the condition. He was confessedly non-plussed and fell back on the obtrusive gastro-intestinal symptomatology for an expla- nation. “It is probably,” he wrote, “owing to some dis- order of the digestive and assimilative organs that its characteristic symptoms have their origin.”? Anemia in his day was no more successful than at present in its claim to the rank of an entity, but was generally regarded as but a symptom of some stated, bodily process. Combe, however, could not disabuse his mind of the impression that, in the spectacle of this case, he had witnessed the working out of a law, obscure indeed, but nevertheless self-contained and inevitable. He states, “. . . if any train of symptoms may be allowed to constitute anemia a generic disease the following may be considered an example of it in its most idiopathic form.” Channing (106) as early as 1842 described severe anemia occurring in puerperal cases. His cases depended on the presence of sepsis of the endometrium and are not to be confused with the chronic hemolytic anemia of pregnancy which resembles pernicious anemia so closely. Elliotson’s (171) Practice of Medicine, 1846, refers to certain cases of grave anemia, which from his descrip- tion were probably Addisonian. He wrote of the great debility, corpse-like appearance, wax-like skin, blue scler- otics, colorless mouth and tongue, the feeble pulse readily excited, the bad appetite, constant thirst, sweating and terminal edema of the legs. He mentioned an “aggravated species” with dark foetid stools, nausea, and constant vomiting, which showed at autopsy “internal softness and paleness’, lack of blood, and excess fluid in the serous membranes. He referred to Combe’s case and noted that no etiology had been discovered. He praised iron in treat- 18 PERNICIOUS ANEMIA ment but admitted that “relapses were very usual.” He then offered a theory, based on an idea of compensatory congestion and anemia occurring simultaneously in dif- ferent parts of the body, due to the action of emotion or gravity. Finally he quoted Andral,—“organs look anae- mial less from lack of blood than from lack of colouring matter”—the disease being thus construed as a degener- ation toward a condition normal in white-blooded animals. Before and during this period Thomas Addison, phy- sician to Guy’s Hospital, London, had become keenly interested in a group of cases presenting pallor and asthenia. It later transpired, through distinctions drawn by Addison himself, that this group contained really two diseases; first, disease of the suprarenal glands or Addi- son’s disease; second, the peculiar disease which forms the subject of this book. Since Addison’s time, Guy’s Hospital has always maintained a special interest in this anemia. Addison in 1849 under the tide of Anaemia, Disease of the Suprarenal Capsule, described the ane- mia as ‘a remarkable form of anaemia which though incidentally noticed by various writers, had not attracted by any means the attention it really deserved. It was a state of anaemia incidental to male adults and had been with him for years a subject of earnest enquiry. .. .” At this time he had not distinguished it sufficiently from the other disease. It was in 1855, in his introduction to his work, On the Constitutional and Local Effects of Disease of the Suprarenal Capsules, that he described it, for the first time in history, as a generic disease, under the name, “Idiopathic Anaemia” (5). “As a preface to my subject, it may not be altogether without interest or unprofitable to give a brief narrative of the circumstances and observations by which I have been led to my present convictions. EPS TORICAL OUTLINE 19 “For a long period I had from time to time met with a very remarkable form of general anaemia occurring with- out any discoverable cause whatever—cases in which there had been no previous loss of blood, no exhausting diarrhoea, no chlorosis, no purpura, no renal, splenic, miasmatic, glandular, strumous or malignant disease. Accordingly, in speaking of this form in clinical lectures, I perhaps with little propriety, applied to it the term ‘idio- pathic,’ to distinguish it from cases in which there existed more or less evidence of some of the usual causes, or con- comitants of, the anaemic state. “The disease presented in every instance the same gen- eral character, pursued a similar course, and, with scarcely a single exception, was followed after a variable period by the same result. “Tt occurs in both sexes, generally, but not exclusively, beyond the middle period of life; and so far as I know at present, chiefly in persons of a somewhat large and bulky frame, and with a strikingly marked tendency to the formation of fat. “Tt makes its approach in so slow and insidious a man- ner that the patient can hardly fix a date to his earliest feeling of that langour which is shortly to become so extreme. “The countenance gets pale, the whites of the eyes become pearly, the general frame flabby rather than wasted; the pulse perhaps large, but remarkably soft and compressible, and occasionally with a slight jerk, especi- ally under the slightest excitement. There is an increasing indisposition to exertion, with an uncomfortable feeling of faintness or breathlessness on attempting it; the heart is readily made to palpitate ; the whole surface of the body presents a blanched, smooth and waxy appearance; the lips, gums and tongue seem bloodless; the flabbiness of the solids increases; the appetite fails; extreme langour and faintness supervene, breathlessness and palpitation 20 PERNICIOUS ANEMIA being produced by the most trifling exertion or emotion; some slight oedema is probably perceived about the ankles. The debility becomes extreme; the patient can no longer rise from his bed, the mind occasionally wanders; he falls into a prostrate and half torpid state, and at length expires. Nevertheless, to the very last, and after a sickness of perhaps several months’ duration, the bulki- ness of the general frame and the obesity often present a most striking contrast to the failure and exhaustion observable in every other respect. “With perhaps a single exception, the disease in my own experience, resisted all remedial efforts, and sooner or later terminated fatally. “On examining the bodies of such patients after death I have failed to discover any organic lesion that could proper or reasonably be assigned as an adequate cause of such serious consequences; nevertheless from the dis- ease having uniformly occurred in fat people, I was nat- urally led to entertain a suspicion that some form of fatty degeneration might have a share at least in its produc- tion; and I may observe that in the last case examined, the heart had undergone such a change, and that a por- tion of the semilunar ganglion and solar plexus, on being subjected to microscopic examination was pronounced by Mr. Tuckett to have passed into a corresponding condition. “Whether any or all of these morbid changes are essen- tially concerned—as I believe they are—in giving rise to this very remarkable disease, future observation will probably decide. “The cases having occurred prior to the publication of Dr. Bennett’s interesting essay on Jeucocythemuia, it was not determined by microscopic examination whether there did or did not exist an excess of white corpuscles in the blood of such patients.” HISTORICAL OUTLINE 21 This brief and famous description placed idiopathic anemia on a fairly firm basis as a clinical entity and dis- tinctive disease. Even before Addison’s work, Barclay (22) in 1851 described a case under the title, Death from Anaemia,—an important document because it con- tains the first mention in the literature of the glossitis which later, through the emphasis of Hunter, became an important diagnostic symptom. Many case reports fol- lowed between 1857 and 1871, notably by Wilks (655), who taught the disease to students, Cazenave (105), Bristowe (71), Habershon (244), Barclay and Dickin- son, and King (335). Palmer Howard in Montreal and Trousseau in Paris taught the disease in the ’sixties. Austin Flint, 1860, and Fenwick, 1865, suggested the possible dependence of some cases on degenerative changes in the gastric mucosa. Gairdner in his Clinical Medicine, 1862, recorded a case which he described as follows: “A mysterious form of anaemia . . . a remark- able case of pure anaemia, fatal, without any explanatory organic complication. The blood presents an extreme deficiency of red, and certainly no increase of white, cor- puscles. After death which occurred from pure exhaus- tion, every organ was carefully examined, and the only morbid appearance presented were in the heart, liver and kidneys, which were all more or less occupied by fatty granular deposit. I have only to say in regard to this most mysterious form of disease that it has no real relation to the chlorosis of young women. In fact the only two cases which I have seen exactly resembling this one, occurred in men and at middle age. The general appearance is much more that of malignant disease than of any other condi- tion with which I am familiar.” In Germany, Lebert (364) described it in 1858 under the name essential anemia. From his narrative, especially with regard to the mortality, it is evident that either his follow-up records were imperfect or that he grouped with 22 PERNICIOUS ANEMIA the others some cases not of the idiopathic variety. “In a series of cases I have observed the whole picture of anemia without any organic cause, and without finding anything post mortem to explain it; and I have therefore termed these cases, essential anemia. This idiopathic ane- mia seldom ends fatally; when it does, one finds no organ essentially diseased. In rare cases idiopathic anemia may end fatally, even without being complicated by any loss of blood or any organic disease . . . we should not for- get therefore that anemia can, of itself, though seldom, lead to death.” Perroud (496), earliest of the French school to observe the disease, emphasized the fatty transformation of the liver as the etiological factor, and the anemia, cachexia, and edema as results. Curiously little impression, however, seems to have been made on English and Scotch writers by Addison’s important communication. Striking evidence of this is the fact that Bennett in his Practice, 1867, totally ignores the subject, the more striking since he was sufficiently interested in blood to have been the discoverer of leukemia. Tanner, 1869, likewise makes no mention of idiopathic | anemia. But Guy’s Hospital Reports from 1864 to 1878 contain 23 cases, collected by Taylor. English medical attention was really roused, not by Addison’s description but by an editorial in the Medical Times and Gazette, in the November, 1874, issue on page 581, entitled ‘“Pernicious Anaemia: a new Disease,” which reviewed the work of Biermer and of Immermann and stated, ‘““We are not aware that any case has as yet been reported in Great Britain; but no doubt there will soon be many observers on the look-out for it.” Addi- son’s death in 1860 saved him from a realization of the inglorious lot of the prophet in his own country. Biermer of Zurich published several papers between 1867 and 1872 on this disease but improved on Addison’s EUSTORICAL OUTLINE Z3 description merely in mentioning the tendency to small hemorrhages. His conception was more inclusive than Addison’s, for his designation, pernicious anemia, took in several types of anemia, such as bothriocephalus, car- cinoma, malaria, as well as Addison’s idiopathic. To all of these Biermer applied the term progressive pernicious anemia, and to the latter, as a distinguishing appellation, the prefix “primary”. His work was original and impor- tant. Addison, however, was later accorded, even by Con- tinental writers, the priority he deserved. Although Biermer’s publications served the function of stimulating general medical interest in a neglected subject, it is to be regretted that not only his broad definition but his con- fusing nomenclature have remained, though not unas- sailed, somewhat to the present. The account of Biermer (60) may best be presented by repeating Hunter’s résumé: “Professor Biermer gave an address on a form of pro- gressive pernicious anaemia, often observed by him, which seemed to be generally associated with fatty degen- eration in the circulatory apparatus, and, in consequence, with capillary haemorrhages in the skin, retina, brain, meninges, and other serous membranes. He had observed the peculiarities of this form for the last five years, and had already, 1868, made a preliminary communication upon it. Since then the number of his cases had increased to fifteen, so that it could be said that the disease, in the Canton of Zurich, at least, was not uncommon. It was found amongst poor people; especially in women about thirty years of age, among whom, in addition to poverty, puerperal conditions appeared to be favouring causes. It occurred, however, also among old and young of either sex. The youngest patient was 15, the oldest 52: insuffi- cient and unsuitable feeding, unhealthy surroundings, dis- charges—especially persistent diarrhoea—sometimes also haemorrhages, usually preceded the disease and caused it. 24 PERNICIOUS ANEMIA The most common cause, according to his observations, was chronic diarrhoea with and without gastric distur- bances. Chlorosis appeared to be rarely a cause; it was but rarely also that the disease originated spontaneously, without a cause. Neither with splenic disease nor with malaria had the disease any connection. The only organic lesions which so far had been found in some cases, and which might be blamed for the disease, were follicular ulcers of the colon. “The symptoms were as follows: (1) Appearance of anaemia and hydraemia. Great pallor, poor nutrition, but no disappearance of subcutaneous fat as in cancer or phthisis; often a yellow-white complexion without jaun- dice. In advanced cases slight oedema of the face, feet, and hands; also some ascites. (2) The usual nervous symptoms of anaemia—weakness, giddiness, palpitation, etc. (3) Digestive disturbances consequent on the anaemia —anorexia, weak digestion, sometimes gastric discom- fort, very often periodic diarrhoea. (4) Circulatory dis- turbances—bruits in the heart and great vessels, the former so marked as often to raise the question whether valvular disease was present. The bruits were systolic; usually over the base rather than over the ventricle, where they were of a more blowing character. The murmurs were not always to be heard at first, but they always appeared later and became stronger. In the arteries of the neck bruits were also to be heard, occasionally also over the jugular vein. If the heart’s action were excited, the heart impulse diffused, and the cardiac dullness in- creased (as was often the case). The picture presented was very like that of cardiac disease, and might, especi- ally as fever was often present, be mistaken for endocar- ditis. Post mortem, however, nothing of the kind was discoverable, but simply partial fatty degeneration of the heart muscle. The heart’s action was usually quickened, the impulse diffuse and undulating, never strong. (5) HISTORICAL OUTLINE 25 Fever was unessential, but was met with from time to time in nearly all cases; sometimes very slight, at other times more marked; without special type, and only for short periods. In one case it was for a time like that of typhoid, and it was for that condition that the patient was sent to the hospital. Usually it was slight and appar- ently causeless; hence in the clinic it was often for the sake of brevity termed anemia fever. He thought the fever was of a ‘humoral character’ but considered it also possible that the small haemorrhages in the body, as also the gastric disturbances, might be causes of it. Definite local causes of the fever were not to be found. (6) Of interest also were the retinal haemorrhages, which were generally present even in cases in which there were no subjective symptoms of visual disturbance. If absent in the first instance they usually appeared later. In one case they were so severe as to cause sudden loss of sight in the left eye. They were to be found post mortem, and formed very striking pictures. (7) Subcutaneous haemorrhages and petechiae were not so common. Haematuria and epis- taxis were only once observed, albuminuria quite excep- tionally. (8) Capillary haemorrhages in the brain, the subdural arachnoid, and the pia mater, were, on the contrary, common, sometimes without any characteristic symptoms during life. One patient died of a large capil- lary haemorrhage in the brain. Another was seized sud- denly with pain in the right arm and leg, impaired speech, right hemiplegia (including facial paralysis), the whole symptoms passing off in half an hour. Delirium was often present in the later stages. The course of the disease was in all cases one of gradual increase of anaemia and hydraemia, appearance and increase of heart symptoms, accidental capillary haemorrhages, serous effusions, occa- sional fever, consequent anorexia, and often diarrhoea. Pneumonia and erysipelas were rarer complications. Death occurred in all cases, with the exception of one, 26 PERNICIOUS ANEMIA which left the hospital improved. Post mortem—lIn addi- tion to the anaemia there was generally found fatty degeneration of the musculi papillares of the heart, and of the small vessels, the former explaining the heart mur- murs and the latter the capillary haemorrhages. The papillary muscles appeared yellowish and mottled, the muscle of ventricular wall and septum was often similarly affected. It was exceptional, however, for the fatty degen- eration of the heart muscle to be excessive. In the large arteries there was nothing abnormal, or, at most, slight fatty degeneration of the intima; this latter was more common in the smaller arteries, e.g., of the kidneys; still more common in the capillaries, especially of the brain. In three cases small flat extravasations were found in the subdural arachnoid, without however, any sign of pachy- meningitis; they were therefore probably purely haem- orrhagic in origin and connected with the fatty changes in the capillaries. The capillary haemorrhages in the brain, retina, epicardium, and pericardium were to be referred to nutritive disturbances in the capillary walls. Both these and the fatty changes in the heart muscle were caused by the altered condition of the blood, and were analogous to the fatty changes caused in tissues by cutting off their blood supply. Liver, spleen, kidneys showed noth- ing special.” As before stated, Biermer’s work excited rhuch interest in England where Addison’s description had not made a very wide impression. On the continent it created so deep an interest that the disease is still known as Biermer anemia and most of his teaching receives current accep- tance. It will be evident that Biermer included in this group anemias of which the cause was known and there- fore not of the idiopathic variety specified by Addison. For this reason his description cannot be regarded as being so faithful as that of his English contemporary. Pye-Smith (506), a pupil of Addison, in an article in EISTORICAL OUTEINE 27 Virchow’s Archiv in 1875 drew the attention of Ger- many to his master’s work. Later, in 1883, he (507) published a conclusive vindication of the identity of the disease and deprecated the tendency to merge it with other anemias in Biermer’s group of progressive pernicious anemia. The first monograph on the disease was that of Miiller (459) in 1877. Among Americans and Canadians at this period W. Pepper (493), Osler and Gardner (480), and Kinnicutt (337) were the chief writers on this subject. In Germany, Quincke (510), Eichhorst (165), Cohn- heim (123), Eisenlohr (167), Rosenstein (537), and Ehrlich (161-164) led opinion. In England, Bramwell (63) introduced arsenic in treatment and MacKenzie (390) stressed neurosis as an etiological factor. In America, Starr (589) as well as Cary (104) described successful blood transfusion in treatment. In 1886 Hunter (289) described intraperitoneal trans- fusion and in 1888 published an important paper on the pathology (292). Probably no person has spent more of his life in the study of pernicious anemia than Hunter. He has worked since 1885, publishing at frequent inter- vals, and his name will always be closely associated with the disease. Clinically and pathologically he is to be credited with greatly increasing our knowledge. Briefly, he had been ‘the strongest exponent of the disease as an entity, deserves great credit for his work on hepatic sider- osis, emphasized the importance of glossitis as a diag- nostic sign, and has written two valuable monographs on the disease. The first—Pernicious Anemia, London, 1901 —reviewed the literature very thoroughly, demonstrated hepatic siderosis, advanced many arguments in favour of an infective and gastro-intestinal hypothesis, and pre- sented many pathological and clinical observations. The second—Severest Anaemias, vol. 1, London, 1909—dis- tinguished idiopathic from septic anaemias. He construed 28 PERNICIOUS ANEMIA the former as a specific, infective hemolytic disease, ag- gravated by an added (and predisposing) element of sepsis. He minutely described the glossitis. After an analytical review of the literature he deprecated the term “pernicious” and advocated the name Addisonian ane- mia. From a practical standpoint, oral sepsis, even aside from its bearing on anemia, stands, as a conception and a proved reality, largely to the initial credit of William Hunter. On the other hand, few believe that glossitis is constant as he maintains and no one has confirmed his statement of the importance of unsanitary drains in the etiology; it will be pointed out that he entertained the ideas of Cohnheim and Ehrlich almost as little as Ehrlich entertained Hunter’s, and it should be finally stated that Hunter never presented any really convincing reasons for faith in his often repeated dogma that pernicious anemia is a specific infection. The remarkable quality of Hunter has been his sustained enthusiasm, and his greatest serv- ice, as the writer sees it, lies in this—that he gave a powerful impulse to the study of features other than hematological. That a confusion of almost indecipherable character should have marked the first forty years of our knowledge of this disease is not remarkable. In view of the confusion which still exists after seventy years, it may be character- ized as inevitable. The haziness of earlier conceptions, the false interpretation of symptoms as causes, the variety of nomenclature, the divergence of definitions, and the con- flict, therefore, of rival classifications all tended to pro- duce confusion. After Addison’s description, the tendency of English clinicians was to exclude all cases in which any evident cause could be detected. This bred an attitude that the anemia was primary and essential, and that all the manifestations of the disease, as then recognized, were the result of the blood impoverishment. Today, of course, such a position is untenable, and the blood state HISTORICAL OUTLINE 29 must be regarded as but one result of the still unknown fundamental process. Opinion being as it was then, any new discovery, such as bone-marrow changes (Pepper, Cohnheim) or atrophy of the stomach (Fenwick, Osler, Kennicutt) was not readily included among the mani- festations of the disease but used as reasons for exclud- ing the cases described from the pure “primary” class. In other words, there was a tendency to attach etiological significance to any important pathological observation and to regard such observed cases as of a “‘secondary” nature. Again, not only did American and English phy- sicians suffer from this confusion incidental to growth of knowledge, but they began applying the continental epi- thet “pernicious” even to their purest cases of Addison’s anemia, whereas the Germans and Swiss used this name for any severe macrocytic anemia whether or not the cause was apparent. To all this was added the uncertainty which the remissions impose on the interpretations of treatment. The net result was the most glaring and sus- tained confusion which has ever clouded the history of a disease. It became an international medical pastime to exclude cases from published reports on the basis of purity of type, each critic employing his own individual or local standards of judgment. The cure for all this was more knowledge, and the cure came slowly. In 1891 Ehrlich practically created hematology a sci- ence by the discovery of the value of aniline dyes for staining blood smears. From this time dates accurate information of the blood picture. Ehrlich became especi- ally interested in megaloblasts (large nucleated erythro- cytes) and initiated the school of megaloblastic degener- ation, the chief tenet of which is that marrow degeneration of a megaloblastic type constitutes the essential process in this anemia. This was a step further than Cohnheim had gone in regarding the marrow condition as a rever- sion to an embryonic type of blood formation. Muir 30 PERNICIOUS ANEMIA (457) in 1894 made a study of the bone marrow, and interpreted the findings as caused by an exorbitant regen- erative effort to compensate for the loss of destroyed cor- puscles. His mind was impressed previously by Hunter’s contention that blood destruction was effected in the portal circulation by poison absorbed from the intestine. The view-point adopted by Hunter and by Muir, viz., that the marrow changes were purely of a compensatory character, has had a tremendous and lasting influence. A definite Ehrlich school remains on the continent today and regards the marrow changes as fundamental to the anemia, and caused by a “noxa”’ from the gastro-intestinal tract. The nervous features began to be recognized about 1884, but further description of the growth of our knowl- edge of the changes will be withheld until a later chapter. The present century has established the almost invari- able association of achlorhydria with the disease, in- creased our knowledge of the pigment condition, made distinctions in the blood picture from similar anemias, rendered all the clinical features familiar, and facilitated diagnosis. Etiologically, several definite hypotheses have been worked upon and the intestinal flora has been exten- sively studied. Final and unfavorable judgment has been passed upon splenectomy in treatment, and blood trans- fusion is recognized for its limited value. It must be admitted that the entire field of pernicious anemia has been particularly barren of results. Recently the observa- tions on the effects of liver diet have been sufficiently startling to arouse a new and widespread interest in the disease. CHAPTER III ETIOLOGY HISTORICAL ETIOLOGICAL CONCEPTIONS Combe (128), who described the first recorded case, saw no cause whatever, but suspected the digestion and assimilation of food. Elliotson (171) wavered between an ill-defined notion of gravitational or emotional effect and one of a change to white-bloodedness. Addison (5), who enjoyed the somewhat unique distinction of having propounded no hypothesis, merely wondered if fatty de- generation had anything to with it. Fenwick (199) con- sidered the degenerative changes in the gastric mucosa to be significant. Perroud (496) attributed the whole complex to fatty degeneration of the liver. Biermer (60) felt that even in his cases of idiopathic origin, sufficient cause could be seen in the bad hygienic conditions, or in the diarrhoeas of his patients. The only lesions he could associate etiologically were ulcers of the colon. Mackenzie (390) believe that neurosis was a definite factor. Cohn- heim (123), Ehrlich (163), and with them most of the early continental observers, regarded the marrow condi- tion as the cause of the anemia. The English school and many European authorities came to believe that blood destruction of abnormal degree was the means of blood depletion, and that the marrow changes were regenerative and compensatory. The early bone marrow observations of Pepper (493), of Cohnheim (123), and of Osler and Gardner (480) resulted in emphasis being placed upon the abnormal type of blood formation seen and in the noting of phagocytosis of red blood corpuscles in this tissue. Ehrlich became espe- cially interested in the presence of megaloblasts in the marrow and the circulating blood. Whereas Cohnheim [ 31] 32 PERNICIOUS ANEMIA had been content to regard the marrow changes as a rever- sion to an embryonic type of blood formation and as of primary significance in the etiology, Ehrlich went a step further and conceived the marrow changes as degener- ative in nature. This hypothesis of megaloblastic degen- eration, rendered vivid by its author’s classical stains of the blood tissues, substantially implanted itself in the minds of Ehrlich’s contemporaries and has exerted a pro- found influence even to the present day. Ehrlich held up the megaloblast as a simple and infallible point in the diagnosis of pernicious anemia and he embraced the inevi- table and logical corollary that all anemias showing mega- loblasts were pernicious anemia. This classification placed megaloblastic anemias in a primary group and normo- blastic anemias in a secondary group, and ran parallel to Biermer’s clinical classification, which permitted the term pernicious anemia to be extended to several severe anemias of known etiology. The English school, before and during Ehrlich’s studies, had developed a different view-point. Of first importance to the English investigators was an exclusive definition of the disease. Following in Addison’s foot- steps, they applied the term pernicious anemia only to cases of idiopathic origin, and excluded all cases, in spite of the blood picture, in which any cause was evident. To them pernicious anemia was, at that time, largely a dis- ease of the blood. The anemia was primary and uncaused, and all other manifestations were the results of the anemia. This fixed idea resulted commonly in the misin- terpretation of newly discovered pathological facts. Suf- ficient reference has already been made, in the previous chapter, to the unfortunate and almost hopeless confusion which resulted. In any synoptic review of this most involved period (1870-1900), one must recognize the stabilizing effect of the work of Hunter, although it failed in its entirety to ETIOLOGY 33 achieve the conclusive results which, in its beginning, it might seem to have promised. Its stabilizing effect lay chiefly in its direction toward other than purely hemato- logical studies. Hunter (290-302) emphasized the clinical signs and symptoms of the digestive tract. Particularly his careful work on hemosiderosis of the liver has exerted a far-reaching effect on subsequent thought. Briefly he demonstrated by gravimetric analysis that the liver in pernicious anemia contains more iron than the liver in other anemias. Siderosis had been little observed on the continent and, when found, had been frequently dis- missed as due to iron medication and of no constant or specific importance. Hunter, on the other hand, held up hepatic siderosis just as stoutly as Ehrlich has held up the megaloblast, as an alleged specific finding. Then Hun- ter by a process of synthetic thought, which has always impressed the writer as at once natural but unwarranted, supposed this deposit of iron-bearing pigment in the liver was the result of abnorma. blood destruction in the portal area. (It should be noted, in passing, that the more recent experimental work of McMaster, Rous, and Larimore (420) makes it seem probable that liver siderosis does not connote any specific bodily site for blood destruction. ) Hunter believed that a toxin, probably produced by a specific micro-organism in the lumen of the intestine, was being absorbed into the portal blood and was there caus- ing an intense destruction of blood corpuscles, the freed pigment from which was then deposited in the liver lobules. However little or much of truth may be contained in this hypothesis, it was the first, and it was a daring at- tempt to explain the anemia by extensive blood destruc- tion. Muir’s (457) study of the bone marrow in 1894, largely confirmed the morphological findings of the earlier investigators. But Muir, having been impressed by Hunt- er’s insistence on the importance of alleged portal blood destruction, found it possible to interpret the marrow 34 PERNICIOUS ANEMIA changes as a very extensive and energetic regeneration undertaken in response to a severe bodily demand for blood. Thus were established two contending schools of thought. The one, initiated by Cohnheim and led by Ehr- lich, taught that the anemia was due to a primary altera- tion in the marrow, of the nature of an embryonic reversion, or, otherwise expressed, of a megaloblastic degeneration. This school approached the subject from an almost purely hematological angle. The other, initiated by Hunter, and supported not only by Muir but later by Askanasy and other European students, taught that abnormal blood destruction was the essential funda- mental process, and that the extreme marrow changes were to be regarded as a compensatory regenerative activity in response to an urgent physiological need. This school approached the subject from a physiological and clinical, as well as a hematological angle. Many observers, notably Mott (456), Henry (264), Russell (542), and Earl and Purser (159), while willing to admit abnormal blood destruction to a degree, believed that it depended upon the circulation being presented with inadequately formed corpuscles. They therefore regarded abnormal blood formation as fundamental, and abnormal blood destruction as a consequence. The importance of the digestive system became appar- ent through the combined work of Fenwick (199), Flint (205), Barclay (22), Hunter, and others during the period 1852-1890, with particular emphasis on the atrophy of the gastric mucosa, the specific glossitis, and the familiar train of gastro-intestinal symptoms. From 1884 onward to the present, the importance of the nerv- ous system has become increasingly clear, owing to the work of some fifty observers. Whereas until the early nineties the disease was regarded generally and chiefly as a blood disease, it is now of necessity regarded as a ETIOLOGY 39 much wider tissue involvement, the blood features being but one of these outstanding system changes. Within the historical period, as here briefly outlined, may be detected the issues which remain today. The chief issue is the problem of the relative importance of abnor- mal blood destruction and abnormal blood production. It is a problem involving a close scrutiny of all the hemato- logical data in our possession. It further involves an etio- logical evaluation of other manifestations of the disease, of other possibly related factors, a comparison with simi- lar clinical anemias, and a critical review of experimental findings. EVALUATION OF THE HEMATOLOGICAL DATA The typical, full-established blood condition is a very severe anemia of which marked oligocythemia and com- plete corpuscular complement of hemoglobin are two characteristic features. Morphological alterations in the red blood cells stand out as the most highly characteristic feature. A marked degree of anisocytosis, rendered so graphic by the now familiar Price-Jones (503) curves, is constantly present and depends upon the presence par- ticularly of macrocytes and megalocytes and also, but to a less degree, of microcytes. The macrocytes are, more- over, characteristically of an oval rather than a circular outline. Among the cells of normal or subnormal size, poikilocytosis is commonly present in a more or less marked degree. The shapes exhibited are somewhat char- acteristic of the disease, viz., forms resembling Indian arrow-heads, Grecian urns, dumbells, as well as unsym- metrical figures impossible to describe. The white blood cells are reduced in number, with absolute reduction in the polymorphonuclear neutrophils. The blood platelets are markedly reduced in number. Nucleated red blood cells—normoblasts and megalo- blasts—while characteristic and to some degree diagnostic 36 PERNICIOUS ANEMIA when found, occur much less frequently than formerly taught. In the blast crises, when occurring in high per- centage, they are not usually of good prognostic signifi- cance, although when occurring in lesser numbers, especially in conjunction with increased numbers of reticulocytes and polychromatic corpuscles, they are of good prognostic significance. The disturbed state of the bile-pigment metabolism is evident from the hyperbilirubinemia, the increased output of urobilinogen and urobilin by the liver, and the increased output of urobilin by the kidneys. The bilirubin of the blood is apparently fixed in some physico-chemical union with the plasma proteins, so that it does not readily dialyze. Van den Bergh (618) has shown that this plasma biliru- bin behaves differently in the diazo-reaction from the bili- rubin associated with hepatic obstruction or disease. The peculiar jaundice of grapefruit hue, when present, is due to staining of the tissues by this bilirubin. Blankenhorn (48) shows that hyperbilirubinemia may sometimes be present without jaundice. Moreover, considerable anemia may be present without any marked hyperbilirubinemia, but, as a rule, severe anemia is accompanied by a marked increase of this pigment in the plasma. Minot (440) has found that the simple observation of the degree of stain- ing of the plasma is a fair index to the severity of the anemia and may be rendered of comparative value by determining how much water must be added to the plasma to cause the color to disappear. The increased loss of bile-pigments by the stools and the urine is very tangible evidence of disturbance of the pigment metabolism. The siderosis of liver, spleen, and kidney, the latter betrayed by siderosed cells in the urinary sediment, indi- cates disturbance in the metabolism of iron-containing pigment. These features as well as the fact that the red blood cells, however large, are normally filled with hemo- ETIOLOGY af globin, indicate that the body is overcharged with iron pigment. Free hemoglobin may be detected in the serum and occasionally in the urine in severe stages. Sellards and Minot (570) have shown that patients with perni- cious anemia will excrete hemoglobin in the urine when injected intravenously with doses of an aqueous solution of this pigment which cause no such excretion in nor- mal individuals or in patients with anemia following hemorrhage. Peabody and Broun (489) made a comparative study of the vertebral bone-marrow in pernicious anemia and other diseases as well as in normal persons killed by trau- matism, with special attention to the phagocytosis of the red corpuscles by the clasmatocytes. They found in pernicious anemia bone marrow a degree and an acuteness of phagocytosis, sufficient to suggest that this process of blood destruction may be a factor in the production of the hyperbilirubinemia. Custom during the past twenty years has classified the hematological data in somewhat the following manner: A. Evidences of abnormal blood destruction :—the oligocythemia, the small microcytes, fragmented erythrocytes, the phagocytosis of corpuscles by the clasmatocytes, the deposits of iron pigment, and the abnormal features of the bile-pigment metabolism. B. Evidences of abnormal blood formation :—the mac- rocytes and larger microcytes of the circulation, as well as the occurrence of nucleated red blood cells, especially megaloblasts. C. Evidences of blood regeneration:—the occurrence of immature red blood cells (polychromatic cyto- plasm, nucleated forms, reticulocytes) and rising figures both for the red blood cell count and the hemoglobin percentage. 38 PERNICIOUS ANEMIA One of the most striking statements which it is pos- sible to make in connection with the problem of blood destruction in this disease is as follows—the only site and the only mechanism of blood destruction which has been demonstrated is the phagocytosis by the clasmato- cytes of the reticuloendothelium in the bone marrow. Osler (479) could not suppose this to be of any specific importance since he observed an apparently equal degree of phagocytosis in the marrow in some cases of pneu- monia. Peabody and Broun (489) found a very abnor- mal increase in phagocytosis in certain cases dying of hepatic cirrhosis, pneumonia, typhoid fever, and tuber- culosis. The most marked instances, however, were en- countered in patients dying in the acute stage of pernicious anemia. On the other hand, in the case of a patient dying in a remission of this disease, phagocytosis of red blood corpuscles was not a striking phenomenon. The problem of whether the erythrocytes so engulfed are effete or specially marked for destruction, is not set- tled. The phagocytosis is apparently an acute and active process because hemosiderosis, characteristic of a more sluggish phagocytosis, is practically absent, according to Peabody and Broun, in the marrow of the pernicious anemia. The greater problem as to whether or not this phago- cytosis can account for the degree of oligocythemia pres- ent is also impossible to settle, but from comparison with other diseases, in which great phagocytosis occurs with- out a corresponding degree of oligocythemia, the answer may be temporarily given in the negative. The degree of biliruminemia corresponds roughly, and in a direct manner to the degree of oligocythemia, so that both are greatest and both are least at the same times in the disease. As the erythrocyte count and hemoglobin percentage rise in a remission, not only does the degree of bilirubin in the plasma decrease, but there appear the ETIOLOGY 39 accepted evidences of regeneration, and the red blood corpuscles show a more normal type of formation. These facts are demonstrated very beautifully by Murphy, Mun- roe, and Fitz (463) in connection with remissions caused by liver diet. Conversely, when a relapse occurs, the bili- rubinemia increases, and the red blood corpuscles exhibit increased evidence of abnormal formation. There is there- fore generally to be noted a somewhat indivorcible rela- tionship among the three features which custom has separately recognized—abnormal destruction, abnormal formation, and regeneration. As Archibald (13) and as Minot and Lee (446) have pointed out, it is possible to recognize five somewhat dis- tinct types of the disease, depending upon the balance maintained between blood destruction and blood produc- tion. In the first there occurs a rapid unremitting course with oligocythemia, a marked degree of abnormal blood formation and of bilirubinemia. In the last there occurs a long monotonous course with much evidence of abnormal blood formation and a less degree of bilirubinemia—the so-called myelotoxic cases. Between these extremes there lie three types of remitting cases. The middle type of the five is one in which may be synchronously observed evi- dences of abnormal formation, hyperbilirubinemia, and the appearance of immature forms. It is this type of case particularly which suggests that an abnormal state of the marrow might explain the whole blood condition. Minot remarks that this type of pernicious anemia bears a defi- nite resemblance to acquired hemolytic jaundice. The two crucial questions emerging from these con- siderations are as follows: (a) Is the marked oligocy- themia the result chiefly of abnormal blood destruction or insufficient blood production? (b) Does the disturbance of the pigment metabolism indicate blood destruction, and, if not, what is its exact significance ? 40 PERNICIOUS ANEMIA Whipple (646) as well as Ashby (19) have questioned the importance of blood destruction in pernicious anemia. The former has advanced an hypothesis with the purpose of indicating that the time-honored viewpoint of the essential importance of blood destruction may, not with- out reason, be modified. In brief, his hypothesis is that the oligocythemia is due to insufficient blood cell form- ation depending upon insufficient available stroma mate- rial and that the disturbed pigment metabolism is due to an overstimulation resulting in more pigment being formed than can be used. The work of Whipple and Hooper (647), McNee (422), Van den Bergh and Snapper (621), and of Mann et al. (397, 398, 399) indicates that in addition to the liver parenchyma, the reticulo-endothelium both in the liver and elsewhere, as well as vascular endothelium and serous mesothelium generally, not only can, but constantly do, metabolize hemoglobin into bilirubin. Whipple suggests (645) that the liver parenchyma and the Kupffer cells may be able to reverse their function and form hemo- globin from bilirubin. Doan, Cunningham, and Sabin (150) could actually witness hemoglobin being assembled in the megaloblasts of the bone marrow. Their work indi- cates that the megaloblasts are actually daughter cells of the reticulo-endothelium. Due reflection upon these sev- eral points suggests the possibility that in pernicious anemia the total hematological manifestations may result from abnormal cell metabolism on the part of the reticulo- endothelial system. It is much too soon to make more than the suggestion, but, in this connection, the recent nutri- tional work of Barker and Sprunt (25), of Mosenthal (454), of Gibson and Howard (223), and of Minot and Murphy must be considered. A detailed study of these papers suggests that the feeding of certain as yet unde- termined food principles brings about a complete reversal of a blood relapse into a blood remission and makes it EP MOLOGY Al appear not impossible that the blood phenomena of per- nicious anemia are due immediately to the absence of certain factors of nutrition, essential to the normal metab- olism of the productive cells of the bone marrow. The bone marrow in pernicious anemia shares the unsatisfactory state of normal marrow studies. Exten- sion of the red marrow and marked erythroblastic activity are well recognized, but as Archibald (14) and as Sheard (576) have indicated, this regenerative activity is not necessarily, and perhaps never, a universal phe- nomenon affecting all the bone marrow of the individual. Sheard’s investigations suggested that active regenera- tion was most liable to occur in those parts of the marrow not normally active. The prominent histological feature of this active marrow is the large number of nucleated red blood cells, which may constitute up to 25 per cent of all cells present. We recognize megaloblasts, erythro- blasts, and normoblasts. The non-nucleated red corpuscles exhibit the same size variations as are found in the gen- eral circulation, none being so large as the megaloblasts but many paralleling in size the erythroblasts. Many of the clasmatocytes lining the sinuses may be seen phagocy- tosing red corpuscles, most of which contain hemoglobin. The marrow shows very little siderosis. Zadek’s (668) claim to have demonstrated a return to fatty marrow during remission is not perfectly sound. The spleen may be regarded as playing a role sub- servient but not essential to the disease. Splenectomy, in addition to causing certain metabolic changes and a greater delivery of immature marrow cells, does little to prolong life in the majority of cases. Histologically the spleen presents a combined picture of sclerosis, siderosis, and phagocytic activity, the pulp containing many red blood cells showing poikilocytosis and fragmentation. The uncommon cases with splenomegaly may represent a somewhat distinct type of the disease and do well follow- 42 PERNICIOUS ANEMIA ing splenectomy provided the operation is performed sufficiently early. The not infrequent enlargement of the liver coincides with the accepted signs of increased blood destruction. The liver presents a more extreme example of siderosis here than in any other disease. Fatty degeneration varies from moderate to extreme and affects chiefly the centres of the lobules. Kahn and Barsky (331) found the glyco- genic and ureogenic functions normal, as also the func- tions as tested by Bauer’s galactose and Strauss’s levulose tests, while the sulpho-conjugation test indicated a de- ficiency in detoxication function. ETIOLOGICAL EVALUATION OF OTHER MANIFESTATIONS Among the manifestations, other than hematological, which appear to bear a specific relationship to the disease, the following are to be particularly designated :—glos- sitis, achlorhydria, nerve tissue degeneration, the fatty changes, and the remissions. In addition, the general metabolism requires description. All other symptoms and signs will be purposely neglected, in this chapter, as not bearing either constant or apparent relationship. What is written of this glossitis may be applied to the stomatitis, pharyngitis, oesophagitis, and even gastritis which, judging from symptoms, may co-exist as the apparent extension of the same process. Noted first by Barclay in 1852 and its incidence later somewhat over emphasized by Hunter, the glossitis is now granted a spe- cific relationship to the disease. No one except Percy (495) has supported Hunter’s contention that glossitis occurs in every case. Panton, Maitland-Jones, and Rid- doch (482) found it in 25 per cent or slightly higher. In the early active stages the tongue, always clean and moist, may present a fiery red or carmine hue, a painfully fis- sured dorsum, and sometimes vesicles containing serum. Later, when the organ is anemic, the glossitis is manifest ETIOLOGY 43 chiefly by a mottled red appearance along the borders or in patches of hyperemia on the surfaces. Small ulcers may be seen. In the final stages of the disease the process is usually less noticeable and the tongue presents, in gen- eral, an ironed-out, atrophic appearance. The papillae are dwarfed or absent. Even when thus comparatively quies- cent, the glossitis may recur in periodic attacks of sore- ness and marginal redness even in late stages. In patients with very long remissions of the disease, the atrophic tongue remains as a permanent hall-mark, of equal sig- nificance to the permanent macrocytosis which has like- wise been frequently noted. The glossitis is troublesome in varying degrees in different cases showing it, and interferes with eating, sometimes with sleeping. It is not infrequently the initial symptom of the disease. Local treatment fails to benefit it. During the disease if is characterized by an irregular periodicity. A troublesome glossitis reappearing or recru- descing during a remission often indicates the nearness of a relapse. At autopsy the tongue shows the gross and microscopic features of a combined mucosal and muscular atrophy. At points where the mucosa has disappeared a round cell infiltration will be found in the submucous tissues. In very severe cases a great proportion of the muscular fibres are replaced by fatty connective tissue. Hunter obtained from the interior of such tongues pure cultures of a virulent long streptococcus and considered this micro-organism to be responsible for at least part of the glossal manifesta- tions. The periodicity of the symptom, glossodynia, sug- gests that any causative micro-organism would be one characterized by its tendency not only to crudesce and subside, but also to migrate downward and cause the oesophagitis and gastritis so frequently associated. No specific micro-organism has been isolated from the tongue lesions. The nature of the glossitis is obscure. Faber 44 PERNICIOUS ANEMIA would interpret the glossitis as due to a chronic toxemia with a hypothetical poison responsible at once for all the digestive, nervous, and blood abnormalities. It is of inter- est to recall the occurrence of glossitis in sprue and pellagra, between which two forms Woods notes a great difference, and both of which differ from that of perni- cious anemia. No one has definitely noted glossitis in so- called “pure” cases of subacute combined degeneration of the cord, but it is thought to occur in these cases even in the absence of blood changes. Achlorhydria. Cahn and von Mehring (94), von Noorden (624), Einhorn (166), Stewart (594), Gra- witz (220), Martius (406), and others were first respon- sible for the clinical examination of the stomach contents, 1886-1897, and for thus affording to medicine a physio- logical means of study which has since proved of greater value than anatomical or histological means, especially with reference to pernicious anemia. Grawitz in the late nineties listed “achylia gastrica” as an etiological factor in the broad group of cases which he, in conformity with continental custom, included under the term pernicious anemia. Among Martius’ seventeen cases of achylia, reported in 1897, two died of pernicious anemia and showed, post mortem, pronounced atrophy of the gastric and intestinal mucosa. He took the attitude that while arrest of gastric secretion arising from mucosal atrophy can lead to some degree of anemia, the essential lesion was intestinal mucosal atrophy operating by disturbance of food absorption. Faber and Bloch (185) in 1900 col- lected thirty-three cases of the disease in which the gas- tric contents had been examined and in all of which it had been found either greatly diminished or entirely absent. Similar results were obtained in their own four cases, two of whom showed, post mortem, diffuse inflammation of the stomach wall with destruction and atrophy of the glands. They found no constant or characteristic lesion ETIOLOGY 45 of the intestines, believing that the appearances of atrophy there discovered were artificially produced by post mor- tem distension of the gut. While Faber has never com- pletely repudiated the position which he then adopted, viz., that the stomach changes and the blood changes have a common cause, whether of toxic or infective nature, he recently gives some acceptance to the conception of the achlorhydria being a constitutional phenomenon. Hutchison (312), in reviewing the subject in 1909, showed that as valuable as the many gastric observations had been, belief in the stomach condition as the cause of pernicious anemia was rendered untenable by the accumu- lating evidence of achylia existing for years without blood changes. He favored the view that the achylia, by robbing the intestinal tract of its normal antiseptic, may predispose to pernicious anemia, and was among the first definitely to recommend dilute hydrochloric acid as a rational form of treatment. With the introduction of the Einhorn, the Rehfuss, and the Ryle tubes, and the fractional test meal, many gen- eral cases considered achlorhydric were discovered to secrete free HCl at some phase of the digestive period. But patients with pernicious anemia, even when exam- ined by this improved technique, were still found, almost invariably, to secrete no free HCl at any time. A few isolated instances have been reported in which some free HCl was detected during digestion in cases appar- ently justifying the diagnosis of pernicious anemia. In some cases, autopsy examination proved conclusively that they were not pernicious anemia. All investigators of the gastric secretion in this dis- ease have been convinced of the almost constant occur- rence of achlorhydria. Many reports confirm this opinion, particularly that of Levine and Ladd (370) who, in a series of one hundred and fifty cases by the use of the fractional meal, found achlorhydria in ninety-nine per cent. Hurst (307) is in accord with this finding. Faber 46 PERNICIOUS ANEMIA and Gram (186) in fifty-four cases studied between 1907 and 1922 found achlorhydria in fifty. Piney (499) has seen one case of subacute combined degeneration of the cord without achlorhydria. But Hurst and Bell (311) have shown that achlorhydria is as common in “pure” cases of combined degeneration as in cases showing the specific anemia. Panton et al. (481) reported achlorhydria in all of one hundred and seventeen cases of pernicious anemia. Shaw (575) presénted a case unique because of recovery not only from the disease but from alchlorhydria. Percy (495) found free HCl in but one of one hundred and twenty-nine cases. If one fact has received ample confirmation in connection with the whole subject of pernicious anemia it is this—the stomach contents almost never contain free HCI. Furthermore, so far as critically reported, achlorhydria precedes all other symptoms of pernicious anemia. Faber examined the blood in four cases, as many as twelve years before pernicious anemia developed, and while the hemoglobin percentages were all between ninety and one hundred, achlorhydria was definitely present. Riley (526) has reported two cases in which achlorhydria was present twenty and twenty-five years respectively before the onset of the disease. Other instances have been collected by Hurst: in two cases achlorhydria was discovered twelve years (Bie (59), Gross (237) ); in another ten years (Wilkinson); in another seven years (Faber (182), Cobet and Morawitz (120) ); six years (Levine and Ladd (370) ); five years (Kuttner (350) ); three years (Faber, Wilkinson) ; two years (Charles Hunter (286) ) ; and one year (Levine and Ladd) before the inception of pernicious anemia. Not one case has been reported of any individual, then suffering from true pernicious anemia, who, prior to the disease, was even demonstrated to have a normally functioning gastric mucosa. ETIOLOGY 47 The condition of achlorhydria as it occurs in pernicious anemia, is, moreover, as permanent and usually more permanent than the disease, and does not alter with remissions however long, or with any form of treatment yet employed. The one exception to this rule is illustrated by the case of Shaw’s. Even in three remissions of sev- enteen to twenty years’ duration, seen by Hurst (310), the introduction of the Ryle tube has led invariably to the same finding—persistent achlorhydria. Achlorhydria not associated with pernicious anemia may show in some instances some degree of recoverability, as demonstrated by Hurst in alcoholic achlorhydria. But an achlorhydria of alcoholic origin may progress to a permanent condition and predispose to pernicious anemia, as may also the achlorhydria associated with cirrhosis of the liver. It becomes possible to imagine that of the whole group of pernicious anemia, the attendant achlorhydria may be either one of two types—constitutional or acquired. In such a grouping the acquired forms might be listed as follows:—(1) Alcoholic achlorhydria. (2) The achlo- rhydria resulting from gastro-enterostomy. Hurst (307) found a case at Guy’s Hospital illustrating this syndrome, but achlorhydria due to regurgitation of alkaline jejunal contents might be apparent rather than real. (3) The nec- essary achlorhydria resulting from complete gastrectomy. Hurst (307) knows of five cases in which pernicious anemia followed extirpation of the stomach. As Piney (499) pointed out, since this operation is usually under- taken for carcinoma, any subsequent alleged pernicious anemia would require to be studied carefully with special intent to rule out a secondary deposit of carcinoma in the bone marrow. (4) The achlorhydria of gastric carcinoma. The fractional method in cases of stomach cancer shows achlorhydria in fifty per cent, although in the other fifty pet celit the amount of free) HCl is greatly reduced: 48 PERNICIOUS ANEMIA Hurst (307) has seen typical subacute combined degen- eration of the cord associated with cancer of the stomach, in which achlorhydria was present. Clinicians are all familiar with the occasional association of pernicious anemia with cancer of the stomach, although this double diagnosis must be made with care, since there occurs a macrocytic but not Addisonian anemia not infrequently in such cases. One may accept as bona fide all such cases of pernicious anemia occurring in instances where the achlorhydria might be conceived of as being acquired, yet a major ob- jection remains to admitting acquired achlorhydria as a predisposing cause of pernicious anemia. The instances reported are so few that this group might be supposed to have been potential victims of pernicious anemia in the course of ordinary events, and there is no proof that they did not have achlorhydria previous to those events from which they are credited with having acquired it. The bal- ance of collected evidence favors the view that the achlor- hydria of pernicious anemia is a condition long antedating the beginning of the disease. Among the causes which have been alleged for this achlorhydria may be noted the following: (1) The anemia. This conception grew up during the initial con- fusion of the subject, but has been completely set at rest by facts already set forth, viz., that the achlorhydria antedates the anemia and persists, unaffected, during long periods of blood improvement. In Hurst’s (307) gastric studies in cases of hemorrhagic and other simple anemias, the curve of secretion was found perfectly normal. (2) The toxic or infective processes which likewise cause the other symptoms of the disease. In the light of this theory the achlorhydria is the functional result either of a toxic parenchymatous gastritis due to the prolonged insult of small concentrations of toxin over a long period, and therefore parallel to our conceptions of other parenchy- ETIOLOGY 49 matous intoxications; or, of an interstitial infectious gastritis resulting, by condensation of fibrous tissues, eventually in atrophy of the secreting cells. In favor of this theory is the fact that from twenty to thirty per cent of patients show a prodromal debility for years previous to the disease, and characterized by marked digestive dis- turbances. Against it is the fact that seventy per cent of patients have been healthy previously, and the very perti- nent fact that gastric atrophy may not be present. (3) Constitutional factors of unknown nature. This hypothe- sis supposes that aclorhydria is a functional phenomenon not necessarily associated with any gastritis. The biopsies of Hurst and Passey revealed that the gastric mucosa in pernicious anemia may be histologically normal although achlorhydria was present. In some cases at least, there- fore, we have the phenomenon of normal architecture associated with absence of function. Again, as Hurst (307) has reasonably argued, a non-functioning gastric mucosa is, for several reasons, more liable to secondary injury than a functioning one. Food matter fails to receive the normal gastric maceration and is hence more liable to cause mechanical irritation. The mucosa, robbed of its normal antiseptic defence, is prone to infection from bac- teria-laden food and saliva from the notoriously unhealthy mouth. The theory regards the achlorhydria of pernicious anemia as caused by some “primary” fault, perhaps some constitutional and even inherited abnormality. It regards the manifestations of gastric sepsis as due to secondary injury and invasion. That a constitutional or even heredi- tary factor may be all important, is strongly suggested by the study of true instances of familial pernicious anemia. In such instances the only tangible link between affected blood relatives is the achlorhydria. Hurst (307) phrases this the “achlorhydric gastric diathesis” and recites many instances of achlorhydria in the blood relatives of per- 50 PERNICIOUS ANEMIA nicious anemia patients. In some instances an absence of gastric secretion has been found in patients’ children as young as six and four years of age, thus strongly sug- gesting that the condition is an inherited one. While clinical study has not elucidated the cause of achlorhydria it has distinguished between it and the con dition properly named achylia gastrica. In England and North America the former term, and on the continent the latter term, are used somewhat promiscuously to indi- cate either condition. The distinction between the two is apparent from the following definitions. Achlorhydria is a condition in which, by the use of the fractional test meal, no free HCl is detected in the stomach contents dur- ing either the digestive or interdigestive period, although combined acid and some degree of peptic activity may be found. Achylia gastrica is a condition in which, when similarly examined, neither free or combined HCl is detected at any period and peptic activity is lacking. The latter definition, if desired, may be rendered more strict by specifying lack of response to histamine and gastrin and inability of the mucosa to secrete neutral red. True achylia gastrica is a rare condition. Either condition may be found in pernicious anemia, usually achlorhydria. The distinction between the two is one of degree of failure of the gastric secretory function. The former is an instance of relative, the latter the instance of complete, delinquency of physiological activity. There exists a tendency to dismiss the subject of achlorhydria with an unjustified assumption that the con- dition is due to the absence of an unrecognized hormone, or to suppose that it is part and parcel of a metabolic dis- turbance of some substance such as, for example, the chlorides. What has physiology to offer in explanation of this phenomenon ? Present conceptions of the physiology of gastric secre- tion are based on the work of Pavlov (488), Edkins, ETIOLOGY ct Carlson, Ivy, and others. Ivy (317) would divide stomach digestion into three phases. (1) The cephalic stage, which corresponds to the psychic stage of Pavlov but includes the operation of lower brain centres than the cor- tical. (2) The gastric phase, which includes the mechan- ical and chemical influence of food on the stomach. (3) The intestinal phase, during which gastric secretion is aroused by contact of HCl, digested foods, soaps, and other substances with the duodenal mucosa. Edkin’s work on gastrin sounds the key-note to present investigations which are largely concerned with establishing a humoral mechanism. Edkin’s gastrin was extracted from pyloric mucosa by weak acid, peptone, or partly digested protein solutions. Similar substances may be extracted from many tissues. That from hog’s stomach and duodenum was shown by Ivy and Fisher (319) to resemble insulin in its lowering of blood sugar, while insulin, on the other hand, does not stimulate gastric secretion. Rogers et al. (532) made extracts from various organs, administered them subcutaneously and found those from thyroid, parathy- roid, liver, and pancreas definitely stimulated gastric secretion, while others did not. But these extracts showed other physiological activities, as depressors and as smooth-muscle excitants, each with effects peculiar to itself. They felt unjustified in assuming the existence of any specific hormone acting only on the stomach, although a common element in their various extracts seemed to act as such. In Ivy, Lim, and McCarthy’s (320) cross-circu- lation experiment between two Pavlov pouch dogs, by feeding the one and noting the gastric secretion in the other, a definite suggestion was obtained of a circulating gastric stimulant, appearing late in digestion. Ivy and Farrell (318) were next successful in transplanting a stomach pouch into the mammary tissues of a female dog and in showing that in this miniature stomach, separated as it was from nerve supply, there appeared an acid 52 PERNICIOUS ANEMIA secretion at a period some hours after a meal. This fur- nishes incontestible evidence of the operation of a humoral mechanism, depending probably on circulating food sub- stances. The secretion of gastric juice is therefore a phy- siological activity for the production of which nervous, mechanical, and humoral factors have been established, but for which no definite hormone had been found. The clinical and pathological studies of human gastric disease teaches the one great lesson that the stomach is a barometer indicating the general condition of well-being or cachexia. Carlson (101) believes that the hypoacidity of pellagra and beri-beri is an expression of the cachexia of diet deficiency. Achlorhydria is frequently found in the toxemias of pregnancy and is always present, so far as critically reported, in the chronic hemolytic anemia of pregnancy which bears so close a resemblance to perni- cious anemia. Faber has shown that of all the cases of dibothriocephalus latus infection which develop the per- nicious-like anemia, only twenty-five per cent have normal gastric acidity, many of them showing achlorhydria. Achlorhydria is liable to be found associated quite fre- quently with the following conditions—exophthalmic goitre, arthritis deformans, cholecystitis, and appendicitis. As will presently be emphasized it may occur, and in fact usually does occur, without association with any disease. Faber and Gram (188) have made a definite recognition of a severe, simple anemia, with low color index, red corpuscles smaller than normal, fluctuant in character and temporarily relieved by iron, which may accompany achlorhydria whether the achlorhydria is uncomplicated or is complicated by exophthalmic goitre or arthritis deformans. Achlorhydria has not been produced experimentally by any purely physiological means. When produced by in- toxications or by prolonged drainage of a gastric fistula, ETIOLOGY 53 it does not appear until the general cachexia would seem to demand it. Not only are we in ignorance of the cause of achlo- rhydria, but we are equally in ignorance, so far as accur- ate knowledge is concerned, of its consequence. Such symptoms as anorexia, persistent painless regur- gitation, feelings of distension, and chronic recurring diarrhoea, might be attributed to achlorhydria except that achlorhydria so commonly exists without them. Achlor- hydria apparently results in disturbances of the intestinal flora of equal degree whether in pernicious anemia or in uncomplicated cases. These changes in the intestinal flora will be considered later. From the fact that free HCl has been recognized as an essential intermediary in the stimu- lation of the pancreatic juice, it might be expected that a condition of achylia pancreatica would result. The inves- tigations of Hurst (307) and of McClure et al. (414) indicate, however, that the pancreatic function is normal both as regards enzyme secretion and alkaline fluid secretion. Achlorhydria exerts a definite influence on the acid-base balance of the blood, as proved by the numerous investigations, from Schittenhelm to Ackman, of the phenomenon of the “alkaline tide” of the urine (41, 99, 102126; V5), 202) 214,232, 234,257, 282, 283, 262, 355, 384, 402, 407, 515, 516, 556). The degree of alkaline tide varies directly with the degree of acidity in the stomach, being absent or diminished in cases of achlorhydria and completely absent in cases of true achylia gastrica. Whatever its causes or consequences may be, achlo- rhydria is almost invariably associated with pernicious anemia. The converse of this statement, however, is not true. Achlorhydria may exist, and usually does exist, without pernicious anemia. Bennett and Ryle (42) found achlo- rhydria in four per cent of one hundred medical students of an average age of twenty years. Wright (667) found 54 PERNICIOUS ANEMIA achlorhydria in 1.6 per cent of two hundred and fifty children between the ages of six and fifteen years. Faber (188) estimated that of all achlorhydric individuals ten per cent develop pernicious anemia. Among the other ninety per cent some may suffer from comparatively less fatal diseases—exophthalmic goitre, arthritis deformans, appendicitis, cholecystitis—although the majority remain in good health. It would seem advisable to adopt the following tenta- tive conclusion: Achlorhydria, a functional abnormality of constitutional origin, is almost invariably associated with pernicious anemia, and forms in these cases a neces- sary link in an etiological chain, to which, by the addition of further unknown links, pernicious anemia is made to appear. Nerve tissue degeneration. Since Lichtenstern (373) reported posterior column degeneration associated with pernicious anemia in two cases diagnosed as tabes, but which were probably cryptogenic pernicious anemia, the subsequent studies of Lichtheim (374), Putnam (504), Dana (137), von Noorden (624), Eisenlohr (168), Min- nich (437), Russell, Batten, and Collier (543), and many others have established the occurrence of combined system degeneration in association with pernicious anemia. Since 1910 the combined work of the Déjerines, Crouzon, and Jumentie (140, 141, 142), of Cadwalader (93), Schaller (550), and others has resulted in better understanding of the nervous system signs and symptoms. Woltman (662) has demonstrated the occurrence of brain lesions similar to those in the spinal cord. Hamilton and Nixon (253) have studied the sensory phenomena in particular and made the important observation of the commonness of peripheral nerve degeneration. Pathologically, the nervous system in a well-developed case shows wide changes. Posterior and lateral column degeneration, in varying proportion, definite cerebral ETIOLOGY 55 degeneration running more or less parallel to the degree of cord involvement, and widespread peripheral nerve degeneration constitute the phenomena. These degenera- tions occur in the myelin sheaths of long nerves and long tracts, being stained by Wiegert’s method, and have sug- gested to Woltman the operation of a toxin. Collier (124) has noted the absence of neurogliar increase following these lesions, a fact which gives them a unique position in nervous generations. Piney (500), noting this, has viewed the alterations as illustrations of abiotrophy. During remissions of the disease no improvement occurs in objective nervous signs, although the process frequently becomes quiescent. The disharmony noted between symptoms and pathological cord findings is to be explained, according to Hamilton and Nixon (253), on the basis of the peripheral nerve degenerations. Blanken- horn (48) has suggested that bile salts in the blood might be seriously considered as the cause of the nervous degen- erations, since bile salts may be found in the blood in cases showing definite nervous involvement but compar- atively little anemia. The obtrusive sensory symptoms of numbness and paresthesia may constitute the first indications of the disease. Marked objective signs may develop rapidly without anemia, or more slowly without anemia and con- tinue for years in a chronic course without anemia until terminally, when the specific type of anemia develops. The commonest type of case is one in which the nervous manifestations begin, some months after the onset of the anemia, with weakness. In later stages of pernicious anemia the true state of the patient is more related to nervous changes than blood changes. A patient may die with a fair blood level maintained. The presence of nerve changes always indicates a more severe phase of the dis- ease than when blood changes are alone present. 56 PERNICIOUS ANEMIA While this type of cord change—combined system degeneration—occurs much more commonly in pernicious anemia than in all other conditions combined, it is not to be forgotten that very similar changes may be found in poisoning with lead, arsenic, ergot, chick-peas, alcohol (chronic), and tea; and in shock, pellagra, diabetes, leukemia, diphtheria, Addison’s disease, tuberculosis, syphilis, typhoid, carcinoma, senility, chronic jaundice, malaria, influenza, scarlet fever, tetanus, and pregnancy. The fatty changes. These affect chiefly the heart and, in most cases, the liver and kidneys as well. These familiar facts must be merely stated because of their probably specific relationship to the fundamental process of the disease, although their nature is obscure. The remissions. A remission is a spontaneous blood im- provement characterized by general symptomatic im- provement. Panton et al. (482) found that 85 per cent of cases showed remissions and 15 per cent did not. The re- missions are subject to no known laws with regard either to their rapidity of onset, their duration, or their excel- lence, in any given case. The excellence of a remission may be judged by its duration, the degree of strength re- gained, the degree of blood regeneration, and the degree of disappearance of morphological abnormality on the part of the blood corpuscles. The objective nervous signs do not improve, although nervous involvement does not often increase during remissions. Glossitis frequently continues during all but the most excellent remissions. A remission is probably a period of comparative free- dom from the operation of the causal process, rather than a period of bodily reactive improvement in the face of continued disease. Nevertheless, the recoverability of all tissues which can recover may be seen to be less and less with each subsequent remission, for, although exceptions occur, there is to be noted a downward gradient when the remissions in any one case are compared. ETIOLOGY o/ While the health of the patient, in the earlier stage of the disease, may be said to follow roughly the hemoglobin level, there occurs a definite disruption of this relation- ship later on, for patients may die while their blood re- mains at a comparatively satisfactory level. In the later stages the true condition of the patient is better expressed in terms of the nervous system involvement. If our conception of the cause of the disease is that of an active destructive agent, then a remission would ra- tionally be regarded as a period during which this agent was either absent or in comparative abeyance. If our con- ception of the cause of the disease is that of a deficiency of certain factors vital to metabolism, then a remission would rationally be regarded as a period during which these factors are replaced. In either case a fluctuating mechanism is apparent. Furthermore, it is to be observed that whereas the blood system and nervous system are affected by remissions, the former positively and the latter negatively, the digestive system retains at least one unaffected principle—the achlorhydria. The general metabolism. Omitting references for the sake of brevity, the following points are selected from the mass of somewhat discordant findings. There is no evidence of any abnormality of carbohydrate metabolism. So far as lipoids are concerned, there is a recognized de- pletion of blood cholesterol during severe phases of the anemia, and usually a high ratio of unsaturated fatty acids in the blood though not to a distinctly pathological degree, a satisfactory usage of fat eaten, and no evidence of abnormal metabolism of simple fats, although there is a tendency to over-storage of fat, and a tendency also, to the pathological infiltration by fat in active tissues. Con- cerning protein metabolism, there is a tendency to a nega- tive nitrogen balance; amino-acids are increased in the blood and the urine shows double the normal amount of oxyproteic-acid nitrogen. Blood creatinin is increased. In 58 PERNICIOUS ANEMIA this connection the extreme muscular wasting, especially in cases of marked cord involvement, should be borne in mind. Any increased protein catabolism is probably an expression of the cachexia, as in that of carcinoma and syphilis. The usually high uric acid nitrogen suggests that the purine metabolism requires further study, especially in view of the benefits derived from feeding with glandu- lar organs. The metabolism of iron has already been dis- cussed. There exists a tendency to chloride retention al- though there is no evidence that an abnormality of chloride metabolism plays an important role in the dis- ease. Studies of the basal metabolic rate have served to suggest that the use of energy is determined by two oppos- ing factors, (1) a positive stimulation connected probably with increased blood production, (2) a retarding influ- ence due to the tendency to storage and infiltration of fat. ETIOLOGICAL EVALUATION OF OTHER POSSIBLE RELATED FACTORS The type or constitutionality of the patients. This prob- lem involves a description of certain alleged constitutional factors common to these patients and some reference to familial pernicious anemia. Addison (5) noted that the disease occurred “‘chiefly in persons of a somewhat large and bulky frame.’ While this is often true, it may also occur in small, lean persons. Maitland-Jones (394) as well as Levine and Ladd, have noted the great frequency of gray or white hair. Sheard (576) among 15 cases found but one exception to this apparent rule. In the 14 cases showing the feature, he determined that the aver- age age at which grayness commenced was 29.4, which was 15 years prior to the average age of the onset of the disease. He further noted, as others have, the frequency of “silky” or very fine, soft hair. Achlorhydria is of course the most striking feature of the disease which could be interpreted as a constitutional ETIOLOGY 59 one. Bassler and Gutman (31), in studying the constitu- tionality of achlorhydric individuals, have placed them in the “adrenotrope” group—females of the masculine build, males of the apoplectic diathesis, with tendency to pigmentations, very firm and stained teeth, and great mental susceptibility to external influence. Anthropological measurements of a most painstaking character have been made by Draper (153) on 45 cases of pernicious anemia. For a full understanding of his motives and methods reference should be made to his book. As compared with similar measurements in other disease groups (gall-bladder, gastric and duodenal ulcer, asthma, nephritis and hypertension, and pulmonary tu- berculosis), Draper found as follows :—people with per- nicious anemia have short broad faces; large mandibular angles; very short noses; short but deep, wide chests; especially wide subcostal angles; and (especially the males) very long thin ears. “The male of the pernicious anemia race, therefore, is a medium to tall individual with short chest, high placed umbilicus, long abdomen, and a tendency to eunuchoidal habitus as shown by his rela- tively long lower extremities. The males of this group show definite feministic tendencies in the domain of the secondary sex characteristics. But the skeletons show average or greater sex divergence in the growth of the long bones. In this case the convergence of sex insignia upon the so-called intermediate form is more marked than in any other disease group. This may be reflected in the wider pelvis of the male of the pernicious anemia group. In commenting upon Draper’s work, Stockard (598) says in part, “The pernicious anemia group tended in their measurements very decidedly to approach the acrome- galics. They had very large subcostal angles and had an average profile that tended toward the acromegalic pic- ture. The anemic persons may by some possibility be a peculiar deviation from the bone growth stage of the 60 PERNICIOUS ANEMIA acromegalics. Both conditions may have some connection with calcium metabolism, and blood disturbance and bone disturbance in this way may be somehow interrelated.” Stockard favors the view that type differences are evi- denced by marked variation in anatomical measurements but that constitutional differences may exist in members of the same type and be due to such influence as the en- docrine glands, so that while type is permanent, consti- tutionality may vary, even in an individual. Further work by Draper, especially on the physiological, psychological, and immunological aspects of the members of these dis- ease groups, will be awaited with interest. A possible re- sult of such investigations may be the division of people into species or subspecies. Sufficient has been written to indicate that there exists some reason why investigators and writers on pernicious anemia should suspect that these patients may possess at lease a definite peculiarity of constitution if not of type. Minot (444) informs the writer that Palmer Howard was first to note the familial occurrence of pernicious anemia. Klein (340) in 1891 saw the disease in three brothers and sisters. Bramwell a little later described a family in which seven individuals in two generations had suffered from pernicious anemia. Since then the phenom- enon has been noted by Caccini (92), Schauman (551, 554), Bulland (241), Cabot (90), Osler (477), Gilbert and Weil (225), Patek (486), Willson (658), Andree (12), Bartlett (29), Roth (538), Minot (440), Piney (449), Matthes (409), and others. Schauman by 1918 had collected information of 24 families in which there was noted hereditary occurrence of either idiopathic per- nicious anemia, or the pernicious-like anemia due to bothriocephalus, or both of these, in the same family. More recent confirmation of familial occurrence has come from the reports of Levine and Ladd (370), Meulen- gracht (430), Gram (218), v. Decastello (623), Muste- ETIOLOGY 61 lin (466) and Gilford (226). Meulengracht (433) has considered the technicalities involved in an hereditary study of pernicious anemia. Hurst has collected many in- stances in which achlorhydria has been found among the blood relatives of patients with the disease, strongly sug- gesting that the obvious link in the chain is absence of gastric secretion. Piney (500) distinguishes between me- galoblasts with reticular nuclei and those with “cart- wheel” nuclei, and contends that the former or true vari- ety are found only (apart from the embryo) in perni- cious anemia and acholuric family icterus, the two “dis- eases of the blood” in which family incidence is well recog- nized. He noted in his own cases a frequent history of the patient not having been a full term infant. Piney believes that the abnormal type of blood formation in pernicious anemia is an embryonic reversion, due to inherited pro- pensities of the individual, and possibly related to the constitutional achlorhydria. The nervous tissue degenera- tions he would interpret as an abiotrophy. Finally he sug- gests the working hypothesis, with which all cannot of course agree, that the various agents capable of produc- ing a “secondary” anemia in ordinary persons will pro- duce pernicious anemia in such individuals as possess the necessary remnant of megaloblastic tissue. This is practically Cohnheim’s hypothesis reinforced by distinc- tions between two alleged types of megabloblasts and by observations on the family incidence. Barker (24) has recently considered the hereditary factors and stated the possibility of the view that pernicious anemia is a geno- typic disease, possible only in biotypes, but requiring for its development certain “releasing factors” in the envi- ronment. He comments upon the difficulties of applying the method of statistical summation and offers three rea- sons why the disease may be absent in families where it might be expected to occur under the inheritance theory. (1) It is a disease of later life, many potential candidates 62 PERNICIOUS ANEMIA dying before it can become manifest. (2) Many cases are overlooked. (3) The possibility that the “releasing factors” have not been operative upon these individuals. The genotypic conception of pernicious anemia is at present of little more than academic interest and whether it eventually proves convincing or otherwise, ordinary studies must be pursued to determine the sequence of events in the pathogenesis. The food factor. The voluminous work on vitamins dur- ing the past decade unquestionably suggested that avita- minosis might play some role in pernicious anemia. Fal- coner concluded that blood changes in vitamine A defi- ciency were neither striking or constant enough to consti- tute specific deficiency lesions. Koessler et al. (346) do not indicate the condition of pigment metabolism in the anemia they produced in rats by chronic vitamine A deficiency and, hence, any comparison with pernicious anemia, lacking this information, is problematical. They indicate that in this experimental anemia, produced by vitamine A deficiency, blood regeneration occurs only with, and in proportion to, the addition of vitamine A. Nothing could appear more logical, since no anemia can improve so long as the set of conditions responsible for the anemia do not change. Simmonds e¢ al. (579) sug- gest that Koessler’s rat anemia was due to deficiency in vitamine E, which is believed to play an important role in the absorption of iron. Whatever may have caused the anemia, it does not, from their description, appear to bear any necessary relationship to pernicious anemia; and in fact Koessler et al. propose such a vitamine A deficiency not as a sole, but rather as a cooperative factor in the etiology of the human disease. Barker and Sprunt (25) emphasized the importance, on general principles, of treating pernicious anemia by liberal and well-balanced diets. Many others have, with no recognizable specific reason of importance, advised ETIOLOGY 63 special diets of various kinds. Mosenthal (454) showed that forced feeding can restore a positive nitrogen bal- ance. Gibson and Howard (223) showed in careful meta- bolic experiments, that more favorable nitrogen and es- pecially iron balances may be established in pernicious anemia when diets rich in food iron, and comparatively low in caloric and protein values are given, and urged the use of iron-rich and vitamine adequate diets in the treatment of this disease. This was an intentional, clinical application of high food iron diets which had been found by Whipple ez al. (648, 652, 651) so valuable in causing blood regeneration in dogs rendered anemic by hemor- rhage. Elders (169), fully convinced of the possibility that sprue and pernicious anemia possess a common etio- logy, and equally convinced that sprue is a deficiency dis- ease, suggested that pernicious anemia might be found at least amenable to improvement by well-chosen food. Minot and Murphy (447) found it permissible to specu- late “on the possible partial role that some nutritional ex- cess or deficiency may play in the etiology of the disease.” With a special diet rich in proteins of good biological value, particularly liver, low in fat and carbohydrate and with vitamines well supplied, these investigators have obtained remarkable therapeutic results, more constant and lasting than those obtained by any other form or forms of treatment. The published work of Minot and Murphy has brought the whole problem of nutrition in pernicious anemia to a sharp focus of interest. Their results have suggested the possibility that dietary factors may actually play a role in the production of the disease. No studies of the pre-disease diets of patients have as yet appeared. SIMILAR CLINICAL ANEMIAS Waugh (637) in his classification of anemias would regard pernicious anemia as the idiopathic member of a limited group designated as “hyperchromic hemomyelo- 64 PERNICIOUS ANEMIA toxic anemias.” This group includes the chronic hemolytic anemia of pregnancy, dibothriocephalus anemia, some cases of gastric cancer, some cases of sprue, and others which will be mentioned. The common expression “pernicious blood-picture” is a loose unstandardized term, the meaning of which varies according to the views of the person using it. It is some- times erroneously used to describe a frankly aplastic anemia in which evidence of pigment disturbance does not appear. Disturbance of pigment metabolism is of primary importance. But there are several anemias whose hematological data as a whole suggests pernicious anemia. Such are encountered in a few each of the following con- ditions :—carcinoma of the stomach, syphilis, pregnancy, dibothriocephalus infection, sprue, colonic cancer, balan- tidium coli infection, aleukemic leukemia, malignant metastases to the bone marrow, and as Minot (442) as well as Meulengracht has pointed out, in a very occa- sional case of myxedema. These instances, however, judged even by purely microscopic evidences in the blood smear, seldom fulfill the requirements of pernicious anemia. The crucial test is the predominance of macro- cytes, heavily staining, and exhibiting in at least 80 per cent of their number definite ovality of outline. It is there- fore possible by rigorous microscopic standards to ex- clude most of these instances. All standards we possess are nevertheless very occasionally defeated by cancer of the stomach, sprue, and fish-tapeworm infection. Needless to remark, even such blood identities as these sometimes are do not justify their designation as pernicious anemia. But when, in addition to blood identity, there appear in such cases the additional features of glossitis, achlorhy- dria, and combined degeneration of the cord, escape from the dilemma is found by making a double diagnosis. Such a dilemma may actually be encountered in gastric and colonic cancer, and in sprue. ETIOLOGY 65 There is little doubt that carcinoma of the stomach and of the colon may at times produce a macrocytic anemia in which the macrocytes are circular rather than oval and exhibit a degree of achromia never seen in perni- cious anemia. It is also true that sprue not infrequently produces a severe anemia with marked anisocytosis, but this is not pernicious anemia but merely the anemia of sprue. Furthermore, a few cases of dibothriocephalus anemia show such a striking identity with that of perni- cious anemia that distinction rests on associated signs or the discovery of the worm. The etiological value of such resemblances is to demonstrate that various known condi- tions can cause very similar anemias, a fact which puts us on guard in interpreting experimental blood-pictures and which indicates, too, that a so-called ‘pernicious blood-picture” is not a strictly specific phenomenon. In instances where the whole Addisonian complex su- pervenes in a known disease, we are driven to choose be- tween accidental occurrence or causal relationship. It is not impossible that sprue, gastric cancer, and dibothiro- cephalus infections possess at times a common meeting ground with pernicious anemia, in the form of a funda- mental process which, once brought into being, is identi- cal in its operation and consequence. A REVIEW OF EXPERIMENTAL FINDINGS Since most of the experimental work on this disease has been dominated by the conception that it is caused by a blood-destroying agent, absorbed from the gastro- intestinal tract, it is necessary to define the so-called “hemolytic theory” and to consider also the general prob- lem of poisoning from the intestine. The requirements of any hypothetical tox. It is clear- ly to be understood that no definite proof of a toxin exists. The absence of in-vitro hemolysis by patient’s serum may be made congruous with a toxin theory by supposing that 66 PERNICIOUS ANEMIA the toxin, wherever produced, is immediately absorbed to the erythrocytes, or is removed from the circulation by the reticulo-endothelial system, the latter being thus ren- dered inimical to the red blood cells. Extracts of the spleen in this disease are not hemolytic. Really the chief reason for hypothesizing a toxin is that in bothriocepha- lus anemia the cause is supposed to be the autolysis pro- ducts of the worm operative through absorption by the intestine. This is not a very logical reason since no one has shown that the truly hemolytic products are absorbable from the human intestine. If a toxin be hypothesized, then unity of toxin is sug- gested by the strikingly similar clinical and pathological pictures in all cases. Plurality of toxins finds its best argument in the occurrence of subacute degeneration of the cord temporarily without anemia, and perhaps in the occurrence of splenomegaly in certain cases. The differ- ence between the so-called “hemolytic” and ‘“myelotoxic” cases might better be called a difference in “activity” and would then depend on the dose of toxin delivered to the body. If a toxin causes this disease per se, by direct action on the tissues pathologically implicated, and without the necessary intermediate codperation of any vital function, it must possess both hemotoxic and neurotoxic powers. To account for remissions the toxin must possess immu- nological properties or be produced by a fluctuant mech- anism, or both. Any toxin must be shown to be specifically active with- in the body. Its lack of hemolytic activity in the test tube would not disqualify it. Any toxin to be seriously considered would have to produce: (1) A megaloblastic marrow reaction, (2) a characteristic blood-picture, (3) nerve tissue degenera- tion without neurogliar increase, (4) remissions either by intermitting doses or in spite of constant dosing. ETIOLOGY 67 No such toxin has been demonstrated. Gastro-intestinal toxemia. Although Hunter’s (297) own investigations of various intestinal poisons did not support this conception he clung to it for several reasons. The marked symptomatology of the digestive tract was one. A still more convincing one was his interpretation of the hemosiderin deposits. Having demonstrated this iron pigment in the liver in higher concentration than in the livers of other anemias, and having accepted hemo- lysis as responsible, he (290) assumed that the hemolysis took place largely within the portal area. Since 1885 the intestinal toxemia theory has held its own with special investigators and particularly with the rank and file of general practitioners. It has many rami- fications and although it merges with the trite and com- mon idea of intestinal “auto-intoxication” so glibly ac- credited with all manner of ailments, any thesis so long sustained deserves consideration. Intestinal intoxication has received a very excellent general evaluation from Alvarez (8). The greatest objec- tions to the idea are the tremendous number of poisons in the lumen of the bowel and lack of knowledge of their individual absorbability by the mucosa. Much investiga- tion of individual poisons has led in almost no instance to any proof of their absorption in harmful amounts into the general circulation. The toxin of B. botulinus is per- haps an exception. Intoxication from high obstruction admits the element of a pathological state of the mucosa. The absorptive faculties of this tissue in health would appear to be uniformly very selective ones. As a second barrier to the ingress of harmful substances stands the liver with its detoxicating functions. Any specific hypo- thesis of intoxication from the gut would require to show at the outset that the suspected substance could pass into the general circulation in a harmful state. The only alter- native to this requirement would be a demonstration of 68 PERNICIOUS ANEMIA increased absorption by the mucosa in pernicious anemia. Such a theory has been advanced by Koessler et al. (346) as one of the fundamental changes in the disease. If this were successfully shown to be true, intestinal intoxication would at once assume greater seriousness. The only actual work in connection with pernicious anemia which might lend support to the theory of intes- tinal intoxication was that of Iwao (321), who reported that tyramine injections in guinea pigs produced a se- vere anemia of “pernicious” type. Since tyramine can be formed from tyrosine by B. coli and is therefore normally present in the bowel, this work looked promising, but Koessler and Harris failed to confirm it. The gastro-intestinal mucosa itself, either alone or in association with abnormal states, has been viewed with suspicion. About a dozen cases have been reported in the literature in which pernicious anemia was associated with chronic intestinal stenosis. Seyderhelm (573) produced a “macrocytic” anemia in dogs by stenosing the small in- testine near the ileo-caecal valve. In such dogs, and in cases of pernicious anemia, Seyderhelm has noted an en- croachment on the ileum of the colonic flora. Haden’s (247) case of clinical and hematological pernicious ane- mia associated with malignant tumor of the gall bladder and partial obstruction of the duodenum and colon, sug- gested to him the absorption of toxin, and an analogy with the toxemia of complete intestinal obstruction. Apart from obstruction or any gross lesion involving the digestive tube, the mucosa itself has long been sus- pected. Berger and Tsuchiya (43) in 1909 found in the intestinal mucosa in two autopsies an ether soluble sub- stance ten times more hemolytic im vitro than a similar extract from normal musoca. On enteral or parenteral in- troduction into animals it was still more hemolytic than its control and produced an anemia bearing some resem- blance to that of pernicious anemia. This work was not ETIOLOGY: 69 confirmed (78). Dogs in whom a severe intestinal catarrh was artificially produced showed in their mucosa a lipoidal substance closely resembling in its action that found in the mucosa in pernicious anemia. Cornell (133) noted, during an attempt to implant B. welchii in the intestine of dogs, an initial severe diarrhoea accompanied by an evanescent mild anemia with definite anisocytosis. How- ard (278) stressed this aspect of the study of toxic lipoids from the intestinal mucosa. The question deserves some further study. Briefly, while there is every reason to sus- pect the gastro-intestinal tract, there is absolutely no reason positively to incriminate it of giving rise by any means whatsoever to a poison responsible for the disease. The intestinal flora. Every organism that inhabits the lumen of the gut in pernicious anemia has been suspected of causing the disease. The enterococcus is increased in the stools and lives higher in the duodenum than in health or other disease. This is also true of B. coli. B. welchii is increased in the stools but no work has been published to indicate whether or not it lives higher in the duodenum. Streptococcus longus has been reported abnormally pres- ent in the duodenum in a high percentage of cases. From all the investigations made, two facts are significant. A good case has not been made out against any organism, and no exceptional one specific to the disease has been found. The B. welch theory. This micro-organism (B. aerogenes capsulatus, B. perfringens) is an anerobic, program-positive, encapsulated bacillus which spores with difficulty on artificial media. When living cultures are injected into the ear veins of a rabbit and the rabbit killed and incubated, a “foamy” liver develops. The or- ganism has been divided into four groups by Simmonds on the basis of its power to liquify gelatine. It was first identified by Welch in a case presenting gas in the tis- sues at autopsy. It was later shown, especially in the 70 PERNICIOUS ANEMIA great war, to be a constant factor in the production of gas gangrene. Bull and Prichett (80) demonstrated a soluble exotoxin possessing distinct hemotoxic and lethal elements. This toxin is thermolabile and has immunolo- gical properties. The antitoxin from the horse or rabbit neutralizes in vitro the hemotoxic and lethal elements and cures the symptoms of an acute experimental infec- tion in guinea pigs, if promptly administered. A possible relationship between this organism and per- nicious anemia was first suggested by Herter (268) in 1906. He found B. welchii or its spores numerically in- creased in the stools of this disease as compared with the stools from normal or other diseased conditions. Sim- monds (578) later confirmed this finding. Although he was working at a time before the exotoxin was known, Herter felt that the stools showed altered chemical fea- tures due to this organism. He very tentatively suggested that B. welchii might be the cause of the disease, evidently meaning that in causing it, it led a life confined to the lumen of the intestines, while its harmful growth pro- ducts were absorbed into the circulation. His hypothesis therefore must be interpreted as a specific application of the intestinal intoxication idea, for he made no sugges- tion of tissue invasion by this organism. Cornell (134) showed that B. welchii caused a chronic infection when injected subcutaneously or intraspleni- cally into rabbits. This infection ran a course of a few months and was characterized, among other symptoms, by an anemia of varying intensity, the constant feature of which was anisocytosis. This anisocytosis was due to a direct action of the exotoxin on the erythrocytes and oc- curred in vitro in washed cells. The smear picture bore no little resemblance to that of pernicious anemia, but the macrocytes were characteristically circular rather than oval, the microcytes appeared like contracted rather than fragmented cells, and neither blood platelets nor leuko- cytes were depressed sufficiently. ETIOLOGY 71 Kahn and Torrey (332), working at the same time on the effect of intravenous injection of the toxin in mon- keys, obtained very similar blood pictures, but with high- er color indices and more leukocyte depression. Reed, Orr, and Burleigh (518) showed that a highly virulent strain of B. welchii would produce an infectious anemia in rabbits whose acuteness or chronicity depended on the age of the culture used but that, in any case, anisocy- tosis was conspicuous and resembled quantitatively that of pernicious anemia. Moench, Kahn, and Torrey (448) in an analysis of the fecal flora in 35 cases of pernicious anemia showed that B. welchii gives uniformly higher counts than normal, that among 26 different strains isolated 50 per cent con- formed to Simond’s Type I, but that none could be shown to be more hemolytic or pathogenic than strains from normal stools. They consider that if B. welchii is to be brought into etiological relationship with pernicious ane- mia it must be because of its increased numbers and ac- tivity at a level of the tract higher than ordinary, where absorption is more active. They support Seyderhelm’s (572) observation of the invasion of the ileum by the colonic flora and consider this to be of importance. Nye (475) showed that an equal or even greater in- crease of B. welchii could be demonstrated in the feces of cases of uncomplicated achlorhydria. He feels that the phenomenon depends on an alkaline condition of the prox- imal ileum and is therefore merely a consequence of achlorhydria and not an etiological factor in the disease. A bacterial study of the stools at Guy’s Hospital (180) does not seem to have confirmed the invariable presence of B. welchii in increased numbers. There is no convincing evidence to support this hypo- thesis. The toxin has neurotoxic properties but the chronic infection in rabbits showed no combined system dis- ease, no alterations in gastric secretion, and no remis- 72 PERNICIOUS ANEMIA sions. The toxin has never been shown capable of ab- sorption from the intestine. In fact it is questionable if the organism living in the gut could produce a toxin com- parable with that produced under very special culture conditions. It probably cannot be regularly found in the internal organs after death and its presence might al- ways be due to agonal invasion. In some animals this or- ganism may be cultured from the liver during life and health. No agglutination or complement fixation by the serum on the organism or its toxin has been found, al- though both have been looked for. The blood picture pro- duced by the chronic infection or by the continued injec- tion of toxin, while definitely suggestive, is really not the blood picture of pernicious anemia and may best be classi- fied as a toxic, macrocytic, hemolytic anemia. Finally B. welchii antitoxin has been repeatedly administered to patients without visible benefit. The streptococcus theory. Hunter (303) made micro- photographs of the glossitic lesions showing a long strep- tococcus in the subepithelial layer of the tongue at those eroded areas where the mucosa was gone. From such les- ions he claims to have obtained this organism in a highly virulent state in pure culture. To this organism he attri- buted largely the septic manifestations which so fre- quently accompany or antedate the true specific anemia, but he never incriminated it as the cause of the latter. Hemolytic streptococci have been found in the gall blad- der in cases of cholecystitis associated with pernicious anemia. Knott (345) found, as did Hunter, large num- bers of living streptococcus longus in the gastric contents of patients and in increased numbers in the saliva. Ryle (544) sets forth, as characteristic of a streptococcus fever, a rapidly progressive anemia, a curiously smooth, red, desquamated tongue, both of which features are caused by a circulating cytolytic toxin. Newburg (470) has reported a case of pernicious anemia in which a hem- ETIOLOGY 7s olytic streptococcus was cultured from the blood. Hurst (311) is the leading exponent of the streptococcus theory of the cause of the disease. Having first demonstrated that achlorhydria was as constant in “pure’’ cases of subacute combined degeneration of the cord as in pernicious ane- mia, he made cultures of the duodenal contents during life on 4 patients with the former and 7 with the latter form of the disease, and employed as controls 26 cases, either normal, or suffering from conditions without achlo- rhydria. Table 8 shows his results. TABLE 8 Streptococcus longus in the duodenal contents, (Hurst) Number _S. longus of Cases present Percentage INO iin atl pees eas eee ce SE Ls 4 0 Infective jautidice 2... 8 0 LES) Various medical cases ............---..- 14 3 Pernicious) anemia 2008.02.40. 7 7 100.0 sup Comb, Degen. Cord,, -.._..... 4 4 t ; No detailed description of the technique employed in this culture work has come to our notice, but accepting the results as stated to be bacteriologically beyond criticism, their interpretation is hazardous. Hurst concludes in part that the presence of Streptococcus longus in the duode- num is evidence of active infection of the intestine. This may be true but does not mean necessarily any tissue invasion. He leans rather to the view that this organism by decomposing unaltered protein gives rise to hemolytic and neurotoxic bodies which on absorption cause the dis- ease. To make such a hypothesis convincing the organism would need to be shown capable of forming such bodies, and these bodies would need to be capable of intestinal absorption. No records of this having been done appear. Experimentally the Streptococcus longus has not been shown capable, by tissue infection, of producing an 74 PERNICIOUS ANEMIA anemia of the pernicious type. Hurst states, “In one of our patients an autogenous vaccine made from the S. longus isolated from the socket of an infected tooth gave rise to a temporary aggravation of the sensation of pins and needles in the hands and feet each time it was in- jected.’’ Cornell noted the same phenomenon when patients were injected with formalized or plain B. welchii toxin. Probably it is due to a non-specific protein reaction and of no great significance. Again, no serological reactions on pernicious anemia in connection with the streptococcus have been found, and anti-streptococcus serum exerts no beneficial effect on patients with the disease. This latter fact has been amply attested (55,632). Recently Moench, Kahn, and Torrey (448) found streptococci very numerous in the stools of thirty-three cases of pernicious anemia. The strains were of the nor- mal intestinal types, with no representatives of the hemo- lytic group being encountered. The B. coli theory. Adami (2) suggested in 1900 that in pernicious anemia “we deal with a subinfection by means of hemolytic intestinal bacteria of the colon group.” A similar supposition played a part in this auth- or’s explanation of hepatic cirrhosis. It means that these special strains of B. coli invade the intestinal wall, enter the portal blood, and then break down, somewhere in the body, liberating destructive endotoxins which are hemo- lytic and neurotoxic. Such a hypothesis defends itself in so far as it at once circumvents the difficulties inherent in an intestinal intoxication theory. It is plausible in that it specifies an organism abundantly present in the lumen of the gut. Moench, Kahn, and Torrey (448) were struck by the uniformly high counts for B. coli in the stools of pernicious anemia patients, being much higher than for normal persons or people with other pathological condi- tions. Lowenberg (387) recently showed, in culturing the duodenal contents, that B. coli was present in eighty-five ETIOLOGY 75 per cent of cases of the disease and in only thirty-five per cent of cases of uncomplicated achlorhydria, whereas not nearly as great a discrepancy occurred between the two same groups with regard to the finding of enterococci (ninety per cent and seventy-five per cent respectively). Routine cultures of pernicious anemia organs at autopsy frequently show B. coli in the spleen and bone marrow. Percy (495), in cultures of organs made at laparotomy on spleens, gall bladders, and appendices of nine cases of pernicious anemia, found Streptococcus hemolyticus in seven cases, B. coli in five, Strept. viridans in four, and Stapholococcus albus in one. Experimentally Nyfeldt (476) by injecting rabbits intravenously with either the whole autolyzates or extracts of autolyzates of various intestinal bacteria, particularly B. coli, was able to pro- duce a blood picture and histological lesions resembling pernicious anemia in seven out of sixteen, while the other nine developed a simple anemia. OTHER DATA CONCERNING INFECTIONS Sellards finds frequently in spleens removed at oper- ation in pernicious anemia an anerobic bacillus resembling in all details that isolated by Plotz in typhus fever, but not bearing, in his opinion, any etiological relationship to the disease. Macora (392) has reported the finding of B. typhosus at autopsy in the spleen and bone marrow. Stanzani (588) has noted anemia of “pernicious type” at the height of typhoid fever. MacLean made a careful blood examination on twelve cases of typhoid fever in the Montreal epidemic, 1927, but was unable to make any similar observation, any anemia present being of a simple nature. Kline (343) has reported the finding of B. proteus in the bone marrow. Ecker and Brittingham (160) report the production of a hemolytic exotoxin from this organism. 76 PERNICIOUS ANEMIA Wood (661) has found the monilia psilosis in the feces of fifteen cases of pernicious anemia, while from forty cases which were neither pernicious or sprue this yeast was not recovered. Experimentally by feeding this monilia to guinea pigs on normal diet, he produced a macrocytic anemia with hepatic siderosis and extension of the red bone-marrow with normoblast increase. Wood has been impressed, as has Elders (169), by the striking relation- ship between sprue and pernicious anemia. Musser (465) has emphasized the common finding of free HC1 in sprue. Fontaine (207), in discussing Wood’s paper, stressed the common finding of a simple anemia in sprue, the different type and greater incidence of diarrhoea in sprue, and his own inability to find the monilia in cases of pernicious anemia. The work of Wood is of great importance since he has demonstrated that, at least in the neighborhood of his clinic in North Carolina, many cases are seen in which either the diagnosis of pernicious anemia or sprue is equally justifiable, even when glossitis, achlorhydria, and cord lesions are adopted as diagnostic points. The writer feels that two factors are to be taken into consideration in this connection: (1) The blood picture of sprue itself, especially in the presence of severe anemia, bears a strik- ing resemblance to that of pernicious anemia. (2) Sprue is, in some unknown manner, capable at times of setting in motion the fundamental bodily process which is oper- ative in idiopathic pernicious anemia, and bears to the Addisonian complex the same provocative relationship as is possessed by the fish-tapeworm infection. In a country where sprue is common, it may constitute the “releasing” factor in pernicious anemia. Broun et al. (74) in experimental work with the M. psilosis could not produce a blood picture approximating pernicious anemia. By the use of an antigen prepared from the monilia some cases of pernicious anemia show- ing monilia in the feces gave positive complement fixation ETIOLOGY 77 reactions, but so also did the sera of cases, other than pernicious anemia, who harbored the monilia. Logan (385) as well as Jennings (323) found Balan- tidium coli in the feces of a number of cases of pernicious anemia. Logan does not feel either that all cases of balan- tidium infection have pernicious anemia or that all cases of pernicious anemia have the balantidium. He (386) suggests the importance of a study of toxin production of humanized strains. Meessen (428) believed that he had demonstrated spi- rochetes in the blood of pernicious anemia, but Determann (146) later showed that what Meessen had considered motile spirillae were actually hemokones or “blood dust.” No evidence of a filterable virus has been reported. MISCELLANEOUS THEORIES The following hypotheses have never proved convinc- ing—Sahli’s (545) iron theory, Allport’s (10) “San- guinin” theory, and many theories specifying individual substances such as blood phenols (37). THE VALIDITY OF EXPERIMENTAL BLOOD PICTURES A large number and variety of agents can produce on parenteral injection blood pictures of macrocytic character bearing more or less resemblance to that of pernicious anemia—ricin, saponin, acetanilid, pyrodin, potassium chlorate, pyrogallic acid, glycerine, nitro-benzol, trinitro- toluol, toluodiamin, B. welchii toxin, oleic acid, and vari- ous tissue extracts. Some of these may cause a marrow reaction of megaloblastic type. This heterogeneous col- lection of agencies makes it clear that a macrocytic smear picture is not at all a specific phenomenon. Probably none of these pictures show the finer, and obviously necessary, features of that of pernicious anemia. Exposures over long periods to radium and X-rays give a similar though aplastic picture. It is unlikely that any proposed agent will 78 PERNICIOUS ANEMIA receive serious consideration as the etiological agent unless it can produce, in addition to anemia, combined degeneration, glossitis, and achlorhydria. Moreover, if such an agent could fulfill these requirements it would not be absolutely certain that it was identical with a toxin presumed operative in the disease pernicious anemia, nor, indeed, would it render a toxin theory imperative. CONCLUSION Pernicious anemia appears to be a superstructure of blood-system and nervous-system changes superimposed upon an unknown but characteristically fluctuant foun- dation. Of this foundation we know nothing, but conceive of achlorhydria as its almost constant and only obvious expression. It is not impossible that several different factors may bring the unknown fluctuant process into operation. This process may depend upon idiosyncratic characters of the patient. The wide-spread tissue involve- ment found and the peculiar mass of biochemical changes suggest that this fundamental process is a disturbance of metabolism. CHAPTER IV GENERAL SYMPTOMATOLOGY While the digestive, blood, and nervous systems pro- duce the chief and specific symptoms, every system except the articular is appreciably involved. Physiologically every tissue of the body must suffer from the disturbed metab- olism known to exist. Any conception of the disease is inadequate which neglects its wide-spread bodily conse- quences. The clinical manifestations, while expressive of this extensive involvement, are nevertheless in general painless, mild, and surreptitious in proportion to the debil- ity produced and to the culmination which, until the pres- ent at least, has been almost invariably fatal. No disease shows, of necessity, all its symptom possibilities in any one case, nor does it marshal its symptoms necessarily in any given order of appearance. With this concession one must admit that pernicious anemia is a clinical entity. Vari- ations are those of time and degree, but not of kind. Blood abnormality, nerve tissue degeneration and digestive tract disorder constitute the entity, and no known disease pre- sents a more constant quantum than this triad of symptom groups. Most arguments to the contrary arise from a resemblance of one of these elements (blood abnor- mality) to that found in a few other conditions. The specificity is constituted by the quality but especially by the association of these three system processes. The blood abnormality, in its strict identity, is but seldom success- fully mimicked by other diseases. The type of nerve-tissue degeneration, while sporadically occurring in several other conditions, occurs most frequently by far in associ- ation with pernicious anemia. The digestive tract phenom- ena, though not understood, are constant and, when glossitis occurs, specific. The gathering together of these three great system processes forms a strange disease, re- [79] 80 PERNICIOUS ANEMIA sembled by nothing else in animal pathology and deserv- ing to stand, for the present if not the future, as a definite entity. So slight are the deviations from the fixed type, and so constant are the total reported manifestations over a period of a century, that any attempt to subdivide the idiopathic disease into separate entities, on a clinical or pathological basis, would appear unwarranted. THE HISTORY OF THE PATIENTS One must subscribe, in part at least, to the thesis that a particular type of individual is the most prone to acquire the disease. They are usually large framed persons with considerable subcutaneous fat, fine grey hair, carious teeth, and blue irides. Usually they possess a sensitive mentality. Exceptions occur frequently enough, but the rule stands. No group of patients could have pleased more the fancy of the staunch clinicians of the past century, who laid so much store by diathesis. Translating this word into the more modern expressions, type and consti- tutionality, our century is delving into this difficult phase of the study of disease with calipers and the entire arma- mentarium of modern medicine to determine by actual measurements if definite types and constitutions really do tend to develop certain diseases more regularly than others. Draper found certain acromegalic characteristics in the “pernicious anemia people” and this, coupled with the phenomenon of familial occurrence suggests that, in many instances, our cases develop in individuals of a peculiar constitutionality. The occurrence of achlorhydria prior to the onset of pernicious anemia has been so fre- quently reported that it is now considered probable that most cases have previously been achlorhydric, either from birth, or at least for many years. This may or may not bear some relation to the dyspepsia or diarrhoea volun- teered by some cases as a symptom of long duration antedating their illness. GENERAL SYMPTOMATOLOGY 81 A hemorrhagic tendency is sometimes noted in the past history, such as bleeding hemorrhoids or uterine oozing, perhaps without demonstrable uterine lesion. This may be due to impaired coagulation of the blood or changes in the walls of the blood vessels. While the continuous loss of blood over long periods may appear to be an etiological factor in pernicious anemia later developing, such a fac- tor is sufficiently unusual to be credited with little more than exerting a functional strain, slight or severe as the case may be, upon the hemopoietic tissues, and of assum- ing, therefore, but a secondary contributory role, com- parable to that of sepsis, in the production of the specific anemia. Occasionally the operation of gastrectomy has pre- ceded the onset of pernicious anemia, in which case the obvious inference is made that by artificially instituting an achlorhydria one has placed the patient in a parallel position with other victims whose achlorhydria was the result of constitutional or physiological causes. As Piney (499) has pointed out, however, this surgical operation is usually performed for new growth, and in every case subsequently developing alleged pernicious anemia, metas- tases to the bone marrow must be considered. Chronic alcoholism may be prominent in the history, in which case it may have operated, as Hurst (307) sug- gests, by establishing an achlorhydria. By no means infrequently, a history of some abdominal disorder presents itself. This includes chronic stenosis of the digestive tube at various levels—the so-called “stric- ture anemia.” The writer saw a case of Hanna’s in which the disease followed oesophageal stricture from drinking carbolic acid. Tumors of the stomach and colon are also noted. In all such cases it is questionable how much influ- ence these lesions play in the etiology. It is the general experiance of clinicians that the great majority of patients, prior to the disease, have enjoyed 82 PERNICIOUS ANEMIA fairly good health and that the onset, however judged, was more or less sudden. Until the inception of their ill- ness they may be regarded as cases of uncomplicated achlorhydria. More careful inquiry may in many instances elicit the fact that some particular feature of the disease was actually present for months before the patient began to be conscious of anything wrong. This applies particu- larly to the sore tongue. The neurological manifestations, especially numbness and parasthesiae, quite often appear first and may remain uncomplicated by blood abnormality — for months. But the glossitis and numbness are really part and parcel of the established disease and, in patients present- ing either of these features independently, the additional discovery of achlorhydria should make the diagnosis pos- sible even before any anemia exists. In the majority of cases, weakness is the initial com- plaint and depends on the initial manifestation, viz., anemia. . In a fraction to be estimated at twenty to thirty per cent of the total, the patients confess that they have not been really well for months or even years beforehand, although none of the recognisable features of the estab- lished disease have been present. This prodromal debility may have consisted of an apprehensive neurosis border- ing on a psychosis. The writer recalls a patient who, for one year previous to developing pernicious anemia, drove his wife nearly to distraction by his introspective mood, his lack of business stability, and his never-ending quest of medical help from every doctor suggested to him. He had achlorhydria, pyorrhoea of a moderate degree, and a mild simple anemia due possibly to oral sepsis. Another patient, a married woman of forty, spent all her spare money on specialists although the reports on the heart, lungs, and nervous system all came back significantly negative. She was determined that something dreadful GENERAL SYMPTOMATOLOGY 83 was in store for her and the ultimate diagnosis of perni- cious anemia acted almost as a relief to her state of appre- hension. A third patient, though apparently a healthy man of forty-two, spent most of his time in bed or in his bed room for one year previous to the diagnosis, being quite disarmed to meet the world by his private conceptions of his own condition. But where the patient, prior to the disease, has been definitely under par, there have usually been present very definite symptoms referable to the digestive tract, par- ticularly an intractable diarrhoea, to which further refer- ence will be made. THE ONSET OF THE DISEASE The disease may declare itself gradually, revealing par- tial glimpses of its whole self over some months, so that the diagnosis may dawn on the physician as the true ex- planation of a tedious association with a vague condition. Again, it may begin suddenly in a seemingly healthy person with a moderate rise in temperature (101°) and be regarded as influenza until the pallor of the pigment- stained sclerotics suggests an examination of the blood. A high seasonal incidence during the summer months, July to September, has been observed by Hunter (301) and by Bartlett (29). Schauman and Saltzman suggest that the confining winter, with lessened sunshine, limited exercise, and comparative absence of green vegetables and fruit are sufficient to precipitate a potential breakdown. Spring pneumonia, tonsilitis, and neurasthenia are famil- iar to every practitioner. Unfortunately patients are seldom seen by physicians at the time of the onset of the anemia. It is to be under- stood that whereas the onset of the disease is usually a gradual process, there must be a time, in every case, where the blood count and the hemoglobin percentage actually begin to decline. Since weakness is the commonest symp- 84 PERNICIOUS ANEMIA tom which takes patients to doctors, and since weakness is due largely to anemia, the patients are usually quite anemic when first seen, with depressed numerical counts and with smear pictures characteristic of the disease. THE COMPLAINT OF THE PATIENT The great majority first consult the physician for weakness alone, although weakness is nearly always pres- ent to some extent even if the complaint is different. The next largest group consist of those who complain either of numbness or tingling in the extremities, of glossodynia or of dyspnoea. A smaller group still come on account of dyspeptic symptoms (belching, heaviness, vomiting, nau- sea, diarrhoea) and are occasionally diagnosed as cases of cholecystitis, a condition which is sometimes present, while many have been explored abdominally for appendi- citis or gastric ulcer. Other more unusual complaints have been noted, such as girdle pains, arthralgia, failing vision, dizziness, lack of mental concentration, hematemesis, hemorrhage from the bowel, and, strange as it may seem, retention of urine from advanced cord change. OUTLINE OF THE SYMPTOMS AND SIGNS Among the general symptoms, not particularly refer- able to any one system are fever and loss of weight. Fever, except in hospital patients, may not be much noted. Temperature charts of patients during severe phases usually show an elevation of some type. It may be irregular and seldom rise above 99.5° F, suggesting a low grade septic condition. It may show daily swings from 97° to 101° and remain thus for days hand-running. Again, it may be sustained around 99.5° to 101°. The presence of such fever has sometimes suggested typhoid or secondary syphilis. Some cases may begin with a fever as high as 101 F. Higher temperatures may occasionally be noted, especially in the chronic hemolytic anemia of GENERAL SYMPTOMATOLOGY 85 pregnancy, which may reach an elevation at times of 106° F. The cause of fever in pernicious fever is unex- plained. During remissions the temperature is either normal or subnormal. A transfusion of blood does away with any fever that may be present. The weight does not, as a rule, suffer as much decrease as would naturally be expected. The panniculus adiposus remains well preserved, giving the patient the well nour- ished appearance which, since the time of Addison, has remained one of the diagnostic features. It is a fallacious guide, however, since, as pointed out by Cabot (91) and by Bloomfield (50), some loss of weight occurs in forty per cent of cases. Minot (440) has noted that weight is not infrequently lost during relapses and regained again during remissions, and cites the instance of a man weigh- ing one hundred and eighty pounds who had twelve rather rapid relapses and remissions. In the first five relapses he lost between thirty-five and fifty pounds and returned to one hundred and eighty pounds with each remission. While at abdominal operations a substantial layer of bright yellow fat is usually seen in the abdominal wall, there is little doubt that some of the weight of these pati- ents is due to abnormal amounts of fluid in the tissues. In cases characterized by dehydrating diarrhoea, marked loss of weight occurs, but is quickly regained when the diarrhoea ceases. “The anemia itself sufficiently accounts for dyspnoea, palpitation, muscular weakness, mental irritability, dizzi- ness, and syncope. Glossitis, pyorrhoea, stomatitis, achlorhydria, anorexia, nausea, vomiting, and diarrhoea are referable to the digestive tract and will be discussed thereunder. The blood data, including features connected with the blood condition, such as weakness, the color of the patient, the enlargement of the spleen and liver, and the problem 86 PERNICIOUS ANEMIA of the pigment metabolism will be dealt with in the chap- ter on the blood system. Numbness, parasthesiae, spastic gait, paresis, ataxia, girdle pains, abdominal crises, and psychoses are refer- able to the nervous system and will receive attention in chapter VIII, while the changes found in the cardio-vas- cular, respiratory, and genito-urinary organs will be con- sidered in a separate chapter. DIFFERENT CLINICAL TYPES OF THE DISEASE The differences, sometimes clearly marked, to be seen in a clinical study of a group of cases, usually depend upon the fact that sometimes one system, sometimes another, presents the first symptoms, or presents some unusually striking symptom. Martin (404) presents three cases in one ward, the first showing sore tongue for eighteen months before anemia began, the second case starting with a virtual transverse myelitis and simple anemia, the third showing a rapid and grave hemolytic anemia with such marked muscular atrophy as seen in chronic poliomyelitis. Martin’s fourth case presented the blood picture of pernicious anemia and a foul mouth, but no other signs of the disease, and became normal after the removal of apical tooth infection. It is suggested that such cases as this last ought to be regarded as severe septic anemia and not diagnosed as pernicious anemia on the blood condition alone. Stern (593) presents four cases, in the first of which the drainage of an infected gall-bladder caused improvement a case of infection with dibothrio cephalus latus, a case with the nervous symp- toms preceding, and, last, a case of syphilis which was seen not to be pernicious anemia at autopsy. Unquestion- ably these are clinical varieties of severe anemia, but not all of pernicious anemia, a term used in a restricted sense to indicate a cryptogenic entity. GENERAL SYMPTOMATOLOGY 87 Whereas many of the so-called clinical types recorded are not instances of true pernicious anemia, and therefore the division into clinical types becomes less interesting, Archibald (13) as well as Minot and Lee (446) have suggested the only fundamental division of the disease into types. This division is based upon the balance main- tained between blood destruction and blood regeneration and is equivalent to a division on the basis of the course of the disease. This will be presently considered in the chapter on the blood system. CHAPTER -V THE DIGESTIVE SYSTEM Previous to 1890, special descriptions of the digestive system had been made in only nineteen cases, and by fourteen different observers, one of whom, Hale White (249), was responsible for six of the cases. Hunter alone by 1903 had made careful observations on twenty-five cases with histological examination of the digestive organs on seven, and by 1909 he had increased the series by fifty. Now that digestive signs and symptoms are regarded as inseparable from the disease, the paucity of the early observations seems surprising. Obtrusive as these manifestations sometimes appear, they are at other times very subordinate. The attitude of the early students is therefore not difficult to understand. If digestive symp- toms were mild they were regarded as secondary to the anemia ; if severe, they were considered as causative. This alternating viewpoint may be traced through most of the early articles. Anatomically, the intrinsic difficulties have caused a half century of indecisive descriptions, but more recently our position has become somewhat more stabi- lized. Physiologically, the observations on achlorhydria, begun in 1886, have been amply increased, and now con- stitute the most solid ground in the entire subject. In Combe’s (128) case the gastro-intestinal symptoms were very marked. Addison (5) noted the anorexia. In one of his cases in 1857, healed ulcers were found in the colon and rectum. Barclay (22) in 1851 reported a case with diarrhoea and sore mouth. Biermer (60) in 1871 noted follicular ulcers of the colon. From then until 1900 the chief observers were Fenwick (199), Flint (205), Ponfick (502), Schauman (553), Burger (83), Miiller (459), Quincke (510), Ejichhorst (165), Nothnagel, [ 88] Tae DIGESTIVE SYSTEM 89 Bramwell (63), Nolen (474), Laache (351), Pye-Smith (507), Henry and Osler (265), Cahn and von Mehring (94), Lewy (371), Kinnicutt (377), Rosenheim (536), Hunter (292), Ewald (259), Hale White (249), Mader (393), Mott (456), Halt, Eisenlohr (167), Nonne (472), Hayem (259), Pepper and Stengel (494), Mar- tius (406), Grawitz (220), Koch, Fletcher (204), Faber and Bloch (185). The chief point of contention has been the question of gastric and intestinal atrophy. Glossitis has been assigned a definite place in the symptomatology. Achlorhydria has been recognized as almost a sine qua non in the diagnosis. This, in very brief outline, covers the trend of events in the investigation of this particular system. SYMPTOMS AND SIGNS ARISING FROM THE DIGESTIVE TRACT At least eighty per cent of patients have symptoms referable to this system. Practically all patients have achlorhydria. The statement is therefore justified that the digestive system always presents some abnormality. French (211), inan analysis of sixty-eight consecutive cases in Guy’s Hospital, found that 45 had gastro-intestinal symptoms, 20 had chronic or recurring diarrhoea, 7 had gastro-intestinal symptoms dating back five years or more before the onset of the anemia. Thus,— Case 5, aged 57, had abdominal pain and diarrhoea since age of 13, Case 7, aged 44, had abdominal pain and diarrhoea since age of 19, Case 8, aged 51, had abdominal pain and diarrhoea since age of 25, Case 11, aged 56, had diarrhoea with bloody stools for five years previously, Case 17, aged 50, had diarrhoea for seven years previously, Case 36, aged 32, had diarrhoea for seven years previously, Case 38, “Bowels loose ever since he could remember.” 90 PERNICIOUS ANEMIA An analysis by Panton et al. (482) of one hundred and seventeen cases showed a distribution of digestive symp- toms as follows: Vomiting in 51, Diarrhoea in 30, Anorexia in 26, Epigastric pain in 24, Painful tongue in 8, Pyorrhoea in 47 out of 93, Carious teeth in 10 out of 93, Achylia in 33 out of 35, Hematemesis in 3, copious in 1. They state that in certain of their cases diarrhoea formed the prelude to the train of symptoms. The question of the relative frequency of digestive signs and symptoms to those of other systems, may be settled by the fact that achlorhydria is practically always present, whereas signs or symptoms of nervous involve- ment occur in eighty-four or eighty-five per cent of cases, and blood abnormality may be absent in ten per cent with- out preventing the diagnosis. Neglecting achlorhydria for the moment, even the other signs and symptoms are equally frequent with those of nervous involvement and almost as frequent as blood changes. But including achlorhydria, which is justifiable, the conclusion is quickly reached that gastro-intestinal changes are the most con- stant, and indeed the earliest, in the disease. Their virtual constancy in the face of possible absence of nervous or blood changes is the best argument for the popular gas- tro-intestinal conception of the etiology, and sufficient justification for those to whom the problem of nutrition assumes causal proportions. The symptoms, glossitis, pyorrhoea, stomatitis, anor- exia, nausea, vomiting, and diarrhoea will be considered in some detail, and in connection with the causative or the physical basis, if any, upon which each appears to rest. THE DIGESTIVE SYSTEM 91 THE MOUTH, ITS CONTENTS, AND THE OESOPHAGUS The symptoms arising from these organs are glosso- dynia, sore mouth and painful deglutition. The signs are glossitis, atrophy of the tongue, small ulcers and hyper- emia of the buccal mucosa, pyorrhoea alveolaris, dental caries, root abscess, and, presumably, oesophagitis. The first mention of the mouth condition is contained in a case-report by Barclay (22) in 1851. “Soon after her confinement she had sore mouth for which she applied for advice, and was ordered to leave off beer and meat, and confine herself to slops. To this she attributed her debility, as she had continued to suckle her child and had never been able to get up her strength properly.” Miller (459) mentioned five cases out of his series of sixty-two in which “there was a peculiar stomatitis. Small whitish ulcers, the size of a split pea, formed in the mouth, especially on and under the tongue. These were very resistant to local treatment, disappearing spontaneously or with remissions, but recurred without special reason, to the great discomfort of the patient, since they were decidedly painful and made mastication difficult or impossible.” Miiller connected these lesions with the blood state, assuming that some chemical sub- stance was secreted into the mouth, which by admixture with the saliva produced an irritating fluid. Quincke (510) noted redness and soreness of the tongue in some of his cases. Eichhorst (165) in one of his own seven cases found painful fissures on the dorsum of the tongue. Laache describes graphically some vari- ations of the stomatitis in three of his eleven cases. In one, the tongue had lost its papillae and, though smooth and clean, was hacked and painful at the borders. Both angles of the mouth were excoriated. Some of the teeth had fallen out and the rest were carious. This patient complained not so much of weakness as of sore mouth, 92 PERNICIOUS ANEMIA of loss of taste and the sense of smell. Another patient complained that not only was his mouth sore, but the soreness extended down the throat and prevented him from taking hot or hard food. Ewald (179) hesitated with regard to naming this condition. He considered the terms erythema bullosum, chronic neurotic stomatitis, pemphigus, herpes, and finally decided that follicular stomatitis was most appropriate. Hunter (292), beginning as early as 1889, has written extensively on the mouth condition, and has done more than all others combined to familiarize the profession with the occurrence of oral sepsis and to delineate the features of the glossitis. Perhaps no one has actually con- firmed Hunter’s statement that glossitis occurs in every case. Again, his deduction that the glossitis is due to the activity of a specific micro-organism responsible for the disease, cannot be accepted except as an obvious hypothe- sis. He believes that the glossitis is an emblem of the gastritis and enteritis (?) of the disease, all being caused by an unknown organism, whose chief characteristics are its ability to produce a periodic local reaction with com- paratively little permanent scarring, and to shift its activities downward so as to affect various regions of the digestive tube successively. He believes, moreover, that septic infection, particularly by a long streptococcus, is the antecedent event which prepares the tongue, the stom- ach, and perhaps the intestine for the reception of the hypothetical organism. He is persuaded, as everyone must be, that septic infection can, and usually does, occur in the mouth without the peculiar glossitis so common in this disease. During the past twenty-five years, the glossitis has been sufficiently observed and confirmed by others to merit its position as one of the specific features of the disease. Such confirmation comes from French (211), Christian (111), Houston, Willson (658), Hurst (307), THE DIGESTIVE SYSTEM 93 Symmer (605), Elders (169), Evans (177), Panton et al. (482), and others. Minot (440) would estimate its occurrence at forty-five per cent or slightly higher. Will- son and Evans (657) found it in only twenty-one per cent of the Johns Hopkins Hospital series. Osler (477) admitted he had not seen it at all commonly. Panton et al (482) found a painful tongue in eight out of thirty-four patients questioned; it was the first symptom in three of these; and they claim to have seen the typical glossitis in one case other than pernicious anemia. Some clinicians have noted a similar tongue condition in cases of arterio- sclerosis. The tongue in pernicious anemia is invariably smooth, clean, and moist. Evans (177) remarks: “A coated tongue and a diagnosis of pernicious anemia is a combi- nation to excite suspicion.” Coated tongues, even heavily furred ones, are common in certain hemolytic anemias, especially when the patient is very ill; but, as Evans also remarks, cases of pernicious anemia come to the autopsy table with tongues devoid of coating. The other features of the tongue depend upon the stage of the disease at which they are seen. In the most active stage of the glos- sitis, which may occur before any anemia is present, or during a first attack or a remission, the organ, on pro- trusion, appears fiery, deep red, sometimes of a crimson or carmine hue, and justifies the common description of “beef-steak” tongue. At this stage it may be painfully fissured in an irregular manner near the tip or along the median line. The whole organ may appear edematous with indentations along its border from pressure of the teeth. It is moist and glistening and may or may not be com- plained of. When it is lifted, the veins on the inferior sur- face are frequently engorged and varicose. Vesicles filled with serum may occur near the tip on either surface. At times when the blood is impoverished and all the mucosae are pale, the tongue presents a definite pallor, except along 94 PERNICIOUS ANEMIA the edges where a mottled reddish appearance is found. Often, at such times, on the dorsum, are areas roughly five millimeters in diameter, quite pink or reddish from local congestion. Simple ulcers with straight or shelving edges, three millimeters in diameter, or slightly larger, and with seropurulent bases, may occur on the tongue borders, on the buccal surfaces of the cheeks, or in the anterior walls of the vestibulum oris, reminding one of so-called cankers constitutionally occurring at times in healthy individuals. Finally there is the small-appearing, ironed-out, atrophic tongue with papillae dwarfed or absent, occurring well on in the disease, subject even still to periodic attacks of soreness and marginal redness, but quiescent,—a permanent hall-mark of the disease, and of equal clinical significance to the permanent macrocytosis sometimes persisting in patients with remissions of twenty years’ duration. Newham, Morris, and Manson-Bahr (471) emphasize as the really specific features of the glossitis the follow- ing points: general destruction of papillae, raw dorsal surface, general glossy appearance, and fissuring at the periphery of the organ. The description by the patients of their sensations vary from a mere confession of sore tongue to comparisons of many kinds. “Tongue raw and tender, looking like a piece of raw liver—causing great pain’ (Hunter). “As if rubbed with sandpaper.” “As if I had burnt it with hot tea.” “Feels raw, as if it had been cut.” Eating frequently becomes difficult, the tongue being especially sensitive to acid foods, sometimes to all foods. It is noteworthy that mouth washes, painting with argyrol, or other forms of local treatment are usually not helpful. The symptom is quite variable in its time of onset, and always marked by an irregular periodicity during its course. On the whole it is most troublesome and severe in the early stages of the disease, and much less so, or THE DIGESTIVE SYSTEM 95 absent, in the later stages. It may remain sore for 2 or 3 weeks at a time, then be comfortable for a month. Again, it may remain sore more or less continuously for months at a time, being worse on certain days than others. Hunter found the sore tongue more troublesome during remis- sions than relapses. Certainly it is often far from com- fortable during periods of remission and may, at such times, be volunteered as the only complaint. A clergyman in whom the symptom proved unusually annoying, habi- tually purged himself to gain temporary relief. As is well recognized, and as pointed out by Riesman (523), Schafer (549), and Strieck (603), glossitis may be the initial manifestation of the disease and exist for at least several months without other definite signs. Ries- man (523) has spoken of it as an inaugural symptom and records three such cases. The first was that of a woman of 54, complaining of a biting, stinging sore tongue. The normal coating had disappeared, leaving it raw and ten- der. The burning sensation spread to the inner surface of the cheeks and lips. As time went on, the tongue was chiefly affected and became streaked with red lines. She said it felt “as if it had been scraped and had no top.” Food tasted queer, and the character of the food made little difference. The tongue was carmine colored and tender to the touch. A small ulcer appeared on the left buccal cheek surface. The teeth were in moderately good condition. The blood counts were normal although some anisocytosis was present. Riesman prophesied she would develop pernicious anemia and the patient obliged him by later dying of it. He reports a second case of a woman with well-cared- for teeth who complained of a sore tongue, though it was never coated or ulcerated, for 3 years before the symp- toms of pernicious anemia began with weakness, at which time the tongue ceased to trouble her, but looked pale, small, atrophic, smooth, without coating, and showed en- tire disappearance of the papillae. 96 PERNICIOUS ANEMIA In a third case, diagnosed at first examination as per- nicious anemia, the patient confessed that for two years previously she had had a severe pain in the tongue and it had felt as if ulcerated, being worse in summer but not troublesome at the time of the examination. Riesman justly regards idiopathic glossitis as a fre- quent inaugural sign of pernicious anemia. Since this feature has been more carefully looked for, most city hospitals have one or more instances of patients seeking relief at the out-patient department for glossitis, and finally being located, after a number of months, in the wards with a diagnosis of pernicious anemia. The writer was told by a patient that six months before the first diagnosis, he had decided one evening to stop smoking, since although he had been trying new brands of cigars for two weeks previous to this on account of a sore tongue, the cigar he tried to smoke this particular evening hurt his tongue so severely that all pleasure was taken away from the habit. A married woman of 34, a patient of the writer’s, not seen for four months, at which time her only complaint was nervousness, stopped her car beside him on the street one day and asked if he could “do anything for a sore tongue.”’ He inquired if she had any other complaints. Pointing to her right foot she said: “It’s becoming so numb I can scarcely work the brake.” That afternoon her blood was examined. The hemoglobin was 60 per cent of normal, the red blood count was 5,000,000 per cubic millimeter, but the smear picture was perfectly character- istic of pernicious anemia. The patient said not only her tongue but her throat had been sore for two months be- fore this examination, but that the numbness in the foot had been noticed for only two weeks. A male cousin of this lady, himself suffering from pernicious anemia, had a sore tongue for three months before consulting a phy- sician for weakness. A man, 64 years old, president of an THE, DIGESTIVE SYSTEM 97 industrial company, continued to attend executive meet- ings for three months when his tongue was so sore that he could scarcely talk, although during this period fre- quent examinations showed absolutely no abnormality of the blood. Finally his hands and feet became numb and the blood condition heralded itself with marked anisocy- tosis. While glossitis may be the inaugural symptom and ap- pear for months previous to the recognizable disease, there are many cases who never recall having experienced the symptom at any time, although even in these cases examination may show the uncoated, smooth, atrophic organ. Occasionally one sees normal appearing organs with which only imagination could detect any fault. While the cause of this glossitis is obscure, its local ap- pearance,—hyperemia, vesiculation, mucosal and muscu- lar atrophy,—suggests a local infection. Microscopically even in tongues little complained of, there are found, post mortem, areas of marked mucosal atrophy with subjacent chronic inflammation. At certain points the mucosa has entirely disappeared. In mild cases the muscle remains normal. In severe cases, extreme muscular atrophy has oc- curred, the fibres being replaced with fatty connective tissue. Hunter from the interior of such tongues obtained pure cultures of a virulent, long streptococcus, and con- sidered this organism to be responsible for at least part of the glossal manifestations. The periodicity of the symptom suggests that if an or- ganism is responsible, it is a type of infection character- ized by a tendency to light up and subside, and to migrate from one portion of the digestive tract to another. The other view of the pathology would regard any micro-organism found as a secondary invader, and the atrophy as either due to body-wide metabolic disturbance, or to a chronic toxemia by a hypothetical poison responsi- ble at once for all the digestive, nervous, and blood abnor- malities. 98 PERNICIOUS ANEMIA Whatever may be the significance of the fact, the dental condition of patients with pernicious anemia is re- markably bad in most cases. It is the rare exception to encounter a case whose teeth do not show evidence of pyorrhoea. Once again, the exception robs the rule of any imperative significance, for pernicious anemia may de- velop in persons whose teeth are clinically and roentgeno- graphically normal, although it seldom does so. A serious simple anemia may result from root abscess alone, and may be cured by removal of the focus. On the other hand, persons with extreme pyorrhoea and filthy mouths and apical abscesses may show neither anemia nor any symptoms of ill-health. The whole factor of sepsis is to be considered in pernicious anemia as a frequent, but not imperative, influence bearing on the disease. Cases of pernicious anemia with removable sepsis, respond, after its irradication, by being less ill, showing fewer gastric symptoms, living longer, and exhibiting a more purely “‘pernicious” type of anemia. Not only the tongue, but, as stated, the buccal mucosa may show the peculiar reaction of which glossitis is the type. Some cases suffer from a persistent sore throat, and examination may reveal so marked an injection of the faucial pillars, the uvula, and soft palate as to suggest “in- fluenzal sore-throat.”” Presumably a similar reaction oc- curs at times in the oesophagitis as evidenced by the burn- ing sensation on swallowing. The writer has now under his care two first cousins, both with red hair, both 35 years of age, both acquiring pernicious anemia in the same year, though living 100 miles apart, and both suffer- ing conspicuously from glossitis, sore throat, burning on swallowing, and indigestion characteristic of gastritis, Both have achlorhydria and they are progressing at about the same rate. According to Schwenkenbecker (569) a type of dis- turbance similar to the glossitis may affect the nasal mucosa. THE DIGESTIVE) SYSTEM 99 Anorexia, nausea, and vomiting might be rationally ex- plained in the adynamic stages of the disease by the gas- tric atony known to exist. But these dyspeptic symptoms may, and frequently do, appear early, sometimes even before any diagnosis is possible. When of marked inten- sity and accompanied by fever and sweating, they give the most impressive picture ever seen in pernicious ane- mia, of an acute intoxication. The anorexia is usually at first of the nature of a mild aversion to certain types of food. In a few cases persons have been seen to change in their tastes, so that whereas ordinarily they were heavy meat eaters, they now become attracted more to sweet articles. Some, from being nor- mal eaters, become what dietitians call “tea and toast’’ people. Others become whimsical and “picky”. While some declare a special repugnance to pork and fats, more’ seem to specialize on fats. In a few instances, the anorexia is a positive abhorrence of all food, and it is only by the greatest art and tact, that even small amounts of nourish- ment can be given them. Under such circumstances as these, when the disease is fully established, it is quite evident that undernourishment or unbalanced diets have every opportunity to play what rdle they may in the total etiology. The tastes of these patients, however, during health and before falling ill, judged by a detailed study of their pre-disease diets over a decade, do not appear to differ in any remarkable way from those of their associates. In a recent survey conducted by the writer, it was found that from an absolute standpoint they were low in total calor- ies, high in fat, and lacking in protective foodstuffs. But it is questionable how many persons’ diets, in any com- munity, could bear the scrutiny of an expert dietitian, and it is reasonably certain that the 26 patients whose diets were examined were not more remiss than other persons in their vicinity who remained in health. The problem of 100 PERNICIOUS ANEMIA diet, as an etiological possibility cannot, however, be so easily dismissed. The aphorism “‘what is meat to one may be poison to another” may indeed find a potential appli- cation in pernicious anemia, where, owing to a peculiar constitutionality, expressed in the achlorhydria, the diges- tion of food may well prove to be of greater importance than the choice of menus. Nausea and vomiting are not really common. They occur most in the same cases that present diarrhoea. They have no essential connection with pernicious anemia, and, as Hunter (306) and Percy (495) have demonstrated, they depend in many cases upon disease of the teeth, gall- bladder, appendix, or benign conditions of the intestine, such as stenoses, and improve or disappear after the re- moval of the diseased tissues. It is permissible to regard them, in the majority of cases, as due to associated sepsis. They are probably not due to the achlorhydria, any more than the achlorhydria is due to the sepsis, for many vic- tims have had symptomless achlorhydria long before any evidence of sepsis or pernicious anemia appeared. Epigastric pain, fullness, and heaviness are not unusual symptoms. The pain, or burning sensation in the stomach often conforms to the type of symptoms noted in uncom- plicated cases of gastritis, presents no time relation to the taking of food, and may be entirely relieved by irradica- tion of foci of infection in the mouth or accessory air passages. Again, the gastric symptoms, the history and the anacidity, when the patient is observed prior to the onset of the anemia, may suggest cholecystitis, and opera- tion not only proves the diagnosis to be correct but rids the patient of symptoms. Some months later, all the mani- festations of pernicious anemia bring the patient back to the medical side of the hospital. Not only so, but even after the disease is plainly recognizable, cholecystitis, if it be kept in mind, may occasionally be detected, justifi- ably diagnosed, and the gall bladder removed with benefit THE DIGESTIVE SYSTEM 101 to the patient. Jones and Joyce (327) have reported thirteen cases of pernicious anemia in which the clinical, surgical, and post mortem findings established the pres- ence of both diseases. Cultures were made from the gall bladders in seven cases at operation with the following results: Streptococcus hemolyticus in 2, Staphylococcus albus (hemolytic) in 2, Stapholococcus albus (non-hemolytic) in 1. The observers suggest the possibility that such cases represent a group of anemias caused by bacterial alter- ation of the cholesterol of the cystic bile. Percy, who has cultured 7 gall bladders removed at operation in cases of pernicious anemia, obtained organisms (hemolytic strep- tococcus, B. coli, or streptococcus viridans ) in 4 instances. Such cases provide illustrations of superadded septic influences, and are not sufficiently common to be con- sidered essential to the disease under consideration. The epigastric pain is occasionally a prolonged and puzzling symptom, with no associated data, excepting the achlorhydria, to explain it. When it is associated with precordial pain, one may be tempted to regard it as of cardiac origin. At other times it may be referred from the spinal cord and be of the same nature, though of less degree, as the exceptional girdle pain and lightning pains noted in this disease. In such instances of posterior column degeneration, abdominal crises may occur and patients have suffered from fruitless laparotomy under these circumstances. Diarrhoea may characterize certain cases. The word is not used in this connection to signify a transient loose- ness of the bowels or a seasonal attack of dysentery, but to indicate a phenomenon, debilitating and intractable, extending over months and even years. Few normal per- sons, if any, and few patients with other diseases can 102 PERNICIOUS ANEMIA recall comparable diarrhoea. They may not volunteer the information. Sometimes it occurred so long ago (even 20 years since) that they fail to associate it in any way with their present condition, but recall it vividly when reminded. It may have been a matter of five stools a day over a period of two months, or of five stools a day for six months, or for three months every autumn for three years, etc. One patient, a woman of 50, had an attack lasting eight months in England, 12 years before develop- ing the disease in Canada, and a second attack 2 years previous to the disease, lasting one year. During each at- tack she vomited a good deal, and each attack gave place to obstinate constipation. Another patient, a woman of 39, had spent her first married winter, at the age of 20, day and night, mostly on the shovelled path to the out- house. The most striking example among the writer’s patients, was that of a farmer, aged 56, treated for two and a half years for “tuberculosis of the intestines’, who during this entire period, averaged 10 stools a day and became reduced markedly in weight and incapacitated for his work. While waiting for a shave in the barber-shop he found it necessary to absent himself so frequently that he was playfully accused of going to the lavatory to tipple from a supposed flask of whisky. Suddenly the diarrhoea ceased and gave way to constipation. Two weeks later while feeding a threshing machine he noticed marked tingling and numbness in his right arm. Within a month he was a definite case of subacute combined degeneration of the spinal cord, although even after a period of two years since the diagnosis he has never shown any anemia, simple or specific. In some cases, diarrhoea takes the form of a constant looseness of the bowels, with several stools per day, pain- less but urgent. The symptom is usually to be distinguished from the diarrhoea of sprue by not showing the same matitutinal THE DIGESTIVE SYSTEM 103 occurrence but by being spread out over the entire waking hours, and by the stools possessing a less fermentative character. The stools may vary in color from greenish to brown, and, on standing, the outer portion turns darker owing to the oxidation of the blood-derived pigment con- tained in them. Gross evidence of indigestion may be noted in the particles of vegetable and animal fibre passed. Not infrequently mucus, blood, and pus may be detected microscopically or occult blood may be demonstrated. Frank colitis of a mucous character may dominate the picture. In some instances, great rectal discomfort and a sense of local burning may precede the act of defecation. Diarrhoea in some form occurs in 20 to 25 per cent of cases either before or during the disease. Its cause is not clear. It resembles in all respects, even to the inflam- matory character of the stools, the diarrhoea seen so often in achlorhydria without pernicious anemia. It is impos- sible to regard achlorhydria as an imperative cause of such a symptom since it may be entirely absent both in pernicious anemia and in uncomplicated achlorhydria. Cabot is said to regard the diarrhoea as of benefit to the patient. Many practitioners have given up the attempt to check it. Purgation, which causes a temporary diarrhoea, sometimes is followed by a slight improvement in a pa- tient’s feelings. Few patients who have commenced colon irrigations wish to discontinue them. Purgation by drugs or by diet has formed a prominent factor in most of the many “cures”’. ANATOMICAL AND HISTOLOGICAL CHANGES OTHER THAN THOSE OF THE TONGUE Stenosis of the oesophagus has been reported at au- topsy. Fenwick (199) in 1870 demonstrated a well-marked and extensive atrophy of the secretory tubules of the stomach. He found no evidences of chronic inflamma- 104 PERNICIOUS ANEMIA tion, but noted fatty transformation of the glands. He considered the atrophy the result of a slow degenerative process and the essential cause of the disease, for in cases where it could be observed, digestion of food would pre- sumably be so interfered with that a general starvation of the tissues would result. Flint (205) concluded that some cases of severe idiopathic anemia depended upon degenerative atrophy of the gastric glands. Schauman (553) observed in a true case of pernicious anemia a virtual absence of stomach epithelium, the remaining glands being few and badly developed, while the whole tissue was characterized not only by fibrous tissue in- crease but by small subepithelial hemorrhages. In one case, Quincke (510) found the mucosa of the stomach very thin and the glands few in number, and in a second case, a diphtheritic colitis. Bramwell noted slight intes- tinal ulceration. Eichhorst (165) felt that any changes found were due to the anemia and of little consequence. However, in one of his cases the mucosa of the intestine, the upper part of the jejunum, the lower part of the ileum, and all the colon were edematous with small hemorrhages on the edges of the villi. Nolan (474) from a study of two cases believed the glandular degeneration to be the real cause of the anemia. Nothnagel claimed to show intes- tinal atrophy in 84 per cent of his corpses. Pye-Smith (507), in an analysis of 103 cases in 1883, noted the fre- quent occurrence of fatty degeneration of the gastric glands, occasional leucocytic infiltration between the tubules, anda thickening of the mucosa with parenchyma- tous atrophy. Henry and Osler’s (265) case showed atrophy of the gastric mucosa with complete destruction of the peptic glands over the greater part. Toward the pylorus, atrophy was less marked, but a small-celled infiltration, denoting a chronic interstitial inflammation, was plainly made out. “A careful study of the case justi- fies, we believe, the conclusion that a primary atrophy of THE DIGESTIVE SYSTEM 105 the mucous membrane does occur, and bears out the sug- gestion of Flint, Nothnagel and others, that certain of the cases of progressive pernicious anemia depend upon the profound alteration in the gastric tubules.” They mention chronic abuse of alcohol in this case as probably a cooperative factor in producing the atrophy. Lewy (371) thought the same histological picture re- sulted from ulcerative processes, responsible for the hem- atemesis in his case. In Kinnicutt’s (377) first case t1- bules were absent over large areas, while elsewhere tu- bular fatty degeneration, hyaline change, small-celled in- filtration were noted, although there was no fibrosis and the submucous coat appeared normal. In his second case the greatest destruction occurred in the deeper portion of the tubules, and was probably caused by a chronic inflam- matory process. He could not conceive of these changes as being due to a creeping ulceration. Some cases of perni- cious anemia might, in his opinion, be due to the impaired nutrition resulting from consequent functional debility of the stomach. Rosenheim (536) noted cystic degeneration of the mu- cosa as well as other evidences of catarrhal inflammation. Hale-White (249), in an analysis of the gross anatomical features in 17 cases from Guy’s Hospital post-mortem records, noted in 6 cases certain abnormalities. In the first case,—caecum edematous, two blackish small spots on the mucous membrane, almost diphtheritic in appear- ance; in the second—numerous ulcer cicatrices in the large intestine, or newly-healed ulcers, and a little recent diphtheritic inflammatory exudation in parts ; in the third, —thickening of the pyloric mucosa; in the fourth,—the scar of a small healed ulcer one foot above the caecum; in the fiith—a few follicular ulcers in the colon; in the sixth—several scars in the lower part of the small intestine. 106 PERNICIOUS ANEMIA Mott’s (456) case showed no definite microscopic changes in the stomach wall, although he noted that the mucous membrane was covered by a thick layer of glary mucus. Eisenlohr (167) noted in his case not only gastric atrophy but also a complete disappearance of glands and vuli in the intestine. He felt strongly that nutritional dis- turbances consequent on this extensive atrophy caused the disease, and furthermore that the process was one of primary, genuine atrophy. Nonne (472) found evidence of chronic inflammation both of the mucosa and submu- cosa of the stomach but could detect no glandular atrophy. Pepper and Stengel (494), as well as Hayem (259), noted atrophic changes in the stomach, although in one of Hayem’s cases, gastritis without atrophy existed. Ewald (179) emphasized the intestinal atrophy in addi- tion to the gastric atrophy, as the obvious cause of the disease. Martius (406) claimed to have noted pronounced atrophy of the intestinal, as well as the gastric mucosa in 2 of 17 cases, and adopted the view that the intestinal changes noted were decidedly the more responsible for the disease, and acted by disturbance of food absorption. Grawitz (220) found gastric atrophy, in one case mod- erate, in another marked, but was non-committal with regard to its significance. Koch found atrophy in both the stomach and intestine in five cases, thus confirming the observations of Ewald and of Martius, but felt that these findings were secondary to the anemia. Fletcher (204) discovered old inflammatory lesions of the colon, asso- ciated with patchy necrosis, hyperemia, and hemorrhages. These he regarded as due to neurotrophic disturbances. Hunter (292) made similar observations on the occur- rence of inflammation and atrophy in the wall of the stomach. Some of his descriptions are graphic as, for example, the following: “.. . IL found post mortem, marked inflammatory le- sions, both old and recent, in the mucous membrane of the THE DIGESTIVE SYSTEM 107 stomach. The inflammation was localized and, at certain parts, of the most intense description; the changes in the glandular cells and the infiltration with leucocytes recall- ing at once the similar appearances frequently presented by glandular structures, like the kidney, when the seat of a localized infection. “Furthermore, the swollen, pinkish, translucent appear- ance of the small lymphatic glands, lying on the wall of the stomach itself,—under ordinary circumstances scarcely visible to the naked eye,—pointed to some recent, as well as chronic irritation of the stomach wall itself.” Hunter’s conception may be briefly summarized as fol- lows: the gastric atrophy was the result of a gastritis due to septic organisms swallowed from the mouth, but the gastric atrophy was neither the cause nor the result of the disease. It was to be regarded as an associated con- dition. In order to explain the disease, Hunter hypothe- sized a specific infection by an unrecognized micro- organism for whose successful invasion the septic influ- ences had well prepared the tissues. As may be surmised from this brief review, the prob- lem of the gastro-intestinal pathology was in an unsatis- factory state at the close of the last century. Nothnagel, Ewald, and Martius all championed intestinal atrophy as the cause of nutritional disturbances which underlay the disease. It remained for Faber and Bloch (185) to detect the fallacy of this argument, by doing away completely with the conception of intestinal atrophy. By injecting five hundred cubic centimeters of ten per cent formalin into the peritoneal cavity immediately after death to pre- serve the tissues, they found that no atrophy of the intes- tine existed. What had given such an appearance was the post-mortem gaseous distention of the bowel. In experi- ments with dogs they demonstrated how easily this dis- tention might deceive. They showed, moreover, that the 108 PERNICIOUS ANEMIA intestine in pernicious anemia harbored no inflammation in its wall. This left still unsettled the problem of the constancy of atrophy and inflammation in the gastric mucosa. Faber and Bloch, again using the technique of formalin fixation, showed that while atrophy might or might not exist, chronic inflammation (in other words, gastritis) was always present. The observations of these workers have been confirmed by Lepehne (367). No observations on the intestinal his- tology should be seriously considered unless the methods of Faber and Bloch are employed. Such methods might do away with some of the more recent alleged findings of intestinal atrophy. Passey (485) has brought the method of biopsy to bear on the problem of the stomach condition. In one case of true pernicious anemia with achlorhydria, a section of the fundus, removed at operation, showed the oxyntic cells fewer than normal, very little atrophy indeed, but definite evidences of inflammation. This bears out the findings of Faber and Bloch, that whether atrophy is present or not, inflammation is always to be found. The more recent reports on pathological findings in the intestine deal largely with strictures, obstructions, and hypertrophies of the small bowel and with disease of the large bowel. Maynard and Sturton (411) report a case of an individual who nine years before the disease had suffered from colitis, and at autopsy a fine ring of small ulcers was found at a point five feet above the ileocaecal valve. The outer surface of the gut at this point showed a sharp line just as if an end-to-end anastomosis had been performed, although there had been no oper- ation. Microscopically, the mucous layer showed simple ulceration, while the other layers were normal. This ulcer- ated region caused no constriction of any kind whatever. Coates reports a case who showed at autopsy definite THE) DIGESTIVE SYSTEM 109 ulcers of the large bowel with a large ileocaecal gland draining the area of an ulcerated patch. Chapman and Duff (107) in April, 1921, opened the abdomen of a patient on account of a diagnosis of intes- tinal obstruction. The colon was distended but there was no recognizable cause for the obstruction. A colostomy was done and the patient remained in perfect health until August, 1923, when she returned complaining of dys- pnoea, and a diagnosis of pernicious anemia was made. They felt that the pernicious anemia was due to the same toxemia that had caused the paralytic condition of the colon. Faber (181) reported the first instance of intestinal stenosis with pernicious anemia in 1895. Meulengracht (429) has given particular attention to these cases of so-called “stricture anemia’. In 1921 he reviewed seven cases from his own experience and from the literature. In 1922 he (432) reported a further instance in a woman of sixty-four, with three strictures in a certain segment of the small intestine. Haden (248) has reported a case of clinically typical pernicious anemia occurring with a malignant tumor of the gall bladder and obstruction of the duodenum and colon. He considered it probable that the toxic agent responsible for the anemia had arisen as a result of the stasis or of some alteration in intestinal function, induced by the presence and perhaps pressure of the tumor. Ross (534) attended a physician who developed per- nicious anemia soon after swallowing a sharp piece of lamb bone. The bone lodged in the wall of the ileum and was afterwards passed with the stools, but the patient died of pernicious anemia. Kleeman (339) reports the finding of simple pyloric hypertrophy in pernicious anemia. The case was operated upon for a schirrhous growth of the pylorus. Percy (495) who has operated upon more cases of pernicious anemia 110 PERNICIOUS ANEMIA than anyone else has done, stated, in reply to a question by Gibson, that in seventy-seven laparotomies in this dis- ease he had never encountered pyloric stenosis. Mayo (413) has noticed the frequent development of a severe anemia, sometimes indistinguishable from per- nicious anemia, in disease of the colon, particularly of the proximal half. Whereas a few instances of pernicious anemia show various abnormal conditions of the intestine, such as those just described, most cases do not present such findings. Surgeons will agree that similar abnormalities are fre- quently found at laparotomy without any associated pic- ture of pernicious anemia. The obvious inference is that such abnormalities are not essential but may be contribu- tory, in some way, to the development of the disease. To sum up,—it is recognized that atrophy of the gas- tric mucosa may or may not occur; that gastritis always occurs; that intestinal atrophy and infection are not proved and much doubted; and that a few cases show stricture, ulcer, or neoplasm of the bowel. THE FUNCTIONAL STATE OF THE DIGESTIVE SYSTEM The ordinary bad state of the teeth, the gastric hyper- motility, giving place later to atony, and the fact that few patients are free from either diarrhoea or constipa- tion, are mechanical considerations that should not pass unnoticed. No particular study of the salivary secretion has been reported. Dry mouth is a common complaint and Hunter has observed salivation. The reader should refer to Chapter III for a review of the present position with regard to the gastric secre- tion. It was there emphasized that achlorhydria is prac- tically always present, that it precedes the disease, forms the obvious link in familial cases, and may be regarded as a constitutional dysfunction not dependent on atrophy or gastritis. THE DIGESTIVE SYSTEM 111 Kahn and Barsky (331) found abundant pancreatic ferments, and protease, amylase, and lipase in normal quantities in the duodenal contents and feces in pernicious anemia patients. Hurst (307) as well as McClure et al. (414) found the pancreatic function normal both as re- gards enzyme secretion and alkaline fluid secretion. Landau et al. (352) claim to have found pancreatic achylia in patients with pernicious anemia. Kahn and Barsky found liver function normal except that the sulpho-conjugation test showed a deficiency in hepatic detoxication. Thus the glycogenic and ureogenic functions were normal and Bauer’s galactose test as well as Strauss’s levulose test were négative. Arnoldi and Schechter (17) have attempted to establish a relationship between gastric secretion and the functions of the liver and pancreas. BACTERIOLOGY Panton et al. (482) found only twenty-one cases out of one hundred and seventeen in whom the mouth was free of sepsis. Out of one hundred and four cases, forty-seven showed pyorrhoea, ten had carious teeth, twelve had clean teeth, nine had good teeth, and thirteen had false teeth. Lloyd (383) has indicated the frequent associ- ation, in pernicious anemia, of tonsillar and nasal infec- tion with oral sepsis. Oscar B. Hunter (287) noted increased numbers of spirillary forms in the saliva. Kopeloff (347), from his bacteriological work on the stomach contents, showed that the gastric flora was the result of the oral flora, transferred by the swallowing of food and saliva. It is now agreed that the enterococcus, B. coli, and B. welchii are present in the stools in larger numbers than in health. B. welchii, however, is present in equally large numbers in the stools of cases of uncompli- cated achlorhydria. Seyderhelm has indicated an en- croachment of the colonic flora upon the ileum. This general overgrowth of the small intestinal flora probably te PERNICIOUS ANEMIA depends on an increased alkalinity of the ileum and jejunum, resulting from the lack of free HCl in the stom- ach, and cannot be regarded as specific to pernicious anemia (Nye, 475). PARASITOLOGY The following parasites have been found in the stools of pernicious anemia,—Balantidium coli (385, 323), Ankylostomum, Ascaris lumbricoides (567), Strongy- loides intestinalis (487), Taenia solium (145), Tricho- monas intestinalis and Monilia pisilosis (661). Whether these organisms are incidental findings or whether they may at times cooperate in producing the disease is a ques- tion quite unsettled. Where Dibothriocephalus latus is found, it may be considered the cause of the anemia, which is not true pernicious anemia. CHAPTER VI THE BLOOD SYSTEM The anemia, as betrayed by pallor and weakness, is clinically, and was historically, the most striking feature of the disease and directed almost all the early inquiry toward the blood system. Pernicious anemia came upon the medical public, through Addison’s description, at a time when leukemia was much in its mind, owing to the publications of Bennett and of Virchow. One of the first questions arising was whether any relationship existed between the two, particularly whether any increase of leukocytes occurred in “idiopathic anemia.” Some of the names then used to designate the more obvious cellular changes in pernicious anemia have been retained for general hematological description. The early studies of the blood and bone-marrow in this disease defi- nitely stimulated the normal studies of these tissues, which have resulted in the complex and controversial findings of the blood anatomists. During the seventy-five years of histological blood investigation on pernicious anemia the names of Pepper, Cohnheim, Quincke, Neumann, Osler and Gardner, Eichhorst, Laache, Ehrlich, Muir, Askanazy, Pappen- heim, Hunter, and more recently of Bunting, Brown and Peabody, and G. R. Minot require special notice. The time-honored arguments on the relative importance of blood destruction, blood production, and disturbed form- ation can scarcely be said to be settled. On the other hand, the characteristics of the blood picture are well known, and the histology of the fixed tissues has become familiar to students in general. [ 113 ] 114 PERNICIOUS ANEMIA SYMPTOMS AND SIGNS ARISING FROM CHANGES IN THE BLOOD SYSTEM The alterations in this system are responsible for the weakness of the patients, their color, and probably for the occasional enlargement of the spleen and liver. W cakness is a cardinal symptom in pernicious anemia, and constitutes the chief or only complaint in the majority of patients when first seen. It is usually accompanied by dyspnoea on exertion although some patients show a remarkable degree of adjustment to lack of respiratory pigment. Dizziness, defects of memory, lack of concentra- tion, melancholic moods, and headache may be attributed in some degree to mild trophic or oxygenation distur- bances of the cerebrum or meninges, depending on the anemia. The weakness is usually so gradual in its onset that at first it is not subjectively remarked. Ultimately a blood level is reached at which the customary energy demands are not met and fatigue becomes evident. When first seen complaining of weakness, the patient has red blood cells usually numbering two million per cubic millimeter or slightly more. It is possible to estimate, from a comparison of the few cases in which the blood has been followed from the beginning of the anemia, that these patients who come first on account of weakness have had anemia developing over a period of from two months to a year. No estimate can apply in all cases, since the rap- idity of the development of anemia varies in different cases, but it is certain that where weakness is the initial complaint anemia has already been present for some months. Most patients exhibit a lemon- or grapefruit-tinted pallor; a few, merely a pallor, wax-like and intense; a small group are definitely jaundiced. In uncomplicated cord involvement, the complexion is of a muddy gray color. The sclerotics, during phases of rapidly developing fae BEOOD SYSTEM 10S anemia, are usually bile-stained. Patients who have taken arsenic in large doses over a long period usually show some pigmentation of the exposed skin areas. The appear- ance of the patient is due to the anemia, to the staining of the skin and sclera with bile-pigment, and to the tendency to preservation of the subcutaneous fat. The lips are pale and, if not too pale, somewhat cyanosed. In spite of the pallor of the face, there ordinarily remains, over the cheeks, a ‘slight suggestion of pink. Duke and Stafer (157) showed that capillary blood counts were 17.6 per cent higher than simultaneous venous blood counts, owing to the lagging of macrocytes in the narrow capillary beds where the blood flow is slow and the pulse absent. This no doubt explains the suggestion of color in even these patients with marked anemia. It is said that pernicious anemia patients freckle or sunburn very readily. Leuko- derma and bronzing have been occasionally noted, but do not constitute essential features of the disease. The spleen and liver, not infrequently enlarged, are so unavoidably to be thought of in connection with the destruction of blood,sthat their enlargements may be asso- ciated tentatively, at least, with the blood state. Blood abnormality occurs in ninety per cent of all cases diagnosable as pernicious anemia. The blood system there- fore occupies a middle position between the digestive and nervous systems, the former of which is abnormal in one hundred per cent, and the latter in eighty-four per cent of all cases. Distinct emphasis should be laid upon the fact that changes in the blood, in the majority of cases, precede all other symptom-producing changes in any, or all, systems. Otherwise expressed, blood changes are usually the second abnormality to develop, achlorhydria being the first. While such a priority is very usual, it is not obli- gatory. Glossitis or nervous change may appear first, as has been previously stated. The blood changes may begin 116 PERNICIOUS ANEMIA concurrently with either glossitis or cord degeneration, or both. Blood changes, however, are never completely absent. Even cases of so-called “pure” subacute combined degeneration of the cord, which may continue without anemia for years, show anemia of this special type, if at no other time, as a terminal event. Abortive blood pictures strongly suggestive of perni- cious anemia have been seen in the course of other diseases, only to clear up and not return. Mayo (413) has noted this. Warley (666) had a case in a man of thirty-five, with gastric ulcer, who, six weeks after excision of the ulcer, was seen in consultation by competent physicians, and a diagnosis of pernicious anemia made. Within six weeks the anemia entirely disappeared, and his blood has been in good condition for three years since then. Rey’s (522) case may be another example. Terminal blood pictures, strongly suggestive of the dis- ease may occur in other conditions, as in that reported by Gynn and Abram (214 A) in a case of tuberculosis. In this case it is possible from the finding of B. welchii in the portal blood that a macrocytic anemia by this organ- ism was responsible, and that it was not a true “perni- cious” blood picture. The writer saw a puzzling, perni- cious-like anemia as a terminal phenomenon, during six weeks in a case of auricular fibrillation. Piney (499) has emphasized the belief that intercur- rent disease occurring during the course of pernicious anemia either partly or completely obliterates the typical blood picture, and cites Weinberg’s case. Faber (184) as well as Squier (587) makes use of this belief to buttress the argument that the disease is due to absorption from the intestine of foreign protein, such intercurrent dis- ease acting as a desentizer, similarly to the parenteral injection of foreign protein. THE BLOOD SYSTEM OL? THE REMISSIONS The remissions of pernicious anemia constitute one of the most impressive spectacles in the field of medicine. They are considered in connection with the blood changes because they are chiefly reflected in the blood state. Since they give character to the course of the disease and also naturally divide the disease into types, these two subjects will also receive attention in this connection. A remission is a spontaneous blood improvement, accompanied by general symptomatic improvement. It is more or less unlimited as to its length or brevity and to the degree of improvement, is virtually unpredictable, and totally unexplainable. Remissions are not obligatory, since some cases run either acute or chronic courses without improvement. The most acute course seen by the writer was that of a man of fifty-eight, who died five months after the first evidence of blood change had appeared. This is as acute as any case reported, but not more so. Panton et al. (482) found, in one hundred and three patients in whom the point could be determined, that eighty-four showed remissions while nineteen did not. The course of the disease is longer in those showing remissions than in the others. In the above series the average length of the illness with remissions was two and nine-tenths years, and without remissions eight-tenths years. This computation is based on the standard of the first symptom as the beginning of the disease. Of one hundred and eleven cases seen between 1909 and 1920, and subsequently traced, eight were alive at the begin- ning of 1923. The average expectancy of life, from the first symptom, is roughly two and five-tenths years. The number of remissions seen in various cases is from one to twelve, although two or three represent a fair average. 118 PERNICIOUS ANEMIA Some remissions are so short that the blood peak at- tained may be held for only a few days. First remissions have an average length of ten months, while subsequent ones are characteristically shorter and less satisfactory in degree of improvement. Relapses vary in length from a few weeks to several months, occasionally two years. While long relapses are seldom followed by improvement, and therefore consti- tute an unfavorable prognostic sign, they are, in excep- tional instances, followed by excellent remissions. In one of the author’s cases a two-year relapse was followed by a four-year remission. Long courses of pernicious anemia are due to long remissions. Five-year remissions are not so rare as for- merly thought. Von Willebrand (627) reports a remis- sion of 10 years’ duration, Stockton (600) one of 12 years, Speidel and Goss (586) one of 14 years, Swan (604) of 16 years, McPhedran (423) of 18 years, while Hurst (309) has two cases in whom unbroken remis- sions have lasted 20 years, one of the latter patients hav- ing recently donated blood for transfusion. The question of spontaneous cure in the long remissions is an open one with the balance of evidence in the negative. So far as reported, all these cases die eventually of pernicious anemia, although the normal expectancy of life may have been realized. The blood state during remissions will be described later. Briefly, marked increase of red blood cells and hemoglobin occurs, the amount of circulating bilirubin decreases, the color of the skin improves, and the sclerotics become freer of pigment stain. The morphology of the red blood cells approaches normal. The rapidity with which these improvements occur varies considerably in differ- ent cases, and the degree of improvement attained like- wise varies. It is exceptional to find either the erythrocyte count or the hemoglobin percentage as high as normal. Lae BLOOD SYSTEM 119 Former levels are, nevertheless, occasionally attained in long excellent remissions. However long or satisfactory the remission may be, the red blood cell morphology very seldom becomes normal. Remissions in which the macro- cytes entirely disappeared from the blood were phrased by Nageli “absolute remissions.” (In passing, it should be noted that remissions follow- ing the use of liver diet differ in some respects from an average spontaneous remission. Normal or even super- normal blood levels may be attained and cellular morpho- logy usually becomes normal. These points will be con- sidered presently in detail.) The strength of the patient may return sufficiently to enable him to resume his habitual occupation, even manual labor, although he is usually either forced to half- time employment or suffers greatly from fatigue. But many are able for considerable periods of time to do an amount of work which, in view of their blood level, is surprising. Glossitis frequently persists during all but the most excellent remissions, and exacerbations of glossitis may signal the beginning of a relapse. Dyspepsia usually im- proves. The spinal cord signs show, at best, an arrest of prog- ress. Ataxia or paresis are permanent. Some slight im- provement in the parasthesiae or numbness may occur and probably results from the small margin of functional recoverability possessed by nerve tissue, especially the peripheral nerves. Heretofore it has been unusual to see a patient in a long remission with quiescent but trouble- some ataxia, for the reason that cases with marked cord involvement seldom had splendid remissions. The effects of liver diet are gradually bringing out this type of pa- tient. One patient has worked as a charwoman for two years, her blood level above normal, her only disability being residual cord change with ataxia. 120 PERNICIOUS ANEMIA The first remission is usually and in all respects better than subsequent ones, for in the latter there is the ten- dency to less and less blood improvement. The final remis- sion may pass almost unnoticed. While this downward gradient in successive remissions is the rule, cases are seen in which the second or third remission is incompar- ably better than the previous one or ones. The patient’s health, in the first stages of the disease, roughly follows the hemoglobin level, for a remission is largely a blood improvement and a relapse is largely a blood failure. In arthritis deformans, diabetes, chronic nephritis, and asthma, there occur periods of spontaneous improvement little remarked because so unspectacular. In pernicious anemia the fluctuating symptom is the ane- mia, one calculated by its effect on the complexion and energy to make the phenomenon obtrusive and spectacu- lar in the extreme. Nervous involvement may first begin precisely at the peak of a blood remission. The real state of the patient, in the last stages, is actually so unrelated to the blood condition that death may occur with a blood level at which formerly the patient did manual labor. In such cases, nervous involvement is marked. Nevertheless, even in cases of subacute combined de- generation of the cord, long periods up to five years may elapse during which the symptoms and signs show no progress. A remission may begin so gradually that its exact begin- ning cannot be determined. In other cases it has been pos- sible to name almost the hour when the change occurred. At the depth of a relapse patients have been known to express a sudden feeling of improvement,—a peculiar euphoria and assurance,—which has proved a reliable indication of a remission. Patients have roused from coma and requested articles of food so substantial as to amaze their attendants. One such case of Harris McPhedran’s (424) at the Lockwood THE BLOOD SYSTEM 121 Clinic, woke from coma, which had been presumed fatal, and asked for ham sandwiches. Within an hour he made a second similar request and again ate the sandwiches; after a sound sleep he ordered and ate an exceptionally hearty breakfast ; three weeks later he was able to travel fifty miles to the clinic and was found to be in an excel- lent remission. One of Goldie’s (229) cases, after spend- ing the night in deep coma from which he could not be aroused, awoke in the morning and insisted on having his favorite article of diet,—fried potatoes. From that mo- ment he rapidly improved and has been in the most per- fect remission for a period of fourteen years. Goldie has noted severe nasal hemorrhage at the very depth of the relapse in each of four cases, conspicuous because of the exceptionally long remissions which they have since enjoyed. In one case, during what was regard- ed as fatal coma, the patient bled approximately a pint from the nostril, and, waking in the morning confessed to a remarkable euphoria and appetite. He has now been in a perfect remission for five years. On the basis of the balance maintained between blood destruction and blood formation, Archibald (13) and Minot and Lee (446) have suggested dividing all cases into the following groups: (1) Cases of a rather acute nature that progress steadily downward to a fatal termination, the blood destruc- tion always being in excess of blood formation, and never letting up. Such cases are not to be confused with acute hemolytic anemia depending upon sepsis, or with idiopathic aplastic anemia. (2) Cases characterized by marked or fair remissions in the course of the disease, occurring quite sharply or gradually. There is usually considerable blood destruction during relapses and little during remis- sions ; blood destruction may be absent during remis- sions. 122 PERNICIOUS ANEMIA (3) Cases that show persistently a considerable degree of blood destruction with relatively slow, never very striking, remissions, but which do not have serious relapses, except after years or terminally. These cases approach the condition of acquired hemolytic jaundice. (4) Cases of a chronic nature that slowly progress down- ward though interrupted by mild remissions and rarely by moderate remissions. This type merges directly into the next. (5) Cases of a continuous chronic nature that very slow- ly progress downward with usually no or only very slight remissions and with a sluggish, inactive mar- row. Chosroeff (114) made a similar, though much less satisfactory, division into the following groups, (1) chronic intermittent, (2) acute form, (3) aplastic form. The above division into five groups, upon the basis of the course of the disease, is the only justifiable separation of cases into various types. ANATOMICAL AND HISTOLOGICAL CHANGES Neumann’s (468) discovery of nucleated red corpuscles in the bone-marrow in a case of severe simple anemia marked the beginning of hematology (1868). Immerman (314) noted the reduction in the number of red corpuscles in pernicious anemia and thought this explained the fever. He felt justified in dividing the disease into a primary form, severe from the beginning, and a secondary form, in which the severe characters were added to an existing simple anemia. Pepper (493), the first to describe the bone-marrow, regarded the changes as a hyperplasia with so conspicu- ous a production of lymphoid cells that the disease could be classed as a pseudo-leukemia. Cohnheim (123) noted, in the shafts of the long bones, a disappearance of the THe; BLOOD SYSTEM 123 fat and an extension of the red marrow to take its place. Microscopically he found nests of nucleated red corpus- cles, oversized erythrocytes in large numbers, and an in- crease of the marrow cells. To him it was a picture of an embryonic type of blood formation, brought about by a reversion from the adult type and the cause of the anemia. Quincke (509) described the great differences in the size of the circulating erythrocytes and particularly the bizarre shapes of many of them, applying to this latter phenomenon, for the first time, the term poikilocytosis. He considered the peculiar features of the blood, as com- pared with simple anemias, a result of its greater inten- sity. Neumann (469) confirmed the bone-marrow findings of Cohnheim, but considered them the result of a severe compensatory effort to overcome the anemia and there- fore not of specific importance. Eisenlohn (167) pointed out, additionally, very small microcytes in the marrow as well as large and small “corpuscle-holding cells” (phago- cytic cells), but having found similar marrow changes in a case of gastric cancer he concluded that carcinoma of the stomach might be one of the many causes of perni- cious anemia. Osler and Gardner (480) described a case in which 3 or 4 phagocytic cells, each containing 5 or 6 red corpus- cles, were found in a single microscopic field of the verte- bral bone-marrow. Ehrlich (161) commented upon the fact that the liter- ature had previously contained but two cases of pernici- ous anemia showing nucleated red corpuscles in the blood during life. By his own staining methods he had then (1880) found them in all forms of severe anemia, irre- spective of the etiology, and described three forms,—nor- moblasts, of the size of red blood cells; megaloblasts, pre- cursors of the very large red blood cells; and microblasts, which were very small and rare forms. 124 PERNICIOUS ANEMIA Riess (524), in five out of seven cases, confirmed the finding of phagocytic cells in the marrow and regarded this as evidence of blood destruction in this tissue. Litten (379), in reply to Riess, stated that he had found such “corpuscle-holding cells” in many various diseases and did not regard them as distinctive of pernicious anemia. Mullendorff (458) confirmed their presence in two cases of pernicious anemia. Osler (479), in a study of the marrow in seventy-five cases of other diseases, frequent- ly found these phagocytic cells, especially numerous in tuberculosis, pneumonia, typhoid fever, and ulcerative endocarditis, and could not regard them as specific to pernicious anemia. Hayem (258) described megaloblasts under the name of nucleated giant corpuscles. Pye-Smith (507), thor- oughly committed to the strict conception of this disease as inviolately idiopathic, suggested that cases showing such marrow changes as had been described, were of a different nature and should be separated from the crypto- genic group. Grawitz (219) described the blood picture of perni- cious anemia occurring in two cases of sarcoma of the bone-marrow. Ehrlich (162) described degenerative changes in the red corpuscles, some of which we have come to regard as signs of regeneration. Geelmuyden (221) found that the marrow in perni- cious anemia contained many more nucleated red blood cells and pigment-holding cells than in health, and that the replacement of fatty marrow by lymphoid tissue, fre- quently seen in pernicious anemia, occurred likewise in other diseases. Fagge (190) regarded the marrow changes as second- ary and compensatory to the anemia. Litten and Orth (380) experimentally produced what they considered a comparable marrow by hemorrhage. THE BEOOD SYSTEM 125 Ehrlich (163) stated his belief that the bone-marrow was responsible for the anemia because embryonic types of cells were found in this tissue and because the granular leukocytes, products of the marrow, were numerically reduced. To him the appearance in the blood of these embryonic cells—the megaloblasts—was a sure sign of the ‘“‘pernicious” nature of the anemia. Hunter (292), reposing in the idea that compensatory hyperplasia explained the marrow findings, unquestion- ably did much to belittle the factor of faulty blood form- ation which the work of Ehrlich clearly revealed. Mott (456), from a study of three cases, while willing to admit a reversal of marrow to an embryonic type of blood formation, regarded the reversal as, purely compensatory. Rindfleisch (528) was overwhelmingly persuaded that the marrow betrayed a diseased condition by its megalo- blastic content, a feature not to be duplicated by mere physiological overactivity. Howell (279) fully described megaloblasts under the name of ancestral cells. Muller (460) was able, from embryological studies, to identify with the megaloblasts both the nucleated giant corpuscles of Hayem and the ancestral cells of Howell, and to show that these cells cor- responded with those found in the embryo. He believed that just as leukemia was a proliferation of the leuko- cytes, sO pernicious anemia was a hyperplasia of the red corpuscles. He cast out as hypothetical the idea of a toxin in the plasma and completely ignored the conception of hemolysis. To him, pernicious anemia was a primary dis- ease of the bone-marrow, the essential feature being the reappearance of embryonic cells, by which the cachexia was produced and the area available for normal blood formation was reduced. Muir (457) considered that the extension of the red marrow with the occurrence of many nucleated forms of 126 PERNICIOUS ANEMIA erythrocytes indicated, above all else, an increased re- generative activity. He noted that the most advanced changes in the marrow occurred in those cases in which the liver was most heavily siderosed. He noted the abnor- mal maturation of the megaloblasts but thought the embryonal reversion resulted merely from prolonged functional strain. Askanazy (21) claimed a lineal descent of normo- blasts from megaloblasts, the latter being merely the older forms. The basic staining of the megaloblasts was really a sign of youth, since it was constantly to be noted in the young red corpuscles of birds and reptiles and always absent from older animals. Contrary therefore to Ehrlich, polychromatophilia in the bone-marrow indicated regen- erative activity and not a cellular degeneration. Pappenheim (483) showed that the breaking up and disappearance of the nucleus within the cell body was not, as Ehrlich presumed, an evidence of degeneration, but in reality the normal process of blood cell maturation. The normoblast and megaloblast were not fundamentally dif- ferent, for all stages of transition could be traced between them. Moreover, great size and staining variations occurred among the nuclei both of the normoblasts and megaloblasts. Both Lazarus (354) and Klein (342) described baso- philic granules in red corpuscles. Engel (172) made necessary discriminations. Perni- cious anemia blood was a reversion not so much to a later embryonic type as to an early embryonic type; and, since he had found megaloblasts in the blood in severe infantine anemias, and Hammerschlag had found them in several cases of chlorosis, they were not pathogno- monic of pernicious anemia, but denoted rather the action of chemical products on the bone-marrow. Ehrlich and Lazarus (164) refuted Pappenheim’s contention as not being in accordance with clinical facts. Pappenheim’s THE BLOOD SYSTEM 127 (484) valuable paper of 1901 made it clear that the ab- sence of megaloblasts from the blood did not mean that the case was not pernicious anemia. He also pointed out that some anemias with normoblastic blood formation could be fatal, and others with megaloblastic blood form- ation (e.g., dibothriocephalus) were sometimes curable. Hence the term “pernicious” could not be identified with a particular type of blood formation. Warthin (636) subscribed to the idea that the marrow changes were compensatory to blood destruction and he demonstrated, for the first time, that increased phagocy- tosis of red corpuscles occurred in the hemolymph glands. Gulland and Goodall (240), after a careful study of the pathology in seventeen cases, felt that the marrow changes—‘“‘undue activity of the red cell and white cell formation”—were fundamental and causal and were pro- duced by the action of heterogeneous toxins. Bunting (82) confirmed the work of Pappenheim and of Engel on the occurrence of megaloblasts in normal marrows of animals and man, and he showed that a differ- ence existed between the marrow reaction to bleeding and to the injection of myelotoxic serum, hemolytic serum, and the poison, ricin. The chief difference may be described as follows,—whereas bleeding produced a moderate and transient appearance in the circulation of normoblasts, the injections produced a much greater and much more lasting appearance not only of normoblasts but of megaloblasts. By injecting these sera or ricin in small amounts frequently over a prolonged period, aniso- cytosis and poikilocytosis were produced, and the blood picture as a whole bore a striking resemblance to that of pernicious anemia. Bunting concluded that a circulatory hemotoxic poison affected not only the mature circulating erythrocytes but directly the bone-marrow cells. He be- lieved that some analogous toxin might be at work in pernicious anemia. By such an hypothesis, and by anal- 128 PERNICIOUS ANEMIA ogy with his ricin intoxication experiments in rabbits and dogs, he could explain as less severe those cases of pernicious anemia with more normoblasts in the blood and as more severe those cases with more megaloblasts in the blood. The so-called reversion of the marrow to the embryonic type became thus understandable and depended on a toxic destruction in situ of the maturer red cor- puscles, with a delivery of ill-developed young forms to the circulation. While no evidence of a toxin in pernicious anemia has yet been produced, this classical work of Bunting is one of the best arguments in favor of such an hypothesis. It will be evident that within this historical period, the main morphological features of the blood and bone-mar- row were described and variously interpreted. Further outstanding contributions will be mentioned in the fol- lowing pages. A.—The fixed tissues. The bone-marrow, spleen, liver, and hemolymph glands are concerned, in health as well as in disease, both with blood formation and blood destruc- tion. In the normal human adult, the bone-marrow is the only considerable erythropoietic tissue, and, in pernicious anemia, there is but little evidence of any resumption of blood formation by the extra-medullary tissues active in the embryo. Increased work in pernicious anemia is ac- complished by extension of the erythroblastic marrow within the bones. The spleen, liver and hemolymph nodes greatly increase their normal but moderate function of corpuscular destruction, by virtue of the clasmatocytes in their reticulo-endothelial tissues. These organs will presently require consideration in connection with the functional state of the blood system and the perverted metabolism of the iron and blood-derived pigments. His- tologically the spleen, liver and hemolymph glands present a picture chiefly of blood destruction, while the marrow presents a double picture,—of destruction, on the one THE BLOOD SYSTEM 129 hand, and of increased and abnormal formation on the other hand. The bone-marrow was described by Pepper (493) in the following words: “Marrow from the canal of radius appeared decidedly paler than in health; examined in fresh condition, it was found to be made up almost en- tirely of granular cells, round or nearly so, but varying in size from a diameter of 1-3500 to 1-2000 of an inch. Many of the larger of these cells exhibited a single dis- tinct spherical nucleus without the aid of reagents” (acetic acid). “Marrow from sternum quite red; very little oil; made up of crowded cells roundish and granu- lar ; on treatrnent with acetic acid, showing in most cases a single round faintly granular nucleus; the cells varying in size from less than a white blood cell to twice that size, the smaller ones preponderating.” Cohnheim’s (123) description was, in part, as follows: “So much the more astonishing were the marrow find- ings. For in all the bones, not only the vertebrae, sternum, and ribs, but also all the long bones, the marrow was in- tensely red in the diaphyses as well as the epiphyses and, moreover, without hemorrhages. Under microscopic ex- amination there was a corresponding absence of fat cells. Instead were found (1) colorless, so-called marrow cells, varying in size, many quite like lymph-cells, but very many relatively large with one or sometimes two large phlyctenular nuclei of epitheleoid constitution ; quite rarely also giant cells with several nuclei, and still more rarely, a marrow cell containing blood corpuscles. (2) At least in similar quantity, pigmented elements. Of these the usual bi-concave red discs formed the decided minority. More considerable was the number of globular, red non- nucleated cells of different dimensions, the smallest of the diameter of normal red cells, the largest more than double that of the unpigmented cells, and between these limits, every size. But most striking at first look into the micro- 130 PERNICIOUS ANEMIA scope and most common were the red nucleated cells varying in size, but the majority resembling the smaller epitheleoid marrow-cells. . . . I was particularly struck by the flexibility and elasticity of the larger cells which would draw out to a point at times if they were pressed between others on a slide, or wedged in, until, on being free again, they resumed their old form.” Osler and Gardner’s (480) description was as follows: “The marrow (of the sternum, ribs, clavicle, fibula and vertebrae) has a dark, violet-red color, is thick, some- thing of the consistency of spleen-parenchyma in fever. It contains: (1) Colorless corpuscles (marrow-cells) of various form, with granular protoplasm and distinct ve- sicular nuclei. Most of them are larger than the white cells and have usually only one nucleus. Besides, there are many small round elements like lymph cells. (2) Red cells of two sorts: (a) the usual bi-concave, somewhat irregu- lar-shaped discs, and many with long processes, as also observed during life. These form the great bulk. (b) Small round non-nucleated cells about 1-4 to 1-2 the usual size, similar to those seen in the blood. They are very numerous in the fibula where they form a good 1-4 of the colored elements. (3) Nucleated red cells (Neumann’s transition forms) are numerous in the sternum and ribs; in other bones mentioned they are very scarce or else, on account of the pallor of the red cells, too difficult to find. Generally they are larger than the usual red cells, but show like them a very uniformly colored stroma with a finely granulated nucleus. They exhibit round, not bi- concave discs, often with irregular outlines or one sharp process. Their staining is usually just as deep as the ordi- nary red cell, sometimes deeper or paler. The nuclei are round or elliptical and occupy 1-4 to 1-2 of the cell’s volume. They are solid granular and appear stained in the cells. Not one nucleolus could be seen. The position of the nucleus in the cell was varied but soon after death it ap- THE, BEOOD SYSTEM 131 peared centrally anchored. In the tests on the following days, on the contrary, many nuclei lay on the margin (peripherally) and others had passed out of the cells and seemed now quite unpigmented. . . . (4) Blood-corpus- cle-holding cells very plentiful in the vertebral marrow, where in one field 3 or 4 appeared each holding 5 to 6 red cells with plainly preserved pigment and definite shape. They are rare in the sternum and ribs and quite lacking in fibula and clavicle. (5) Of giant-cells (myelo- plaxes of Robin) 1 or 2 were found in the sternum and ribs. (6) Fat cells in the clavicular marrow, not elsewhere (i.e., in sternum, ribs or vertebrae). (7) Everywhere in the marrow 12-30 hours after death, Charcot’s octahe- dral crystals were to be found.” Gulland and Goodall’s (240) summary was as follows: “Tn all cases the marrow was hypertrophied and dark red as seen with the naked eye. In every case, however, we found a smaller proportion of red cells or, perhaps more correctly, a larger proportion of white cells than might have been expected. Thus, in only six of the seventeen cases, red cells preponderated; in five, myelocytes; in five, lymphocytes; while in one case lymphocytes and myelo- cytes were present in equal numbers, and together were the most numerous elements seen. “In every case there was marked evidence of blood destruction, as shown by red and white cells which had been ingested by large phagocytes and, in seven of the cases, pigment showing the free iron reaction was pres- ent. Giant cells were found in all cases but were seldom normal. They were usually small and degenerated. Eosin- ophile cells were very numerous, except in two cases. Basophile cells, some of which had the large granules noticed in the spleen and intestine, were seen in three cases.” While marked erythroblastic activity with extension of the red marrow is a point upon which all may agree, this i392 PERNICIOUS ANEMIA phenomenon does not usually, if ever, affect all the bone- marrow of the individual. In the cases of Archibald (14) and of Tidy (612) certain portions of some of the long bones, e.g., femur, tibia, and ulna showed complete aplasia, although the marrow of the other bones in each case proved erythroblastic. Arthur Sheard (576) found in each of two cases, that the bone-marrow had not under- gone uniform hyperplasia throughout. In certain portions of the long bones, notably the greater part of the tibia, the lower portion of the shaft and both extremities of the femur and humerus, and also the lower half of the radius, the marrow had failed to react to any appreciable degree. In the second case, limited areas of these parts were defi- nitely aplastic. The color of these portions of fatty mar- row was light yellow and not the bright canary yellow which characterizes the fat in other parts of the body. These findings suggest, as Sheard remarks, that in many more cases of pernicious anemia than has heretofore been supposed, the erythroblastic reaction of the bone-marrow does not occur in a uniform manner throughout the bones of the whole body. A further point regarding the distribution of the eryth- roblastic portions of bone-marrow is of interest. It has been shown in the normal adult that the red cellular mar- row of the humerus and femur is confined to a small area at the upper end (diaphysis) of each bone, while the whole radius, ulna, tibia and fibula are filled with fat. The surprising feature in Sheard’s two cases was the absence of erythroblastic reaction in those portions of the humerus and femur which normally should contain some amount of erythropoietic activity, and the presence of such reac- tion in the greater parts of the shafts of these bones, which normally contain little or no demonstrable cellular tissue. In any given bone, therefore, the condition found may be complete aplasia, complete erythroblastic activity, or THE BLOOD SYSTEM 133 distinct areas of both conditions. There is another type of marrow sometimes seen,—segregated foci of red-mar- row ona generally aplastic field. The marrow extends at the expense of the fat and even the bone trabeculae until it occupies all or some portion of the shaft. The fat and bone are removed by a process of softening and simple atrophy, not by the activity of osteo- clasts or leukocytes. Active marrow is of a dull red or chocolate color. Histological sections or stained smears show a confus- ing aggregation of various types of cells among which are to be distinguished red corpuscles in various stages of development, white corpuscles in various stages of development, phagocytic cells, and giant cells. The definitive erythrocytes show all the abnormalities of size and shape that they exhibit in the circulation blood —macrocytes, microcytes, poikilocytes. Among the nucle- ated red corpuscles may be distinguished examples of all the developmental stages,—(1) megaloblasts or parent cells, larger than any erythrocytes found, may reach twenty w in diameter, and consist of basophilic cyto- plasm with a large reticular nucleus usually placed cen- trally ; especially large megaloblasts are sometimes termed gigantoblasts. (2) Erythroblasts are smaller but similar in appearance to the megaloblasts, and are paralleled in size by some of the larger macrocytes. (3) Normoblasts, somewhat larger than normal erythrocytes, have cyto- plasm taking either the acid or basic stain, and nuclei, central or eccentric, which have lost the reticular char- acter and become pyknotic. The relative numbers of non- nucleated and nucleated red corpuscles varies greatly in different marrow specimens. Among the nucleated types, some specimens show a preponderance of normoblasts, others of megaloblasts, When megaloblasts and the larger erythroblasts dominate, it usually is in a case which gives evidence otherwise of an acute or severe course, and these 134 PERNICIOUS ANEMIA cells represent a physiological dislocation bringing the marrow nearer to the early embryonic type. Preponder- ance of normoblasts indicates less severe stress, the marrow not having been forced to the limit of its embar- rassment. The presence of nuclear remains within the cytoplasm, revealed by vital staining within the macro- cytes, is taken as evidence of abnormal maturation of the nucleated predecessors. Thus, reticulum, Cabot ring bodies, Howell-Jolly bodies, stippling, extruded nuclei, and polychromatophilic cytoplasm indicate prematurity and physiological disability, resulting in part from the necessity of short-cuts from the normal, more orderly type of development. The white corpuscles, especially the myeloblasts and myelocytes, and also cells of the lymphoid series, show, in the marrow, decided leukoblastic activity. Sometimes the granular series, sometimes the lymphoid series predomi- nates, the one over the other. Eosinophilic cells are, as a rule, rather uncommon. This mysterious activity of the white corpuscles has been a confusing factor, not only by obscuring observation of the red corpuscles, but in the earlier studies, by suggesting a relationship to the leuke- mias. A distinct parallelism exists between the behavior of the red corpuscles and the granular white corpuscles, viz., that in spite of this narrow evidence of hyperactivity, fewer cells of both kinds are delivered into the blood; and again, it is precisely at the same time—during blast crises—that the primitive cells of both series appear in largest numbers in the circulation. Phagocytosis of corpuscles by the clasmatocytes of the reticulo-endothelial system of the marrow has received fresh investigation by Peabody and Broun (489). They confirmed the work of Osler and Gardner (480), that an abnormal degree of phagocytosis of red blood corpuscles occurs in the bone-marrow of pernicious anemia. They interpret the non-retention of hemosiderin granules by the THE BLOOD SYSTEM 35 clasmatocytes as an indication of a very active, destruc- tive process in this disease. Mononuclear giant cells are relatively few as compared with normal and usually smaller in size. Such abnormal- ity of the megakaryocytes may, on Wright’s theory of the origin of blood platelets, explain the thrombocytopenia which accompanies the well-established anemia. It might naturally be supposed that, during remissions, when a more nearly normal number of erythrocytes is being delivered to the blood, that the marrow, thus giving evidence of physiological improvement, would likewise show an improved histological and anatomical picture. Comparatively few contributions on this point have appeared. Zadek’s (669, 679) case which died of inter- current disease during a remission was examined, but possibly not extensively enough to rule out the error aris- ing from the phenomenon described by Archibald and by Sheard. The right femur, left tarsus, and sternum were investigated. The right femur showed fat cells and nor- mocytes preponderating, very few normoblasts and no megaloblasts. Among the white blood cells, the granular series slightly outnumbered the lymphoid series, with ten per cent of the total white count made up of myelocytes, and no myeloblasts. In the sternum, isolated megaloblasts and a plentiful supply of myeloblasts were encountered. These findings can scarcely be regarded as conclusive evi- dence of a return to a normal picture. Peabody and Broun (489) found in a single case of a patient dying in a remis- sion that phagocytosis of red blood corpuscles was not a striking feature. From present information the conclusion is drawn that the bone-marrow during remissions appar- ently shows less of the early embryonic features and less phagocytic activity than during the active periods of the disease. The spleen’s softness, due partly to post-mortem change, was noted by Combe (128) in 1822. This organ in per- 136 PERNICIOUS ANEMIA nicious anemia received comparatively little attention dur- ing the last century. Pepper (493), in one case, found it somewhat enlarged (half more than normal), the pulp dark and softened, but no leukemic lesions present. In a second case, the spleen was “slightly enlarged; the cor- puscles healthy; on handling it, distinct crepitation was perceived, owing to decomposition of its tissues, despite the general good preservation of the corpse. The splenic pulp was soft and purplish, without any leukemic patches or enlarged Malpighian corpuscles. Under the microscope the field was crowded with small round cells (smaller than the majority of the cells in the marrow) spindle-shaped cells and very pale red blood globules.” Warthin’s (636) eight cases showed a great range of differences in the splenic findings. The following three examples best illustrate this variability: Case VII, Spleen about four times the normal size; capsule stretched, smooth. On section, deep red in color, very soft. Trabe- culae and follicles covered by pulp. Microscopically: atrophy, acute and chronic congestion, hyaline vessels, increase of reticulum of pulp, great decrease of lympho- cytes in pulp; the majority of the cells in the pulp are large mononuclear cells of varying size and shape. Many of these contain pigment, very little of which gives the iron reaction. They also contain red blood cells in different stages of disintegration. Larger cells containing two to three nuclei are also numerous in the reticulum and si- nuses. A few large giant cells resembling those of the bone marrow also found. Many of the larger mononuclear phagocytes are colored brown or yellowish; in others the pigment is granular. Small collections of granular pig- ment of a brown color are found throughout the pulp. Only a small portion give the iron reaction. Case III, Spleen weighs two hundred and eight grams; about nor- mal in size and shape. Notches on the anterior margin well marked. Capsule slightly thickened and wrinkled. THE BLOOD SYSTEM 137 Consistency soft. On section, the pulp is bluish-red, stroma slightly increased, follicles somewhat diminished in number but of fair size. Microscopically: atrophy and chronic congestion; moderate hemosiderosis. Case V, Spleen weighs ninety-six grams. Small, triangular in shape; small notch at the lower portion of the anterior margin. Capsule thickened and wrinkled. Small white pearly nodules scattered over the surface. Microscopi- cally: marked atrophy ; no hemosiderosis. Gulland and Goodall (240) condensed their splenic findings as follows: No marked or constant change was found in connection with the Malpighian bodies. The pulp showed considerable variations as regards the kind of cell preponderating. In most cases there was congestion, and normoblasts and megaloblasts in varying numbers were noticed. In a few cases lymphocytes definitely preponder- ated in the pulp. At least half the cases showed large giant cells ingesting red corpuscles, and sometimes also white cells; giant cells resembling those of the bone mar- row were seen in one case. In two cases there were numer- ous basophile cells in the pulp, and some of these showed the dropsical appearance noticed in those of the intestine. Pigment was present in varying amount in all the cases. Usually a certain proportion of this gave the iron reaction —1in some cases in very large amount. The pigment was found free in the pulp or in leukocytes or endothelial cells. Eppinger’s idea of hypersplenie, based on constrictions of the sclerosed splenic artery, as the cause of the disease, can be dismissed on account of the facts that arterioscler- osis of this organ occurs in non-anemic diseases, and, in any case, could not account for the remissions. Mayo (413) found the spleen frequently smaller than normal at autopsy but almost never smaller than normal when removed at operation. The average weight of fifty spleens at operation was four hundred grams, not includ- ing two exceptionally large ones, of two thousand two 138 PERNICIOUS ANEMIA hundred and twenty and one thousand six hundred grams respectively. He considered it likely that the spleen was enlarged in the earlier stages of the disease and con- tracted in the terminal stage. He was certain that the size of the spleen had no relationship to the severity of the disease. It is generally considered that, whatever its size, this organ presents a combined picture of phagocytosis, hemo- siderosis, and accumulation of abnormal red blood cor- puscles. Slight evidence of embryonic blood formation is, at times, seen and represents one of the organism’s attempts at extra-medullary hematopoiesis. The liver is considerably enlarged in about half of the cases. In some such cases, passive congestion is a factor, as evidenced by the “nutmeg” appearance, but in most cases the enlargement is to be attributed to the disease itself, and specifically to the increased blood destruction occurring within it. The degree of fatty degeneration varies considerably in different cases, but is always suffi- cient to leave a fatty smear on the knife after sectioning it. The fatty change is to be seen at the centre of the lobules while deposition of pigment occurs at the periph- ery. In all cases of pernicious anemia the liver gives the characteristic Prussian blue reaction for free iron, al- though in some more intensely than in others. In the middle zone of the lobules, the liver cells present a necrotic appearance. Between these rows of necrotic cells the wid- ened capillaries present, within their endothelial cells, engulfed red corpuscles and often excessive aggregation of hemosiderin granules. It is a combined picture of parenchymatous degeneration and phagocytosis by the reticulo-endothelium. Changes in the lymph glands, first mentioned by Fer- rand (196) and by Quincke (510) received exhaustive attention from Warthin (636), who presented as the constant findings “dilatation of the blood sinuses and THe BLOOD SYSTEM 139 evidence of increased hemolysis, as shown by the in- creased number of phagocytes, containing disintegrated red blood cells and blood pigment.” We must regard the hemolymph nodes of the body as organs capable at times (not only in pernicious anemia) of greatly exaggerating their normal but moderate function of blood destruction and also of harboring centres of extra-medullary blood formation, even of an embryonic type. B.—The fluid tissue. The bloodlessness of these pati- ents at autopsy represents the true gross pathology of the blood system and was the first feature of the disease to be remarked. The heart at autopsy may contain as little as one ounce of blood, which has a very thin, watery appear- ance, the clot being soft and the serum stained with bile and blood pigments. The histological features which constitute the blood picture of pernicious anemia are to be presented as partly numerical and partly morphological. Since the estimations of the numbers of the red and white blood corpuscles, of the blood platelets and of the percentage of hemoglobin are procedures for measuring the functional state of the blood system, they will be considered under the next section. The typical blood picture of pernicious anemia may be defined as one of severe anemia in which the red blood corpuscles tend to be much larger than normal, character- istically oval in outline and well filled with hemoglobin, and in which blood platelets and polymorphonuclear leu- kocytes are reduced in number, with the appearance, at times, of nucleated red corpuscles. This brief description must be supplemented by many remarks on the vari- ations in shape of the erythrocytes, and other points of importance. Such a typical blood picture occurs in the large major- ity of cases. Levine and Ladd (370) found it in seventy- six and nine-tenths per cent of one hundred and fifty 140 PERNICIOUS ANEMIA cases. Christian (112) roughly estimates that a typical picture is to be found in but sixty per cent of cases. Such figures are based upon what may be found in the first examination of patients. A blood picture, more or less well-developed, will be found, however, at some stage of the disease in every case, with the single exception of a very few cases of fulminating cord change who die quickly without anemia. Whether the blood picture is typical or not, it will not suffice in itself to make the diag- nosis, but must be correlated with other system changes, viz., those in the digestion and nervous systems. In its typical, or fully-developed state the blood picture, while not pathognomonic, is almost so. Other pictures resembling it more or less closely will be discussed in the chapter on diagnosis. Even the smear appearances are so characteristic and so nearly limited to this disease, that one would be able from a stained smear alone to diagnose the disease with a high degree of correctness. While it is never advisable or necessary to base the diagnosis on the smear alone, the fact that it can be done with so high a degree of probable correctness, indicates a high degree of specificity in the strictly-evaluated morphological features. (a) The red blood corpuscles. These present the two important and essential features,—anisocytosis and mac- rocytosis. Variations in size and the presence, especially, of cells larger than normal, constitute the ground pattern upon which all other characteristics may be set. Anisocytosis of a mild character may antedate the actual anemia. It sometimes appears before any fall in the erythrocyte count has occurred, and sometimes, but more seldom, before the hemoglobin percentage has started to fall. A very mild degree may be found in achlorhydric individuals, and in those suffering addition- ally from arthritis deformans. This mild anisocytosis, while not greater than that of some simple anemias, is distinctive because of its occurrence without anemia. A THE BLOOD SYSTEM 141 similar phenomenon in a simple anemia would be accom- panied by marked depression of the erythrocyte count and the hemoglobin percentage. Such an early anisocytosis, accompanied by achlorhydria, is, next to increased vol- ume index, the earliest indication of incipient pernicious anemia. Anisocytosis depends, of course, upon the fact of the presence, at one time, of three graded sizes,—microcytes, normocytes, and macrocytes. The degree of anisocytosis varies with the severity of the anemia. The most marked degrees are found during periods when the anemia is atom 7 most pronounced and when the blood serum contains the most bilirubin. This intensification of the anisocytosis is due more to the Fic. 1.—Curve of red blood corpuscle diameters eee of in case of pernicious anemia, compared with macrocytes than to normal (J. W. Shackle and A. C. Hampson id » 252). a decrease in size of microcytes. At such times, a most remarkable degree of size variation may occur, somewhat greater than has been found even in those anemias which resemble the Addisonian most closely. The phenomenon is strikingly illustrated in a form of graph devised by Price-Jones (503) which shows the number of cells occurring at any diameter. It will be noted that normal blood presents a well- pointed and narrow peak, whereas pernicious anemia blood shows a much wider and flatter curve, the highest point of which lies well to the right of the normal peak. It shows at a glance the occurrence of both abnormal smallness and abnormal largeness, and, particularly, the Aoasson's Anata q c & 8 = S z 2 OUAHETERS Ww fl 142 PERNICIOUS ANEMIA preponderance of macrocytes. This latter feature causes an increase in the average diameter of the red blood corpuscles in pernicious anemia. Price-Jones (503) found that erythrocytes from nor- mal blood had an average diameter of 7.21 yu. This was based on the measurement of ten thousand cells from twenty healthy persons. The erythrocytes from pernicious anemia blood had an average diameter of 8.24 yu. This was based on the measurement of ten thousand cells from twenty patients. The graph shown in Figure 2, indicates, in addition to these facts, that in the simple anemia following hemor- rhage, the curve is only slightly flat- iit o6ccntsenena tened and favors | 10 a Fe ge the microcyte side. 90 The observations | 2°° 370 i S of Price-Joneshave | s¢ sooomeccas |] idooaidiaceie been confirmed by | * (Aon 20€ASES OF - ANAEMIA. several physicians 7 , = 824 ft (395236; 252.308) and indicate that the diameters of the red blood cells : Sr DIAMETERS IN AL in pernicious ane- Fic. 2.—Curves of red blood corpuscles diame- mi j j ters in healthy persons, anemia following la 1M relapse give hemorrhage, and in pernicious mer & 1 ie mean diameter of red corpuscles rice- a very wide per ara centage frequency curve as compared with normal blood or blood in simple anemia. Bell, Thomas and Means (39) found that in spon- taneous remissions, or those induced by treatment other than liver diet, the diameter-percentage-frequency curves showed an approach to normal but indicated that the changes typical of pernicious anemia were still present to some degree. THE, BLOOD SYSTEM 143 Medearis and Minot (427) found that in fourteen cases in whom remission followed the use of liver diet, the mean diameter of the red blood cells became normal in eleven cases and even less than normal in three cases, when the red blood cell count increased to between 4,200,- 000 and 6,300,000 per cubic millimeter. Further information, particularly agreeable to the mathematical mind, may be gained by computing the median diameter and the diameter dispersion. The median diameter differs from the mean or average diameter. The median diameter is such that if its value be X, then half the cells present have diameters greater than X, and half have diameters less than X. In order to determine the median diame- ter, a summation frequency curve is first plotted on ey = & s K = Ss Ss = Q 6 MICRONS Fic. 3.—Percentage frequency curves for the diameters of the red blood cells in two cases of pernicious anemia during relapse and marked remission, contrasted with normal (Medearis and Minot). arithmetic proba- bility paper where the figure for the Heavy solid line (- ) normal, averaged data. a A ( ) case 7 (table 1), red blood cells 1,200,000 per cubic millimeter fifty percen tile Al (-------- ) case 7 (table 1), red bloed cells 5,020,000 per cubic millimeter . B (--n--en eee ) case 2 (table 1), red blood cells 2,400,000 per cubic millimeter Sra d e gives the B! (-e-e-e-2-2-*) case 2 (table 1), red blood cells 4,500,000 per cubic millimeter desired determina- tion. This median diameter represents the centre of the range of the red blood cell diameters. From such a summation frequency curve another value can be computed, viz., the diameter dispersion, which is the difference in diameter readings at the eighty-four and sixteen percentile grades. The diameter dispersion is a quantitative measure of the amount of anisocytosis. Figures 4 and 5 show the summation-frequency curves in normal and pernicious anemia bloods. 144 PERNICIOUS ANEMIA Figure 6 repre- sents the summa- Mh tion-frequency- BRRRRRERRER curves of pee) | ous anemia red blood cells, in re- lapse and in liver- diet remissions, as compared with normal. Medearis and Minot (427) found Seeee) Seana that in patients BP //Ane with remissions ie following the liver diet, the red cor- puscle diameter 45 50 55 60 65 70 75 G0 65 90 95 100 105 10 15 dispersion falls and D M LAMETERS IN MiICRONS aay be well eed peat us rateable. é of, digeaberor of eee t , the upper norma col dinsctery in 20 sera oe limit or may remain slighly above nor- mal. This means that anisocytosis may become even less than normally occurs, or be but slightly more than esses Chae aS WN TTT 22 BiiRVer eo aaa AS ASS es ro ZA normal. This stim- 7, jencueuee ulates these authors eal Lest fa lat to Ao sgoe /aeueeceee to speculate as THA EDuaeL Roane rs aie pet oll ch contains some fac- tor which matures REE EE EEE and produces cells 45 50 85 60 65 70 75 80 05 90 SMT OS NOMS eDeS oes at a greater rate DIAMETERS IN MICRONS than normal so that Fic. 5.—Curves of distribution of red blood cell diameters in 25 cases of pernicious anemia the size of the cells (Bell, a homap san Aiea): THE BLOOD SYSTEM 145 is diminished. They present the following table which summarizes the data concerning the red blood cell size of fourteen cases before and after taking liver diet. It is of interest to note that in two or three twenty-year remissions, not induced by liver diet, Hurst (309) noted a persistence of macrocytosis. During any re- mission there is a lessening of the de- gree of anisocy- tosis, noticeable without microme- ter measurements, and proportional to the excellence of the remission as guaged by the blood counts and the clinical im- provement. In some good spon- taneous remissions of three years du- DIAMETER OF CELLS IM MICRONS x Fic. 6.—Summation-frequency-curves for the ration the smear diameters of the red blood cells in the same two lee of pernicious anemia for which per- looks com pata- centage frequency curves are given in Fig. 3 _ a (Medearis and Minot). = tively normal, al Solid line ( ) normal, averaged data. though in almost A (—— ———) case 7 (table 1). ved blood cells 1,200,000 per exbie millimeter Al (-------- ) case 7 (table 1), red blood cells 5,020,000 per cubic millimeter every field there 1S ) case 2 (table 1), red blood cells 2,400,000 per cubic millimeter A eee 5) (table 4) ied toed onl €600 00 per able linda liable to appear an isolated macrocyte with ill-defined borders and, in the writer’s experience, deficient hemo- globin complement. The occurrence of macrocytes. The abnormally large red blood corpuscles constitute, as Laache (351) first indicated, the essential feature of pernicious anemia cel- & S = S ry = Ss zx = SS & S ~ z = 5 ce) ~ ~ Ne ) w Ss S s iat 146 PERNICIOUS ANEMIA lular morphology. The feature becomes increasingly striking during severe periods of the disease and, while less so during remissions, seldom if ever entirely dis- appears. The remissions due to liver diet evidently prove exceptional to this statement. The macrocytes are characteristically of an oval out- line. In one case, by two-diameter measurements of all erythrocytes over 7 u, ovality was detected by the writer in eighty-nine per cent of the macrocytes. This point is not without diagnostic significance, for frequently enough a macrocytic anemia may be encountered characterized by macrocytes of a circular outline. These large oval cells are well filled with hemoglobin, as also, indeed, are all the erythrocytes in relapse, for it is practically impossible to find an instance of any con- siderable achromia, or of much anisochromia. Even in unstained, wet preparations the red blood corpuscles may be seen to be well filled with pigment. In stained prepara- tions, the macrocytes stain very distinctly, usually heavily, a fact dependent upon either their normal hemoglobin saturation or, as Bowell has suggested, upon their chem- ical reaction. The macrocytes of especially large size are sometimes called megalocytes. Both varieties are the chief indications to be encountered in an average case of disturbed blood formation. They are thought to arise by an abnormal type of maturation of the parent erythroblasts in the marrow. In health, the megaloblasts (very large forms with reticu- lar nuclei and basophilic cytoplasm), as well as their im- mediate progeny the erythroblasts (somewhat smaller cells of similar type), give rise to the normoblasts (forms much smaller, with pyknotic nuclei and cytoplasm taking either stain). The next form recognized is the nucleated erythrocyte, a cell of equal size to the fully matured red corpuscle, but possessing a pyknotic nucleus. The normo- blast and the nucleated erythrocyte by loss of their THE BLOOD SYSTEM 147 nuclei (through absorption or extrusion) become the definitive erythrocytes, the adult functional red blood corpuscle. In pernicious anemia, this orderly process does not obtain. The macrocyte is considered to represent an erythroblast which, after loss of its nucleus, is prema- turely delivered to the circulation, and is, therefore, an indication of abnormal blood formation. The occurrence of muicrocytes and potkilocytes. While any red blood cells smaller than occurs in normal blood might be called a microcyte, the term is generally reserved for very small cells, first noted by Eichhorst (165) and then called Eichhorst’s corpuscles. The occurrence of small red blood cells is really more characteristic of simple anemias than of pernicious anemia. Microcytosis is num- erically less a feature of this disease than macrocytosis. To a limited extent, however, it is a feature. The exact mode of origin of microcytes is not clear, but the presence of many microcytes is taken as an indication of increased blood destruction. Poikilocytosis is a feature of pernicious anemia, but it often is less marked in this disease than in severe, chronic simple anemias. Many bizarre shapes are to be noted,— forms resembling Grecian urns and Indian arrowheads are common but many unsymmetrical forms impossible of verbal description also occur. Small, irregular, normally staining portions of red blood cells, not deserving to be called cells, are frequently encountered. They appear to have been broken off from an erythrocyte. In some exceptionally severe cases, espe- cially near death, when the accepted signs of blood de- struction are very marked, many, or, occasionally, the majority of the red blood cells present blunt-ended pseu- dopods, 3 or 4 to a cell, anda few actually show an oozing out of their stroma. Such fragmentation forms and such disorganized corpuscles are regarded as microscopic evi- dence of increased blood destruction. 148 PERNICIOUS ANEMIA TABLE 9 The diameter of red blood corpuscles in pernicious anemia dur- ing relapse contrasted with their diameters during remission (Medearis and Minot). Red blood | Mean Median 5 cells diameter | diameter Ss}al/alalale|e ay mo.| mil-| mil-| mi- ean Peri mi- lions} lions} crons} crons| cron.} cons 1 Dla cha] So 2kO)) tess) Castell Asal 2) 20 | 2.4 | 4.4 | 8.43] 7.62) 8.71] 7.69 Sha 7 | 3.7 | 5.1 | 8.16] 7.44) 8.18] 7.43 alba | o- | 50 |---| 7.43) «| 7a 5 7 | 2.8 | 4.5 | 8.30} 7.26) 8.00} 7.31 6 2] 2.6 | 4.8 | 8.50} 7.62) 8.43) 7.61 i 411.2] 5.0] 8.23) 7.24) 8.31) 7.25 8 3] 1.8 | 5.1 | 7.98) 7.40] 7.93] 7.44 9 D2 On| U5ic50|ee GO MOsSLluds8/A| anol 10f | 2] 3.2 | 6.4 | 7.40) 7.23) 7.46) 7.25 MS. NOLS) 05s || iri S425 | aetedl re O 12 Th Wha) Sasi) Sf laces GI) Wa zal 13 TPP Sale ah [ele] Ge Fae, 14 NORE || Sssip Si | sO. Gy Pale] Av. | 5 | 2.1| 5.2| 8.17] 7.33] 8.19] 7.35 Smallest and great- | Dispersion est diameter s s 2 a eo n an ay "2. | es che Vv o ovo vo [a4 [a4 4 4 microns | microns | mi- | mi- crons| crons 3.7-13.0 | 6.3-10.0) 3.80] 1.24 4.0-10.0 | 5.5- 9.5) 2.54] 1.34 5.6-10.0 | 5.5- 9.5] 1.87] 1.25 6.2-10.0 | 5.6-10.0) 1.57] 1.32 EE oles & 6.3- 8.8] ....] 0.96 3.0-13.0 | 5.0— 8.8] 2.04) 1.00 4.4-11.9 | 5.6-10.0} 2.07] 1.50 3.8-12.5 | 5.0— 9.4) 3.37] 1.33 5.0-11.3 | 5.6—- 9.4} 2.00] 1.30 5.6-11.3 | 5.0- 8.8} 2.12) 1.25 5.0- 9.4 | 5.6— 8.8] 1.70] 1.06 4.0-11.25} 5.0—- 9.4) 2.65] 1.25 1 5.0-10.6) g | 1.25 1 5.6-10)4)) Some 1 5.6- 8.8} g | 1.10 407-1163) '5.5=9)5 |e ees * Previously the red blood cell count had been about 1,500,000 per cubic millimeter. +The lower figures (4b) are those for measurements made after patient had re- mained in marked remission for one year. t Previously macrocytosis had been marked. Liver had been eaten daily for seven weeks before first measurements were made. § At time of relapse, there were so many small cells that the values for the average diameter and median were less than is usual in pernicious anemia with low red blood cell counts. However, there is a high dispersion. | Measurements were not made. The cells showed a distinct macrocytosis. Microcytes were plentiful and anisocytosis marked. tak SLOOD SYSTEM 149 The occurrence of immature forms. Megaloblasts prob- ably occur in the circulation in every case of pernicious anemia at some stage of the disease. But in the routine smear examination of a number of patients they will not be encountered at all frequently or perhaps not be seen at all. While confirmatory, they are by no means essential to the diagnosis. Their presence even in moderate numbers indicates severe physiological strain upon the marrow. They occur in large numbers in the blast crises and are usually increased after splenectomy. Normoblasts, indic- ative of a less degree of physiological embarrassment, occur quite frequently in pernicious anemia, as they do also in severe simple anemias, and are present in large numbers in most blast crises. Other evidences of im- maturity,—polychromatophilia, reticulum, Howell-Jolly bodies and Cabot bodies,—will be considered presently. Ellerman (170) by photomicrographs in two cases of pernicious anemia, demonstrated the presence in the blood of hemoglobin-free, rudimentary erythrocytes, the so-called erythrogonia. (b) The white blood corpuscles. The polymorphonu- clear neutrophils show a tendency to a high number of lobules in their nuclei. There occur in pernicious anemia what Rolleston referred toas giant polymorphs, but which Cooke (131) refers to as macropolycytes. There are two forms, depending upon the nucleus. In the first, the nucleus and cytoplasm are normal but the cell is very large (over 14 » in diameter). In the second, which resembles the megakaryocyte of the bone-marrow, the nuclear bulk is great absolutely and relatively to the cyto- plasm and may be in the form of a band or contain from two to fourteen lobulations, while the cytoplasm contains large neutrophilic granules. The cause of the macropoly- cyte is unknown, but they are regarded as evidence of great urgency in the bone marrow activity. Cooke regards the second form, resembling megakaryocytes, as of grave 150 PERNICIOUS ANEMIA significance since no case in his experience has lived beyond a few days after their appearance. Eosinophil polymorphonuclears were quite commonly found in Levine and Ladd’s (370) cases. They have been said to occur most numerously in the early stages of the disease. Arneth (16) found the lymphocytes mostly small, which is, according to this authority, tantamount to a right-handed shift of his scale. Myelocytes and even myeloblasts of the various types may appear in the blood, especially during blast crises or the agonal state. The blood platelets are usually larger and of more irregular outline than normal. THE FUNCTIONAL STATE OF THE BLOOD SYSTEM The normal function of the blood is to maintain proper nutrition and respiration of the tissues, to preserve itself in the face of hemorrhage by clotting, and to act as a common carrier for immune substances, hormones and vitamines. The normal function of the blood-forming and blood-destroying organs, which comprise the hemolyto- poietic system, is to maintain the formed elements of the blood in normal characters and numbers. The functional state of the blood system, as a whole, may therefore be judged, from a practical standpoint, through a study of the following points. (1) The balance between production and destruction of blood cells. (2) The state of the blood and bile pigments. (3) Physical and chemical changes in the blood. The oxygenation and nutrition of the tissues will be considered in connection with the metabolism. (1) The balance between production and destruction of blood cells. Normally blood production and blood de- struction proceed in a correlated manner, at an equal rate, so that the number of blood cells in the circulation is Pay BLOOD) SYSTEM 151 remarkably constant. The blood count at any given time is necessarily a numerical expression of the balance in this profit-and-loss system. The profound oligocythemia which characterizes per- nicious anemia means, and means only, that a disturbance of the normal balance exists. This disturbance may be due to any one of the following factors. (a) A greatly de- creased production. (b) A greatly increased destruction. (c) A considerably decreased production combined with a considerably increased destruction. (a) The factors of blood production. In the normal adult human organism, the production of red blood cor- puscles and of granular leukocytes is restricted to the bone marrow. In pernicious anemia, the same restriction exists, except that a few scattered extra-medullary foci of hemopoietic tissue may be found at times in the spleen, liver, and hemolymph nodes. These later are of negligible importance. Whatever production occurs, occurs in the bone marrow. The gross and microscopic appearance of the marrow suggest that this tissue is hyperactive. The spread of the marrow throughout the shafts of the bones is the chief reason for thinking that abnormally great production is taking place. McMaster and Haessler (421) showed that the chief factor in causing red bone marrow to spread was the presence of an excessive supply of hemoglobin. Two series of rabbits were bled sufficiently to cause anemia of equal degree in the two series, but to one series was administered, after each bleeding, enough hemoglobin to compensate for that removed by hemorrhage. It was found that the series receiving the pigment showed marked extension of the marrow while the other series did not. This increased red marrow showed extreme vascularity and erythrogenic islands of great size, with normoblasts. The conclusion from these experiments was that the stroma material for making red blood cells was practically inexhaustible and that, if the BSS PERNICIOUS ANEMIA organism be supplied with sufficient hemoglobin, the mar- row would quickly spread, with evidence of increased blood production. It is quite possible, as Whipple sug- gested, that in pernicious anemia too much hemoglobin is produced, and this excess not only causes the spread of the red marrow, but its unused excess is converted to bilirubin. There is no way of being sure that the appearances of increased erythroblastic activity in the marrow signify a process which results in an actual delivery of increased numbers of erythrocytes to the circulation. In fact, it is quite possible that in spite of these appearances, the total numerical production is reduced below normal. If such be true, the bone marrow would be seen to present a feature of malignant tissue,—cellular hyperplasia at the expense of function. (b) The factors of blood destruction. Although in health the adult spleen is a more active agent in blood destruction than the marrow, it would appear from the work of Doan (149) that in pernicious anemia the rela- tionship is reversed, and that the clasmatocytes of the spleen are not as active in this respect as are those of the bone marrow. In the latter tissue there is a marked ten- dency toward the phagocytosis particularly of young, im- mature, nucleated red blood cells, which presumably have not been in the circulation. Doan’s observations did not indicate that the spleen takes any directly active part in an increased destruction of blood in this disease. This is of course a surprise, but tends to concentrate the atten- tion upon the marrow as the chief destructive agent. Both in the liver and hemolymph nodes increased destruc- tion takes place, but exactly to what comparative extent, is not known. It should be remembered in any case that, besides the phagocytosis of red blood cells in the clasmatocytes of the reticulo-endothelial system, no site or mechanism of blood THE BLOOD SYSTEM 1 destruction is recognized in this disease. Whether this phagocytosis over prolonged periods can account, largely by its own effects, for the degree of oligocythemia en- countered is uncertain. (c) Combination of decreased production and increased destruction. Since we are aware that increased destruc- tion is taking place, the point lacking for this combined hypothesis is the question of whether or not decreased production exists, and it must remain for the present purely a hypothesis. The obvious fact remains that a serious disruption of the normal balance occurs. In few anemias can such low red blood counts be found. The marked oligocythemia is, in itself, one of the outstanding characters of the anemia. Cabot (90) has always emphasized this point. The lowest count on record is 146,000 (Quincke), while counts of 500,000 per cubic millimeter are not at all uncommon. During the first attack, the numbers usually descend to 2,000,000 per cubic millimeter, the descent being more rapid at first and slower later. On the other hand, during a remission, the rate of increase is more rapid at first and slower the higher the numbers become. At the beginning of an attack, very rapid falls may, in exceptional cases, occur, so that the counts may descend from normal to 2,500,000 per cubic millimeter in a period of three weeks, instead of six months as usual. So, too, in remissions, exceptional rapidity of increase may occur. The writer has seen the red blood count rise, within a period of five days, from 900,000 to 3,500,000 per cubic millimeter. Aside from such unusual instances of rapid rise and fall, there is an average curve in which the stage of increase and decrease each extend over a period of six months. The condition of the patient does not parallel the red blood counts at all times, especially not when this count is over 2,000,000 per cubic millimeter. This is shown by the fact that some patients can do manual labor with a count of 154 PERNICIOUS ANEMIA 2,500,000 while others may die with a count of about 3,000,000 per cubic millimeter. Changes in the blood volume will, as in any anemia, influence the blood counts. A leukopenia also exists, and except in early stages, or in the presence of associated infection, is a diagnostic point of importance. The degree of leukopenia is roughly proportional to the anemia, becoming less during periods of improvement. Total white blood counts as low as 1500 to 2000 per cubic millimeter are not uncommon during severe stages. The condition is one of leukopenia with lymphocytosis, but Arneth (16) found a low absolute number both for polymorphonuclear neutrophils and lym- phocytes. He, as well as Briggs and Coates have found that the polymorphonuclear cells show a right-handed shift on the Arneth scale. Thus Arneth found that neu- trophils with two nuclear segments decreased from the normal thirty-five per cent to sixteen per cent. He con- siders the smallness of the lymphocytes equivalent to a right-handed shift (or “negative reaction’). The blood platelets are reduced in the well established anemia, but not necessarily in the earlier stages. The blood platelet counts vary, usually from 50,000 per cubic millimeter down to a virtual absence. Allard (7) has sug- gested a platelet index, which is a figure obtained by di- viding by fifty the number of platelets per one thousand red blood cells. These figures are chosen because, taking two hundred and fifty thousand per cubic millimeter as a normal count, this would give a proportion of fifty blood platelets to one thousand red blood cells, or a normal index of 1.0. In pernicious anemia he finds the platelet index low, usually 0.2 or less. As will be seen subsequently the blood platelet count is a useful guage of the bone marrow vitality. The bone marrow condition as reflected in the circulat- ing formed elements. It is but‘natural to suppose that the visible products of the bone marrow would convey impor- ti BLOOD SYSTEM 155 tant information with regard to the functional state of this tissue. At least three somewhat distinct functional conditions of the bone marrow may be recognized :— regeneration, depression and exhaustion. The marrow in an early state of regeneration is some- times said to be in a state of stimulation. The signs of regenerative activity are of both a negative and positive character. The negative signs are the reduction or disap- pearance of the degree of bilirubinemia, the gradual dis- appearance of the more striking evidences of abnormal formation, and a lessening in the number of fragmenta- tion forms and of poikilocytosis. Among the positive signs are polychromatophilia, stippling, the presence of mod- erate numbers of blasts accompanied by increased num- bers of reticulated cells, Cabot ring-bodies, Howell-Jolly bodies, increased numbers of blood-platelets, increased numbers of leucocytes, rising counts for the red blood cells, and increasing values for the hemoglobin percen- tage. While the bone marrow in this disease has always been thought of as being in a constant state of stimulation, sudden regenerative signs frequently follow certain forms of treatment. The regeneration sometimes follow- ing blood transformation and administration of arsenic does not differ materially from the spontaneous regener- ation at the beginning of a remission. Splenectomy how- ever does furnish an example of a means of bone marrow stimulation, since it is nearly always followed by a lessen- ing of bilirubinemia, and the appearance in the circula- tion of youthful forms, particularly blasts and red blood cells exhibiting Howell-Jolly bodies, Cabot bodies, retic- ulum, increased blood platelets and leukocytes. Whether or not the splenectomy is followed by a satisfactory rise in the red blood count, the delivery by the marrow of these elements, and their persistence in the circulation often for months, indicate the lifting of a mysterious re- 156 PERNICIOUS ANEMIA straint which the spleen exercises upon the delivery of immature blood cells by the marrow. The liver diet, judg- ing by the description by Minot and Murphy (447) of its effect on blood regeneration, is to be regarded as an- other example of a procedure which causes marrow stimu- lation. Following liver diet, within two weeks the bili- rubin in the blood drops to normal or subnormal levels, there occurs a rise of reticulated cells from 1.0 per cent to 8.0 and even 15.5 per cent within the first ten days, subsiding by the fourteenth day, while the red blood cell count rises gradually in a graceful curve to normal or hypernormal figures. Reticulated cells are young red blood corpuscles, usu- ally but not always larger than normal size, which, when appropriately stained, show within the cytoplasm the well-defined remains of nuclear material. Sometimes this reticulum has the appearance of iron filings attracted to the centre of the cell. Sometimes it is uniformly distri- buted throughout the whole cell in little patches. More is present in some cells than others. The type of reticulat- ed cell which indicates the best regenerative activity on the part of the bone marrow is one in which the reticulum is here and there gathered into firm knots. If, when using brilliant cresyl blue as the vital stain, followed by Wright’s stain, there are seen, in addition to numerous reticulated cells, certain erythrocytes whose cytoplasm takes a peculiar grayish tint, this phenomenon may also be viewed as favorable. Ordinarily in pernicious anemia blood from 1.0 to 2.0 per cent of reticulated cells occur and any considerable increase in their number may be a sign of an imminent blood remission. An increase in re- ticulated cells is usually accompanied by the presence of blasts. If the blasts are moderate in number, the infer- ence is that an orderly regeneration is occurring, but if the blasts are present in very large numbers, the signifi- cance is the opposite. THE BLOOD SYSTEM 15/ Cabot ring-bodies appear in the form of rings, rosettes, - figures-of-eight, double-threaded rings, intertwined rings, and rings composed of dots. They may occur in stippled or non-stippled cells. They may even be extra- corpuscular. They are nuclear remains and probably rep- resent the peripheral portion of the nucleus. They usually occur in cells taking the basic stain. Absent from normal blood or normal bone marrow, they may be found in lead poisoning, leukemia and other severe anemias. They indi- cate an abnormal process of maturation and furnish evi- dence of blood regeneration under difficulty. Munro and McCluskie have recently shown that by overstaining with Giemsa’s stains for 30 minutes or longer, Cabot bodies can be either stained or rendered visible as negatives in a much larger number of cases than formerly supposed. Cells which contain ring-bodies may also contain baso- phile granules or Howell-Jolly bodies, or both. A Howell- Jolly body (Howell body, Jolly body) is a nuclear rest, intermediate in size between a nucleolus and a granule. It is well defined and usually single, gives all the color reactions of chromatin and is a result of pyknosis of the nucleus. The large granule, which is sometimes seen at one point in the circumference of a ring-body is probably of this nature. Like the ring-bodies, these Howell-Jolly bodies imply in the first place immaturity of the erythro- cyte and, in the second place, a pathological mode of ma- turing. (For further information on ringbodies and Howell-Jolly bodies references should be made to Cabot (89), Gruner (239), Barker (23), Schleip (557), Fer- rata and Viglioli (197), and Naegali (467) ). The bone marrow, in a state of depression, is com- paratively inactive. The evidences of depression of func- tion are the absence of the signs of regeneration, marked degree of disturbance of cellular morphology, falling or stationary red and white cell counts and scarcity of blood platelets. 158 PERNICIOUS ANEMIA The bone marrow in a state of exhaustion is much as described in the preceding paragraph, but additional and important evidences are the occurrence of purpura and blast crises. The appearance of many petechial hemor- rhages in the mucosae and skin indicates a functional purpura due to very great reduction in the number of platelets. This thrombocytopenia may occur with purpura in a number of different conditions, but its significance in pernicious anemia is very unfavorable as an indica- tion of marrow exhaustion. The most dramatic spectacle in this anemia, if not in the whole field of hematology, is the agonal blast crisis, during which the bone marrow furnishes the blood stream with samples of almost every kind of blood cell that may ever be seen there,—megaloblasts, normoblasts, reticulated cells, polychromatophilic cells, myeloblasts and myelocytes. As Minot (440) remarks, only the definitely achromic erythrocyte is lacking from this vivid catalogue. An agonal blast crisis is a wholesale delivery of marrow products in response to a desperate bodily demand. Inas- much as this “showing of its hand” by the marrow be- trays its real poverty in mature and functional cells it is of very unfavorable prognostic significance with regard to life. Nevertheless such blast crises may at time be followed by good remissions. (2) The state of the blood and bile pigments. The for- mation of bile pigment from hemoglobin was once con- sidered a proprietary function of the liver parenchyma. But owing to the work of Whipple and Hooper (647), McNee (422), Van den Bergh and Snapper (621), and Mann et al. (397, 398, 399), it is now recognized that, in addition to the liver parenchyma, the reticuloendothe- lium both in the liver and elsewhere, as well as vascular endothelium and serous mesothelium generally, not only can, but constantly do, metabolize hemoglobin into bili- rubin. Whipple’s (645) conception of the relations of bile THE BLOOD SYSTEM 159 pigment to other body pigments has been illustrated by him in the following figure: Hemoglobin liberated in the blood stream is apparently not all eliminated as bilirubin by the liver, but some of it seems to be utilized, after undergoing reduction to the unknown unit structural factors, for the building up of new hemoglobin (315, 316). It has been shown that in- jections of hemoglobin in anemia increase the rate of new hemoglobin construction, presumably by absorption of substances concerned with the “pigment complex” (273), but feeding of hemoglobin, bile pigment, fresh or cooked blood, or the diges- tion products ob- tained from blood, does not increase oo 7a the bile pigments of (~~) — | bile-fistula animals ARS (274). Contrary to the hypothesis of (—)— Wilbur and Addis (654), of a con- Fic. 7.—Graphic illustration (Whipple) of the servation of bile relations of bile pigment to other body pig- A ments. pigment factors by absorption from the intestine and reconstruction into hemoglobin, the work of Whipple and Hooper (273, 274) affords no evi- dence of such absorption. In bile-fistula dogs under ob- servation for two years these investigators found no evidence of pigment lack, no anemia, no fall in pigment production and no reaction to the feeding of bile pigments (645). The amount of bile-pigment excreted by the liver de- pends partly on liver function and partly upon the amount of hemoglobin waste products in the body. The liver possesses a constructive function and not a simple passive eliminative function (649). In bile fistula dogs, maximal S 160 PERNICIOUS ANEMIA bile pigment elimination occurs under certain conditions, for example, a combination of splenectomy and anemia (276): The suggestion of Whipple (645) that the liver paren- chyma and the Kupffer cells may be able to reverse their function of forming bilirubin from hemoglobin, affords a possible explanation for a partial source of hemoglobin. Such a hemoglobin-producing function might with equal reasonableness be ascribed to the marrow reticulo-en- dothelium, in spite of the fact that these cells are be- coming so heavily laden with duty—particularly with the important function of producing the red blood cells themselves (150). Urobilin is probably formed in the liver under abnor- mal conditions of the biliary tract and in the intestine by the action of digestive juices, possibly by bacteria. The bile pigment substances in the bile (bilirubin, biliverdin, urobilin) are not absorbed by the intestine and are lost to the body as true excretory products. With this brief survey of the present position of the normal pigment metabolism, it is in order to consider the pigmentary condition in pernicious anemia. The hemoglobin is found thoroughly filling the red blood cells. Since these cells have an increased average volume, the total amount of hemoglobin is greater in pro- portion to the number of cells than in simple anemias. Such is expressed in the commonly high color index. Much criticism may be offered as to the degree of accu- racy obtained by the ordinary clinical hemoglobinometers. The differences obtained by more accurate methods are not sufficiently great to negative the general impression, which has grown up with the subject, that a high color index usually obtains in pernicious anemia. A diagnosis of pernicious anemia is not infrequently possible how- ever in the presence of a color index less than 1.0. Indices below 1.0 are sometimes encountered, particularly during THE BLOOD SYSTEM 161 the early stages of a relapse or a remission. Panton et al. (482) found among 117 cases, three individuals in whom the color index was persistently below 0.7 throughout the period of observation. Autopsy on these 3 cases confirmed the diagnosis. These authors regard 0.7 as a high index in the presence of severe anemia. Campbell and Cony- beare (98) found 0.96 as the lowest in a brief series of selected cases. They felt the color index could be as low as 0.7 in pernicious anemia, and made the point that many healthy persons show a color index of 0.9 or even 0.8. Faber and Gram (189) report a case of true perni- cious anemia in which the color index during a remission and part of a relapse resembled that of a simple anemia. They furnish the following instructive table: Taste 10 Variations in color index at various stages of disease (Faber and Gram). we Vv 3 rs u ” $ : E py) Se BS Se & g a ga ee ge % 8 3 o 5 fw 2 = Color Index S = < at goad At time of admissions (OSME@XAMMINALIONS) 0 fccesccesccccescscee: | 1.05 1.45 91 9 0 At acme of remission (G4eexaminations)) geese 19 08 1.3 ks AWE) Before discharge in unimproved or deteriorated condition (iexaminations) yp ee 1.9 1.35 1.6 OO aisty before jdeathy) ..2..c.c5210 2s cceaece ee 2.15 0.9 1.5 88 12 It will presently be seen from the use of the “saturation index” by Haden, that although the average red blood cell in pernicious anemia is larger than normal, and there- fore contains more hemoglobin, it is not more highly sat- urated with this pigment than is the average normal red blood cell. The color index, when computed from strictly accurate data, is a very convenient method of forming an estimate 162 PERNICIOUS ANEMIA of the increase in volume of the average red blood cell. A plus index is highly characteristic of pernicious anemia. The fact that all the erythrocytes in the circulation in this disease are normally saturated with this iron-con- taining pigment, combined with the fact that an abnor- mally high amount of bilirubin occurs in the plasma, renders it difficult to believe that any dearth of iron exists in the body, and still more difficult to accept the hypothesis that iron deficiency plays any etiological role. The hemoglobin in pernicious anemia contains a nor- mal proportion of iron, shows a normal combining power for oxygen (368), and retains its crystalline character (11). Characteristic absorption bands for oxyhemoglobin may at times be seen in the serum (73). Free hemoglobin may appear in the serum (73) and give it a bright pink color in markedly severe cases and especially just before death. Hematin has been found in the serum (73). In an organism so evidently surcharged with pigment it might be expected that any further sudden increase of hemo- globin could not be accommodated. Sellards and Minot (570) have actually demonstrated that the bodily toler- ance to hemoglobin is reduced. By intravenous injection of graded doses of specially prepared hemoglobin solution into patients with various types of anemias or diseases without anemia, as well as into normal controls, they found that a lowered kidney threshold occurred in per- nicious anemia and acholuric jaundice, because patients with these two diseases excreted hemoglobin in the urine after doses which, when given to controls or cases of simple anemia, caused no hemoglobinuria. Hemoglobinuria may accompany exceptionally severe stages of the disease, in some cases (334, 508). Hourly variations in the percentage of hemoglobin occur, but are less than normal variations (436, 511). Lehman has shown a parallelism between the decrease of fever and increase of hemoglobin in this disease (365). THE, BLOOD SYSTEM 163 Hemosiderin, a yellowish-brown, iron-containing pig- ment, formed from the disintegration products of free hemoglobin, is deposited in the outer portions of the liver lobules, in the spleen and in the kidney, where it may be detected, post mortem, by the familiar Prussian blue reaction. Hunter (290), the first actually to determine the degree of siderosis in these tissues, found that the liver reached a higher iron saturation than other organs in pernicious anemia, and a higher and more constant satur- ation than the livers in other forms of anemia. Combining his own gravimetric results with those of others he fur- nished the following figures for comparison: TABLE 11 Average percentage (by weight) concentration of iron in vari- ous organs (Hunter 300). No. of Condition Cases Liver Spleen Kidney fealttiy treet teeth: Co 2 BELL ele 4 0.080 0.231 Permictous» Anemia) 22.2.2 ).22.-- 12 0.325 0.175 0.064 Wasting Diseases). 4 0.053 0.115 0.003 Hemorrhagic Anemia ...... 3 0.019 0.023 Ankylostomiasis ......... nO 0.077 0.478 D. Latus Anemia ..... ee: 0.214 0.366 Beukemiayee).-: 4 0.238 0.159 0.086 Chronic Malaria (25 1 0.257 0.110 It will be noted that while the liver siderosis is greatest in pernicious anemia, the livers of bothriocephalus anemia, leukemia and malaria show comparable figures. Further- more, the degree of siderosis of the spleen and kidney do not parallel that of the liver in pernicious anemia. Hunter rightly regarded this extreme hepatic siderosis as very highly characteristic of pernicious anemia. He regarded it, additionally, as an evidence that the blood destruction, which he believed to be the fundamental pro- cess in the disease, was taking place in the portal area of the circulation, induced by the absorption of intestinal poisons. This viewpoint does not receive very wide cur- rent acceptance, partly through lack of proof of such portal blood destruction, and partly because of the experi- 164 PERNICIOUS ANEMIA mental work of McMaster, Rous and Larimore (420). They showed that the repeated introduction of small amounts of free hemoglobin into the general circulation, by the subcutaneous route, led to an identical siderosis. Larger amounts of hemoglobin caused a renal pigmenta- tion equal to, or exceeding, the hepatic, a fact in keeping with what is know of the physiology of hemoglobin ex- cretion, and of the findings in human being after out- spoken hemolysis. In view of this work, as well as that of Haessler, we can only regard the deposits of iron-con- taining pigment in the liver, spleen and kidney as an evidence that free hemoglobin, in excess of that which is utilized by body cells, occurs in the circulation. The bone marrow, according to Peabody and Broun (489), is sur- prisingly free from pigmentation. Rous (540) has shown that siderosis of the kidney, in certain other diseases as well as pernicious anemia, may be detected by finding in the urine granules of hemosiderin, both extracellular and intracellular. Bilirubin exhibits in pernicious anemia three departures from its normal physiological behavior. (a) It is increased in the blood plasma, serous fluids and tissues generally. (b) This plasma bilirubin is slightly altered in its physio- chemical state. (c) It is increased in the bile. In health bilirubin appears in the blood plasma but in very high dilution (one or two parts per million). In per- nicious anemia and several other conditions, it is greatly increased—a condition referred to as hyperbilirubinemia. The increase of bilirubin in the bile is a condition re- ferred to as pleochromie. In pernicious anemia, acholuric icterus (hemolytic jaundice), and other conditions where hemoglobin occurs free in the plasma, the bilirubin of the plasma is in a some- what different form from that in which it is present in biliary obstruction. The differences are indicated by sev- eral facts. In obstructive jaundice the bilirubin appears THE BLOOD SYSTEM 165 in the urine, invariably stains the body tissues, and dia- lyzes more or less readily through a parchment sac. In pernicious anemia, the bilirubin is never excreted by the kidney, may or may not stain the body tissues, and will not, as a rule, dialyze from the plasma (48). This altered bilirubin behaves differently in the diazo- reaction, oxidizing less readily, a fact utilized by van den Bergh (618, 619, 620) to establish a valuable differential test. Whereas a “prompt direct” van den Bergh reaction is given by bilirubin in obstructive jaundice, a “delayed direct” reaction is given by the bilirubin in pernicious anemia, hemolytic jaundice and other conditions in which free hemoglobin occurs in the blood. This difference in the bilirubin is presumed to be due to the fact that in obstructive jaundice the pigment in order to reach the blood must traverse the liver cell and is altered in some way during its passage. The jaundice of pernicious anemia is usually of a lemon or grapefruit hue and not so frankly yellow as in biliary obstruction. The sclera, the subcutaneous fat, and the serous fluids of the body are all stained by bilirubin. But definite hyperbilirubinemia may be present in this disease without any jaundice, in a considerable proportion of cases. On the other hand, jaundice always means that hyperbilirubinemia is, or has very recently, been present. The reports by van den Bergh (619, 620), Gram (217), and Lepehne (366) were confirmed by the valuable re- port of Broun, Ames, Warren, and Peabody (73) ; all of these indicated that high values for plasma bilirubin occur constantly in pernicious anemia, during active peri- ods of the disease. In the following table from the report of Broun et al., cases 1, 2, 3, and 6 show only moderate increases, but these, at the time of the observation, were clinically in a stage of remission. 166 PERNICIOUS ANEMIA Tas_e 12 Plasma bilirubin in pernicious anemia (Broun et al.). Red Corpuscles Hemoglobin Plasma Case No. millions (Haldane Scale) “Direct” diazo bilirubin per cu. mm, per cent reaction mg. per 100cc. Ty cane ee a 4.128 105 Delayed 13 Db is Db ane bale, ite 2.392 76 Delayed 0.8 HERERO E CRO gn EN 2.136 59 Delayed 1.0 AN Aa) ee een ee 1.992 50 Delayed 22, eee) eye 40 dan, 1.840 50 Delayed 1.2 tee ee a ee ad 1.704 61 Delayed 1.1 AeA ea A eG 1.600 38 Delayed 18 OS eek eee sae cata 1.500 42 Delayed 2.0 Pe at he AE 1.420 30 Delayed 1,7 LOY 2a OE Sica 1.208 35 Delayed Zz Un Eee Ae Beh ete wea ls 1.200 24 Delayed 1S 11745 Selle HERSSURE Di ita 1.192 35 Delayed 2.0 Ue WRN Bh eg RE 1.072 30 Delayed 2.3 TAAL IRL eS aca 1.028 35 Delayed 2.0 15) ee ee eae 0.936 30 Delayed 3.3 1G) jee een ae 0.928 35 Delayed 1.0 1/2 Serene 0.888 26 Delayed 1.0 18 pee eee 0.850 20 Delayed 1.3 Le ee ee Ps ae | 0.848 22 Delayed 3.4 20) Re See 0.824 22 Delayed 1.0 7A ie Har Toke tee bd 0.656 19 Delayed 1.9 22) Bees eee ae 0.540 14 Delayed 1.0 BSrAs died Me TeV ERE. 0.592 23 Delayed 1.9 Vhs Keak Oh Hy AS otiaree Ly 0.584 17 Delayed 28 ZO eals Sen Ns oem 0.569 16 Delayed 2.5 4 Sicha doe te Be oe, dese 0.480 17 Delayed 4.0 Zaye ot Os Sree 0.472 12 Delayed 28 (23) \ ee eae eet 0.456 10 Delayed 2.5 The next table shows the findings in cases of simple anemia due to various recognizable causes. It will be noted that whereas in pernicious anemia a delayed reaction was obtained, in these secondary anemias the direct reaction was negative. Case No. 38 39 41 Red Corpuscles millions per cu.mm. per cent 1.500 2.128 4.360 2.640 5.272 2.360 1.264 3.672 2.672 1.820 2,792 2.880 3.170 THe BLOOD SYSTEM 167 TABLE 13 Plasma bilirubin in secondary anemia (Broun e¢ al.). Hemoglobin (Haldane Scale) 32 25 21 51 25 “Direct’’ diazo reaction Plasma bilirubin Diagnosis mg. per 100 cc. Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative “Prompt” “Prompt” 0.1 0.1 2.0 9.6 Chronic nephritis Chronic nephritis Pulmonary tuberculosis Pulmonary tuberculosis Bleeding hemorrhoids Bleeding hemorrhoids Bleeding duodenal ulcer Banti’s disease. Gastric hemorrhage Primary carcinoma of kidney with liver meta- stases, not obstructing the larger bile ducts Carcinoma of sigmoid Rhabdomyosarcoma _ in- volving pleura, pericar- dium and other thoracic structures Carcinoma of stomach with liver metastases Carcinoma of head of pancreas involving the common bile duct The next table indicates that a delayed direct reaction may be obtained in certain conditions other than per- nicious anemia; in some of the cases the degree of bilirubinemia is indistinguishable from that of pernicious anemia. 168 PERNICIOUS ANEMIA TABLE 14 Anemia with plasma bilirubin; findings similar to pernicious anemia (Broun e¢ al.). Co) a me 3 é 9 3 < | = b=) 3 & @ a gos 8.2 ES E So Como Eva R= 75) Ou en 3 o% o ag 8 oh) Oo (5) ie} ww ee Ay QA millions mg. per per cu.mm. per cent 100 cc. 42 2.000 Delayed 2.7 Familial hemolytic jaundice 43 1.992 58 Delayed WY Sprue de 2.552 58 Delayed 1:3 Anemia following alco- holic intoxication 45 3.808 50 Delayed 2.0 Lymphatic leukemia 46 2.208 40 Delayed 0.5 Post partum anemia 47 1.174 24 Delayed 0.8 Subacute bacterial endocarditis 48 2.690 49 Delayed 0.9 Subacute bacterial endocarditis 49 4.840 82 Delayed 1.0 Typhoid fever 50 4.840 112 Delayed ed Lobar pneumonia These observers noted also that the plasma bilirubin curve in pernicious anemia usually rises during periods of exacerbation of the clinical symptoms and falls to more normal levels during periods of remission. They noted a customary reduction in plasma bilirubin following blood transfusion, a phenomenon of uncertain significance, but owing probably to a slowing of the blood destruction, an increased utilization of the pigment, or a temporary increase in the ability of the liver to excrete pigment. The colorimetric determination of the degree of plasma staining, by comparing with a standard solution, but without reference to the behavior of the diazo-reaction, gives the icterus index, which is a useful quantitative expression of the degree of jaundice. fae BLOOD SYSTEM 169 The method of Meulengracht (431), or preferably the modification suggested by St. George and Brown (596), is easily employed. The latter observers, employing their modification, found that the icterus index, rationally in- terpreted, is a distinct clinical aid in the differentiation of the anemias, for while simple anemias have generally low indices below the normal range, pernicious anemia and frankly hemolytic anemias have indices above the normal range. They found the method valuable in differentiating from pernicious anemia the severe pernicious-like anemia found sometimes in cases of gastric carcinoma, for in the latter the index is below the normal range. It is to be remembered, as they specially emphasize, that co-existing factors, such as pneumonia, cardiac insufficiency, and chronic sepsis (especially in the biliary system) may in- crease the icterus index above its customary range in any given type of case; and that hemorrhage, especially con- stant oozing, may lower the index below its customary range. In cases of pernicious anemia they employed the index to foretell the occurrence of remissions and re- lapses. Broun et al. (73) found in the plasma in very severe cases with low red blood counts, an ether-soluble pigment which was of very grave prognostic significance, and occurred in large amounts post mortem. It was of the nature of a lipochrome, failed to give the diazo-reaction and gave negative tests for lutein. The pleochromie, or excessive biliary excretions of bili- rubin, which is an undoubted feature in relapses, is not perfectly understood. Schneider (559, 560, 561, 562) be- lieves it to be constantly present even during remissions and to constitute an expression of the immediate hemoly- sis. Sonnenfeld (583), estimating the amounts of bili- rubin in the duodenal fluid during remissions and re- lapses, found as a rule twenty times smaller amounts dur- ing periods of improvement, although two cases in mod- 170 PERNICIOUS ANEMIA erate remissions showed only three to four times less than those in frank relapse. Sonnenfeld was at a loss to explain these two cases and mentioned the possibility, as pointed out by Strausz and Hahn, that a mixture of cystic bile may simulate a pleochromie of the duodenal fluid. Urobilin is normally excreted in small amounts in the urine and is found in small amounts in the duodenal fluid and the stools. Urobilinogen is not normally found in the urine, duodenal fluid or stools. In pernicious anemia, urobilin is found in greatly increased amounts in the urine, duodenal fluid and stools, and urobilinogen ap- pears in these three products. There can be little question that a true wrobilinocholie exists in many cases as Schnei- der and as Giffen et al. (224) believe. But Hansman and Howard (254) noted an absence of urobilinogen in the duodenal fluid in two of five cases of the disease, although these two cases showed increase of this pigment in the stools. Scholz’s (563) findings in the urine and stools were not constant, and he concluded that while the urobil- inogen content of the stools has only slight differential value, a marked urobilin content can determine the degree of blood destruction. Robertson (531) in a study of eleven cases of the disease found urobilin increased in the stools, its amount serving as an index to the severity of the anemia. McCrudden (415) confirmed this finding. Hansman and Howard (254) estimated the urobilin and urobilinogen in the urine and stools of 27 cases of the disease. Their patients were divided into four groups on the bases of the red blood cell levels. Their results may be tabulated as follows: TaBLeE 15 Pigment excretion in relation to blood levels (Hansman and Howard 254). Total average of urobilin and Red blood cells urobilinogen in urine and per cubic centimeter stools Gronp ile ee a ee 4,000,000 to 5,000,000 40,400 Groupecieee ee eee 3,000,000 to 4,000,000 12,400 Groupie eee see ee 2,000,000 to 3,000,000 98,565 Group 4) eat ee 1,000,0000 to 2,000,000 62,950 THE BLOOD SYSTEM 171 The phenomenon of low output of pigment in group 2, in the presence of relatively high blood count, they ex- plain by considering these patients to be, on the whole, in process of remission. The greatest excretion of pig- ment occurred at the blood level represented by group 3. They concluded that an increase of the urobilin and uro- bilinogen above 12,000 dilutions is a constant finding in this disease during the periods of remission; that the presence of even small amounts of urobilinogen in the urine is evidence of a probable pernicious anemia in the absence of signs of biliary or hepatic disease; that a low red blood cell count.with a low urobilin and urobilinogen figure indicates an arrest of the activity of the disease process and anticipates a remission; and that a high red blood count with a high pigment output often precedes a relapse. Schneider regards the increased urobilin and urobili- nogen excretion as an expression, not of the “immediate hemolysis”, but of the “heaped-up pigment in the portal system.” He further believes that splenectomy immedi- ately and permanently reduces excretion of excessive pigment to a normal level, thus doing away with pleo- chromie and urobilinocholie. He finds that where the blood picture and clinical picture of pernicious anemia recur after splenectomy these two features of excessive pigment execretion are lacking, although a distinct rise in pigment output could be observed in one of his cases after thirteen months. While this point still requires in- vestigation, few perhaps will follow him in his belief that fully-developed pernicious anemia is the late bone-mar- row exhaustion from a primary hemolytic process, with the spleen in the role of the chief instrument of blood destruction. Hooper and Whipple (275) obtained from the gall bladder bile in an autopsy of a case of pernicious anemia an unusual pigment which had to be treated with active 72 PERNICIOUS ANEMIA acetaldehyde before it would give the usual bile pigment tests. The true significance of these various abnormalities of the pigment behavior cannot be said to be definitely estab- lished. They have customarily been regarded as evidences of increased blood destruction. The following pertinent paragraphs of Whipple (646) indicate that a different view may be advisable: “We are told that the stercobilin in a case of pernicious anemia is an index of blood destruction. Let us examine some of these figures and, further, let us assume the normal red cell count as 5,000,000 and the pernicious ane- mia count as one million for the sake of simplicity of comparison. If the anemia red cells disintegrate at the same rate of speed as the normal control, and if these products result in bilirubin and then stercobilin we must say the stercobilin figures should be one-fifth of normal. But the stercobilin figures during periods of remission in pernicious anemia often exceed twice or three times nor- mal stercobilin excretion, making no allowance for simi- lar pigments in the urine. This can only mean that the pernicious anemia patient with one-fifth the number of red cells and two or three times the amount of stercobilin output must regenerate its total red cell mass every three days instead of the assumed normal every thirty days. The normal replacement factor for red cells and hemo- globin is believed to be three per cent per day. We must postulate from thirty to forty per cent replacement of red cells per day in a pernicious anemia case if we persist in explaining the stercobilin content as being due to blood destruction. Those who wish to accept this explanation are welcome to do so, but it would be a fleeting and trou- blous life period endured by the red cell in pernicious anemia. “Our conception of pernicious anemia is that there is a scarcity of stroma building material or a disease of the THE BLOOD SYSTEM 173 stroma forming cells of the marrow which limits the out- put of red cell framework. There is plenty of pigment material (an excess in fact) as evidenced by the high color index or the saturation of the red cell with hemo- globin. Wherever we meet with a high color index we should suspect some deficiency in stroma construction or some over-production of body pigments including hemo- globin. Conditions of malignancy, for example, with the hematology of pernicious anemia should yield informa- tion of value when examined with these points in mind. Nothing in this paper should be construed as minimizing the importance of stercobilin analyses for we are confi- dent that such information is of great value. High ster- cobilin figures may be a very valuable diagnostic aid in obscure cases of pernicious anemia, as claimed by Hans- man and Howard. That these figures indicate a corre- sponding destruction of red cells may be doubted and an overproduction of pigment may be a safer assumption.” McMaster and Haessler (421) showed however that stroma building material was practically inexhaustible. The explanation of the pigmentary disturbances may yet fall back, in a general way, to the theories of the ear- lier observers of the bone marrow, particularly Cohnheim (123) and Ehrlich (163) who conceived of the anemia as primarily a disease of this tissue. Faulty nuclear matura- tion on the part of the youngest red blood cells is a func- tional diagnosis fraught with exceedingly great possibili- ties, especially, if, as Whipple (645) has been impelled to suggest, the reticulo-endothelium may be concerned with hemoglobin construction, and, too, as Doan et al. (150) strongly suggest, the reticulo-endothelium gives rise to the megaloblasts. If such conceptions could be established as facts, or even as probabilities, then it would not be beyond the pale of sanity to conceive of disturbed pig- ment metabolism, disturbed blood formation, and all other blood abnormalities of pernicious anemia, as due funda- 174 PERNICIOUS ANEMIA mentally to a diseased condition of the reticulo-endothelial tissue. (3) Physical and chemical changes in the blood. The blood when seen in quantity has a much redder appear- ance than the number of cells would lead one to expect, because of the large average cell size. When a drop of very anemic blood is allowed to absorb upon a piece of bibulous paper, it shows, after drying, a central red area surrounded by a faint pinkish zone. Cabot (90) denoted this as a characteristic of the blood. The serum in severe cases is of a buttercup yellow color, due to the staining with bilirubin in contrast to the straw-color of normal serum. The specific gravity of the serum is decreased, and that of the red blood cells is normal, with a resulting decrease in the specific gravity of the whole blood (222). The refraction is low probably owing to the reduction in serum globulin (222). The freezing-point is practically normal in the majority of cases (222). The specific electrical conductivity of the plasma has been found normal (77). The patients occur in all four of the iso-agglutinin groups. In other words, all the groups may suffer from the disease. Ashby (19) noted that fifty-two per cent of the cases at the Mayo Clinic at one time were of group IV. Oscar B. Hunter (288), from among thirty-eight cases, found thirty-four of group II, three of group IV, and one of group III (Moss classification). After repeat- ed transfusions, some cases develop antagonistic lysins and agglutinins against all donors. Occasionally cases have been encountered, as among other diseases, exhibit- ing the phenomenon of auto-agglutination (122). The serum has been shown by Clark and Evans (115, 116) to possess decreased protective power against hemol- ysis by saponin. This is especially true of serum from severe cases. THE BLOOD SYSTEM WAS The red blood cells show a decreased fragility to hypo- tonic salt solutions. This is marked in some cases, moder- ate in others and absent in a few. As a rule however, pernicious anemia cells are more resistant to hypotonic solutions than are normal cells. Green (235) has shown that this is not a sign of strength but rather of injury. He showed that washed normal red blood cells, after pre- liminary treatment with pernicious anemia serum, show the same increased resistance. He showed also that wash- ed normal red blood cells, after treatment with castor-oil soaps, showed, before liberation of their hemoglobin, the same increased resistance to hypotonic solutions. Eryth- rocytes may give up salt, upon injury, without releasing hemoglobin. This egress of salt raises the tonicity of the environment. The “increased resistance” is therefore due to an inability of the cell to maintain an osmotic difference from the surrounding solution because of greater perme- ability of the cell wall to the contained salts. Green sus- pects that this injury is caused to normal cells by per- nicious anemia serum, and may be due to a hemolytic agent, the condition of injury constituting a phase pre- liminary to hemolysis. The total volume of the blood has been repeatedly de- termined, by different methods, and always found low or normal, but usually low. Lindeman (378) found the blood volume from 1600 to 4200 cubic centimeters, or from 2.4 to 5 per cent of the body weight, as compared with Keith, Rowntree, and Geraghty’s normal figure of nine per cent of the body weight. Lindeman’s method (377) was based on the transfusion of a known amount of un- diluted blood, and is apparent from the following for- mula: If x = initial volume of patient’s blood, a = percentage of red blood cells in initial volume, b = volume of blood introduced, c = percentage of red blood cells in vol. introduced, 176 PERNICIOUS ANEMIA 1 = final volume percentage of red blood cells; then xa -Fibe==1 (Fb bp) xa + be=Ix + Ib xa — lx = lb — be x =Ilb—be a—l Denny (139) employed, as the basis of his method, the oxygen capacity of the patient’s and donor’s blood, using the Van Slyke blood gas pump for making the oxy- gen determinations. Formula: If A = oxygen capacity of patient’s blood before trans- fusion, B= oxygen capacity of patient’s blood after trans- fusion, C= oxygen capacity of citrated blood given, Q = quantity given in cubic centimeters, Boe From nineteen determinations in ten cases of perni- cious anemia Denny found the blood volume reduced in all but two cases. The plasma volume remains essentially normal, the decrease in total volume being due to loss of cell mass. The cases showing normal total volume had a high plasma volume. There is no noticeable relation between the severity of the disease and the decrease in total volume. As Lindeman, Minot and others have re- marked, there is reason to believe that the low total blood volume intensifies many of the symptoms of the disease, such as fatigue, dyspnoea and dyspepsia. Ashby (20) could detect a relationship betwen the throbbing sensa- tions and ringing in the ears (tinnitus) and the low blood volume for, with one exception, these symptoms disap- peared with the establishment of a blood volume of 57 cubic centimeters for each kilogram of weight. She also then Volume = THE BLOOD SYSTEM 177 observed that patients who were in the worse condition at the beginning of treatment had the lower blood volume. She believed that if a patient’s blood destroying mechan- ism would tolerate an increase in the red blood count with a stationary or even compensatory falling plasma volume, it would be of advantage, but that if his blood destroying mechanism was so sensitive that it would not permit much increase in the level of the blood count, then the increase in plasma volume attending transfusion would be help- ful by causing a total increase in corpuscular content without greatly raising the red blood count. Changes in the patient’s blood volume may so influence the blood count as to give an erroneous impression of the total blood cell content of the circulation. Keith (333) also found the blood volume either normal or reduced in pernicious anemia and other chronic ane- mias, although in chronic leukemia the blood volume was almost invariably increased. He employed the dye method of Keith, Rowntree and Geraghty. Lorrain Smith froma study of blood volume by the car- bon monoxide method, concluded that a gain in weight under treatment with no improvement in the hemoglobin level was an unfavorable sign and indicated a dilution of the blood and consequent escape of serum into the tissues. The average volume of the red blood cells in pernicious anemia is greater than normal, whereas in simple anemias it is less than normal. The average cell volume may be determined by the hematocrit or by the use of the visco- meter. The term volume index was introduced by Capps (100) to denote the volume of the red blood cells relative to normal. He measured the mass of corpuscles by centri- fuging a small amount of blood in a capillary tube, the hematocrit of Hedin. A count of the red blood cells was simultaneously made. The percentage by volume of the cells divided by the number percentage of the cells is the volume index. 178 PERNICIOUS ANEMIA While the high color index in pernicious anemia in- forms us that the average red blood cell contains more than a normal amount of pigment, it does not inform us whether there exists a higher than normal concentration of pigment per unit of stroma material. Herz (269) tried to express this latter point by the use of the term “specific hemoglobin content”, and Rossdale (535) suggested the term “volume-color index.’ A simpler term is suggested by Haden, viz., saturation index. Haden (245) in work- ing out very accurate figures for the saturation-index employed the technique suggested by Hooper, Smith, Belt, and Whipple for determining the mass of the red blood cells, and the ferricyanid method of Haldane (Van Slyke’s adaptation) for estimating the hemoglobin. hemoglobin percentage The saturation index ={———_______"—__ volume percentage of cells The following table shows the typical volume, color and saturation indices in normal individuals. TABLE 16 Blood indices in normal person (Haden). Oo oA HO) te B= iey S wei 06 BBS O88 2 y 5g ey a goo) ee 2% che) ce: Me . e Whe Ea SA OG aH I. 2 SEN es a5 uv) 4.99 100 101 1.00 1.01 1.01 4.98 102 104 1.02 1.04 1,02 5.15 104 106 1.01 1.02 1.01 5.28 104 103 0.99 0.98 0.99 4.80 99 97 1.03 1.01 0.98 4.20 83 84 0.99 1.00 1.01 4.56 90 90 0.99 0.99 1.00 5.20 98 103 0.95 0.99 1.05 4.87 99 97 1.02 0.99 0.97 4.97 98 99 0.99 1.00 1.01 The next table shows the typical blood indices in cases of simple anemia due to various causes: (in millions per c. mm.) Percentage by Red blood cells volume of red blood cells & ire) THE BLOOD SYSTEM TABLE 17 Blood indices in simple anemias (Haden). Hemoglobin (in per cent) ow Sa 47 + Volume index Che aS See ola NSASBOH YS BnSssQ RES 0.73 Color index ORS five} £NS 0.83 0.70 1.00 0.45 1.02 0.62 0.59 Saturation Diagnosis 178 Carcinoma stomach Chronic nephritis Banti’s disease with gas- tric hemorrhage Subphrenic abscess Diffuse carcinomatosis Pyelonephritis Syphilis Acute gastric hemorrhage Hemorrhoids Chronic intestinal hemorrhage The next table shows the same indices in fifty succes- sive cases of pernicious anemia. Red Blood Cells (in millions per c. mm.) of Red Blood Cells Percentage by Volume TABLE 18 Blood indices in 50 cases of pernicious anemia (Haden). Hemoglobin (in per cent) Volume Index CN ee ROopNAD DD AW ASX BSRHFSSBLSESERSR UN WWW! Color Index Oe ee pp NON OH WNHH RAN BOUNNH BPH SSRSUBSKRRSSELRANKSE Saturation Index 180 PERNICIOUS ANEMIA 1.39 37 37 1.32 32 1.00 1.39 42 37 1.50 SZ 0.85 1.39 44 39 1.56 1.39 0.88 1.42 42 43 1.51 1.57 1,02 1.48 46 46 1.53 153 1.00 1.52 49 49 1.61 1.61 1.00 1.58 46 44 1.45 1.39 0.96 1.61 39 37 1.22 1.16 0.93 1.62 42 43 1.31 1.34 1,02 1.64 46 46 1.39 1.39 1.00 1.65 42 36 1,27 1.09 0.86 7S 48 38 1.38 1.10 0.79 e755 46 38 1.38 1.10 0.79 1.80 48 39 1.33 1.08 0.82 1.87 56 51 1.50 1.36 0.91 1.87 51 51 1.36 1.36 1.00 1.88 63 59 1.68 1.57 0.93 1.99 56 52 1.40 1.30 0.93 2.10 58 55 1.35 1.30 0.96 2.18 57 57 Lai 1.31 1.00 2.23 75 72 1.69 1,62 0.96 2.27 81 42 1.77 0.93 0.53 2.33 62 58 1.33 1.24 0.94 2.36 68 64 1.45 1.36 0.94 2.41 74 74 157 1.54 0.98 2.60 61 49 117 0.94 0.80 2.60 75 65 1.44 1.25 0.99 2.79 69 65 123 1.16 0.94 2.88 85 77 1.46 1.33 0.91 2.93 79 82 1.35 1.39 1.03 3.16 92 82 1.46 1.30 0.90 3.33 81 80 1.20 1.20 1.00 3.44 75 71 1.09 1.03 0.95 Av. 1.71 47 44 1.41 1.29 0.92 The next table compares the indices in normal blood and in that of pernicious and simple anemias. TABLE 19 Blood indices in various conditions compared (Haden). ae oe oO A= ees) es O Sea ° UO & aot Bee Ses 38 8 [op Te ee SS aie) vo » aa] Bu § oPan] Q © iS tal uM g * u-E oO 358 go 2 Rom) Bo goaclg ds Se Be Hz 4 way CoO a OR Nis 4.74 95 95 1.00 1.00 1.00 Average 52 normal men and women 1.71 47 44 1.41 1.29 0.92 Average 50 cases per- nicious anemia 3.40 63 55 0.94 0.81 0.86 Average 47 cases sec- ondary anemia not due to hemorrhage 0.80 Average 7 cases hemor- rhagic anemia w& on N wn wn Oo N N Oo ON Lie) THE BLOOD SYSTEM 181 It will be seen that in normal blood all the indices are always 1.0, that in simple anemias all the indices are less than 1.0, and that in pernicious anemia while the volume and color indices are increased, the saturation index re- mains practically normal. Haden (525) and Piney (499) have both pointed out that the real size of the red blood cells is better judged from the volume index than from the color index or from the graphic method of Price- Jones. The defect of the graphic method (diameter-inci- dence curves) is shown in family hemolytic jaundice where the cells look small because they are globular in form but the average size, as determined by the hemato- crit or the viscometer, is actually large. Viscometric measurements, Piney asserts, show a high average volume for the red blood cells in pernicious anemia, persisting in remissions. Haden finds that a plus volume index is present even in very early cases of pernicious anemia be- fore other changes are apparent. For this reason he be- lieves that a plus volume index associated with achlor- hydria is practically pathonomonic of pernicious anemia. Mills (436) has shown that the size of the red blood cells in anemias may undergo considerable hourly varia- tions, and he believes that in a certain percentage of cases a definite relationship exists between the percentage of hemoglobin and the cell surface. Rabinowtch (511) indi- cated a similar relationship in normal blood. While most reports on the coagulation time in perni- cious anemia indicate a delay, the studies of Drinker and Hurwitz (155), as well as those of Minot, Denny and Davis (445) show that the coagulation of the blood is but slightly altered. Prothrombin is slightly diminished in all cases, a fact probably associated with reduction of platelets and degrees of bone-marrow aplasia. Bleeding time was always long. Antithrombin and fibrinogen were always consistently normal. Blood transfusion did not affect the latter two factors although it tended to cause a 182 PERNICIOUS ANEMIA slight transient rise in prothrombin. Hurwitz and Drinker (313), from a study of the coagulation factors in experimental aplastic anemia from benzol poisoning concluded that the bone marrow played no part in the production of antithrombin and was not essential to the production of fibrinogen, and that a minimum amount of myeloid tissue was sufficient to maintain the quality of the prothrombin above a dangerous level. From this account of the many changes in the blood system it must be evident, at least, that the respiration of the bodily tissues generally must suffer from the lack of red blood cells and hemoglobin. This functional deficiency is partly overcome by circulatory compensation. In this connection the recent remarks of Graham (215) are quoted: “The tissues receive their oxygen supply not directly from the hemoglobin but from that dissolved in the plasma. The amount of oxygen present in the plasma is dependent upon the percentage saturation of the hemo- globin with oxygen and not on the amount of hemoglobin present. In cases of chronic anemia with varying percen- tages of hemoglobin even as low as 30, the ratio of the oxygen content of the arterial and venous bloods remains constant, irrespective of the percentage of hemoglobin. These physiological facts afford an explanation for the clinical observation that patients suffering from perni- cious anemia with a hemoglobin of 30, and a red blood count of 2,500,000 are very often able to do moderately heavy work without distress.” CHAPTER VII METABOLIC OBSERVATIONS Abnormalities in the digestion, absorption and ultimate fate of the organic and inorganic food constituents, energy metabolism, blood enzymes, and the effects of several forms of treatment on a patient suffering from pernicious anemia, afford a heterogeneous mass of data which, in the absence of a well-demonstrated funda- mental process, cannot be presented with satisfactory perspective, but must be described in a somewhat serial manner. It seems increasingly possible that the causative pro- cess in this disease is of a metabolic nature. It may con- sist in the perversion of metabolites necessary to the nor- mal function of the hemopoietic and nervous systems par- ticularly. To inquire whether such a perversion concerns proteins or lipoids, and whether it results from digestive, assimilative or endocrinous abnormalities would be still farther afield from our present task. It might appear that in the chronic hemolytic anemia of pregnancy and the severe anemia of dibothriocephalus infection a similar metabolic condition was reached. While there is no ex- plicit proof that such is the case, the nitrogen partition in the first of these two diseases was found similar to that obtaining in pernicious anemia (223), and everyone is conscious of similarities in the cachexias of syphilis, gastric cancer and pernicious anemia. The digestion and absorption of food. The nitrogen lost in the feces is above normal (331). Intestinal putre- faction is denoted by increased elimination of ethereal sul- phates (331). The duodenal fluid contains a normal amount of proteolytic enzymes (31, 414). Of the fat eaten, 72 to 89 per cent is utilized (223). There is no evidence of the intestinal formation of abnor- [ 183 ] 184 PERNICIOUS ANEMIA mal amounts of unsaturated fatty acids (223). The duo- denal fluid contains a normal amount of lipase (331, 414). There is no reason to suppose that achlorhydria harm- fully interferes with protein or fat digestion in perni- cious anemia any more than in cases of uncomplicated achlorhydria. Studies of the nitrogen metabolism have indicated, in general, that difficulty exists in establishing a nitrogen balance (230, 231, 417, 438, 449, 492, 533, 616). Mosen- thal (454) as well as Peppard (491), following the thera- peutic suggestions of Barker and Sprunt (25), gave forced feedings with high protein and caloric diets, and found that favorable nitrogen balances could thus be readily obtained. Gibson and Howard (223) applied to pernicious anemia for the first time, specifically and in- tentionally, the high-iron diets which had been used ex- perimentally by Whipple et al. to produce blood regener- ation in dogs rendered anemic from hemorrhage. The diets employed by Gibson and Howard produced favora- ble nitrogen balances as a rule. Such favorable balances were accompanied by favorable iron balances. But nega- tive nitrogen balances and coincident iron retention obtained in some cases. The nitrogen partition in pernicious anemia has been found, on the whole, but not constantly, to show the fol- lowing characteristics—low urea nitrogen, moderate am- monia nitrogen, and high uric acid nitrogen (144, 223, 438, 533, 601). Gibson and Howard (223) found that blood transfusion increased the total N excretion, and the urea, uric acid and creatinine nitrogen figures, for a period of at least two days. Weicksel (640, 641, 642) found after transfusion, increase of total N, and uric acid nitrogen, gradually subsiding to pre-transfusion levels after five days. He attributed the increase of both to the destruction of the transfused blood cells. METABOLIC OBSERVATIONS 185 Minot (438) noted, after splenectomy, a more favor- able nitrogen balance and a rise in the urea nitrogen which had previously been very low. Pepper and Austin (492) noted after splenectomy a positive N balance re- placed, 14 days after operation, by increased nitrogen re- tention and a return to the pre-operative balance after one month; and the uric acid excretion, though never exceed- ing the normal limits, showed a decrease of 22 per cent after operation. Dennis (144) found no changes in the nitrogen partition in two cases subjected to splenectomy. Kahn and Barsky (331) note a considerable increase in the oxyproteic acid nitrogen of the urine. Becker (35) usually found a positive N balance. Following transfusion and splenectomy, Pepper and Austin (492) noted a more favorable N balance and a fall in the uric acid nitrogen. The iron balances were found by Gibson and Howard (223) to follow consistently the gain, the stationary state, or the fall in the blood cell counts and hemoglobin percen- tages, and to be apparently uninfluenced by the deposition in, or discharge of, stored iron from the tissues. The use of their high-iron diet caused favorable balances in eight cases, approximate equilibrium in two cases and a nega- tive, though improved, balance in one case. Coincident betterment of the blood picture occurred. Two cases in which less favorable figures were obtained were being fed on somewhat higher amounts of fat, and these observers suggested that further investigation of fat ingestion should be carried out. Pepper and Austin (492) noted increased iron elimination in the stool following splenec- tomy, as did Gibson and Howard. More work is required on the purine metabolism, in view of the high uric acid N figures, and the benefits de- rived from feeding glandular organs. The perennial interest in the fat metabolism in perni- cious anemia arose in the first place from the investiga- 186 PERNICIOUS ANEMIA tions of Schaumann (555), Tallquist (606), and Faust (192, 194) upon the cause of dibothriocephalus anemia. These investigators found that the proglottides of this worm contained cholesterol oleate as 10 per cent of their solids. Cholesterol oleate was regarded as the causal fac- tor because it was hemolytic im vitro. However, it was practically harmless on parenteral injection. The ground- up worm-bodies were hemolytic both im vitro and in vivo. Schwartz (568) has somewhat recently shown that in the cases of anchylostoma, trichuris and the anoplocephaline cestodes, the strong hemolysins are alcohol soluble sub- stances bound to the worm tissues and that freeing these fractions from ether-soluble substances renders them more hemolytic. He therefore abrogates the importance of oleic acid in worm anemia. Adler (4) in 1913 produced blood crises in rabbits by feeding non-toxic amounts of unsaturated fatty acids. Joannovics and Pick (324, 325) showed that subacute poisoning with toluylendiamin caused a tremendous in- crease of oleic acid in the liver and marked hemolytic anemia. They also demonstrated that in acute yellow atrophy of the liver and in phosphorus poisoning, either experimental or clinical, active hemolysins could be ex- tracted from the liver and the blood showed large quan- tities of fatty acids. They considered that the unsaturated fatty acids of the liver were the hemolytic agents extract- ed from the liver. From several sources, chiefly from the work of Beumer and Birger (46, 47) and of Berger and Tsuchiya (43) has arisen the conception of a toxic lipoid developed in the intestinal mucosa as the result of (unproved) constitu- tional abnormality of this tissue. Several attempts have failed to isolate from this mucosa any hemolytic substance notably different from those which occur in normal muco- sae, or other tissues. McPhedran (425) has shown that in chemical poisoning no fatty acids more hemolytic than METABOLIC OBSERVATIONS 187 oleic acid are produced. Seyderhelm (571) did for the bothriocephalus proglottis what Schwartz did for other worms,—showed that the active hemolytic agent was an alcohol-soluble substance bound to the tissues, and not the lipoid. Feeding oleic acid to young dogs caused, in Beu- mer’s (45) hands, no anemia. In spite of these negative results, interest in the sub- ject has persisted. Eppinger (173) with King (336), as well as Medak (426), reported increased total blood fats with high value for iodin numbers, and decreased choles- terol in the blood of pernicious anemia. The investiga- tions of others has confirmed the low cholesterol but not the increase of unsaturated fatty acid. The work of Bloor and MacPherson (51), Csonka (136), Dennis (143), Kip (338), and others has shown that in severe anemic phases of the disease the blood cholesterol is greatly re- duced. This is probably a result of the anemia since a similar reduction occurs in severe simple anemias. Such an explanation harmonized with the theory that choles- terol is an intermediary product in fat metabolism, to which the red blood cells are vitally related. The chief reason for interest in cholesterol is its anti-hemolytic qualities; but its decreased concentration in the blood cannot, unfortunately, be used as an argument for the presence of a hemolytic agent. Csonka (136) could attach no specific significance to fatty acids as agents of blood destruction. The attempt of Brinkman and Szent-Gyorgyi (70) to find in linolenic acid the cause of normal and pathological hemolysis was not convincing. As Csonka (136) remarks, unsaturated fatty acids constitute 48 per cent of the fatty acid con- tent of normal blood, and since such acids exist in normal blood and in pathological but non-anemia conditions as well, they cannot be regarded as bearing any primary relationship to abnormal blood conditions. 188 PERNICIOUS ANEMIA King (336) and Bloor (51) found the total blood fat high but Gibson and Howard (223) did not. In fact these latter investigators found the blood and plasma fat very low in severe anemia with increase as the blood improved. Dennis (143) had found the blood fat low in two cases. Although Gibson and Howard found the blood fats low, they were associated with higher iodin numbers, although the total amounts of iodin absorbed were small. They con- firmed Bloor’s finding that the blood cholesterol fluctu- ates directly with the blood count. They found no substan- tiation for the supposition that unsaturated fatty acids cause the anemia. There exists no proof, therefore, that the fat metab- olism in any way enters causally into the pathogenesis of pernicious anemia. The preservation of the subcutaneous fat layer, sometimes even in cachexia and under condi- tions of virtual starvation stands, nevertheless, as a somewhat distinctive feature of the disease. Suboxida- tion exists, as evidenced by the increased neutral sulphur fraction of the ethereal sulphate excreted. The carbohydrate metabolism is apparently not affect- ed. Adams (3) reported three cases of diabetes in asso- ciation with pernicious anemia at the Mayo Clinic over a period of five years, during which time 1000 cases of per- nicious anemia and 2000 cases of diabetes were encoun- tered. Schumann (564) reports a case of the two diseases associated, in which glycosuria disappeared following the use of insulin, the patient dying of pernicious anemia. In spite of Johnson’s (326) contention that a high blood- sugar level attends very severe anemia, the reports of others (434, 52) make it clear that no important dis- turbance of the sugar metabolism occurs. Certain chemical alterations in the blood are found. The blood proteins are reduced in the blood as a whole, de- pending partly upon the numerical reduction of corpus- cles and partly upon a reduction in the serum protein METABOLIC OBSERVATIONS 189 (46, 331, 497). The individual corpuscles show an in- crease in protein corresponding to their increased average size (46). The serum albumin is normal but the serum globulin is very much decreased (46). The blood as a whole shows a lowered total nitrogen because of the reduction in corpuscles, but the plasma shows either normal or high total nitrogen values (497). The relation of the total whole blood nitrogen to the total plasma nitrogen constitutes the nitrogen index, a figure which will decrease in proportion to the severity of the anemia, and might have some prognostic value (497). The only nitrogen fraction increased in the blood is the creatinin (331), due more to a destructive process present in the body than to any failure of the kidney to eliminate this substance. Others have found urea and especially the amino-acids increased (222). Disturbance of the acid-base balance of the body is in- dicated by the reduced COz combining power of the plasma and an increased hydrogen ion concentration of the plasma. In three cases examined by Kahn and Barsky (331) the COs of the alveolar air was 4.4, 4.7, and 4.6 respectively. Reference has already been made to the absence of the alkaline tide in the urine. As Blankenhorn has shown, bile salts are frequently found in the blood, either alone or associated with bili- rubin. This suggests that the liver is implicated in the disease process but to what extent is not known. Liver function (331) has been referred to in the last chapter. The mineral content of the blood is slightly altered. The ash is increased through increased calcium and mag- nesium (331). The serum contains more potassium than normal (46). The total phosphorus content of the whole blood is roughly parallel to the hemoglobin in all persons in whom the values of the total phosphorus in plasma and corpuscles are within normal limits. This parallelism is / 190 PERNICIOUS ANEMIA due to preponderance of phosphorus in the red blood cor- puscles. Immature red blood corpuscles probably contain more phosphorus than adult ones. Buckman et al. (79) give the following figures for phosphorus in pernicious anemia blood: TABLE 20 Phosphorus in blood of pernicious anemia (Buckman, Minot, Doland, and Weld). HPO am 100 ce. oF m2 29 Ke oO ° ae , a “5 S ) 8 3 : Bo a y F) a 5 2 ve 6 SE a of) =: ° as) “a 4 = S) < A = A, S eo © ae 1 58 P.A. 9.8 LAS a 0.8 20 9.6 2 21 P.A. 13.1 13:2 12.0 1.4 30 12.9 3 50 P.A. 11.9 12.1 8.3 13 30 8.0 4 73 P.A. 10.2 10. 9.5 1.8 35 21.3 11 55 P.A. 12.6 13.6 6.9 1.0 55 14.8 12 51 PaaS 13.6 14.8 12 1.7 55 16.4 13 39 REAG 1355 14.0 11.9 2.8 55 29.3 14 50 P.A. 14.2 13.7 15.8 2.6 60 25.9 Haden (246) could find no positive evidence of a dis- turbance of chloride metabolism, although a few cases showed a low chloride content of the blood. The chloride level of the blood bore no relationship, in other anemias, to the free hydrochloric acid of the gastric juice or to the volume index of the red blood cells. Rioch and Cameron (529) found in the active stages of the disease that the red corpuscles contained less chloride than normal but that the plasma chloride is rela- tively constant and normal throughout. They emphasize the importance of estimating the chloride ion in the gas- tric secretion since, in their experience, this ion, as well as HCl, was absent. Major (396) found so little urinary chloride excretion as to suggest a retention. The ingestion of from 6 to 20 grams of NaCl by five patients daily produced no increase in chloride excretion, although these cases gave no evi- METABOLIC OBSERVATIONS 191 dence of renal disease. Major suggested that the retention might bear some analogy to the retention seen in lobar pneumonia and in certain cases of intestinal obstruction. Haden (248) has likewise emphasized the resemblance of the chloride metabolism in pernicious anemia and intesti- nal obstruction. The catalase content of the blood was investigated care- fully by Krumbhaar and Musser (349), and was found diminished because of reduction of red blood cells. They regard the reduction in catalase which follows splenec- tomy as due to the transient anemia resulting. The cata- lase index is the number of cubic centimeters of oxygen liberated, divided by the number of million red blood cor- puscles. Thus :— No. of cc. oxygen liberated by 0.1 cc. blood in 15 min- utes is 37 No. of millions of red blood cells per cubic millimeter of blood is 0.92 Catalase index is 40. From their tables, the following average figures are quoted : TABLE 21 Catalase index in various conditions (average results) (Krumb- haar and Musser). Cc. Oxygen R. B. C. per Catalase C. Mm. Condition liberated Index Pernicious anemia (O)\cases) jyiees tia Sees 45.3 1,480,000 28.6 Other anemias Gilt eases) F 20). VIET es 92.5 3,322,000 28.0 Non-anemia (5 cases) Normal’ (4) cases) 22.00.52 164.1 5,015,000 32.7 (Strauss and Rammelt’s (602) catalase index was the number of grams of H2Oz liberated from 30 cc. of 1 per cent H2O2 by 1 cc. of a 5: 1000 blood solution, divided by the number of millions of red blood cells in this 1 cc. of diluted blood. On this basis, normal blood has a catalase index of 4.6; that of secondary anemia, 4.8; polycy- 192 PERNICIOUS ANEMIA themia blood 3.2; and the blood of pernicious anemia, 8:5). Becker et al. (37) found increased amounts of blood phenols, as well as free phenols in the blood of pernicious anemia. The blood serum of pernicious anemia is said to have less inhibiting effect on pepsin activity than has normal serum, although it is usually considered that in anemias the anti-enzymatic activity of the serum is increased. Simon (580) found in 6 out of 14 patients the presence in the serum of a lipase which differed from normal se- rum lipase in being resistant to the action of atoxyl. This atoxyl-resistant lipase is destroyed by quinine, as are the lipases of the sera from all diseases except those with jaundice of hepatic origin. The origin of this atoxyl- resistant lipase is obscure but it is presumably derived from the pancreas. Simon found it also in cases of pan- creatic disease. The writer (135) was able to confirm the presence of this lipase in only 6 of 36 cases of pernicious anemia, although the sera used were usually more than a day old; in one of the 36 cases a cholesterinase could be demonstrated as well as a tributyrinase. The atoxyl-resis- tant lipase of Simon probably has no great significance in this disease. Stephan (591) claims to have found a proteolytic fer- ment in pernicious anemia serum, derived, he believes, from the reticulo-endothelial cells, and constituting one argument for his hypothesis of overactivity of these cells as the cause of the disease. The organism suffering from pernicious anemia is capable of forming agglutinins to B. typhosus and B. paratyphosus, A. and B. (280). Compensation for diminished hemoglobin content of the blood is accomplished by increased pulse rate, in- creased cardiac output per beat, and increased depth of respirations which is chiefly of value in filling the right METABOLIC OBSERVATIONS 193 side of the heart (191, 453). Meyer and Dubois (435) found the basal metabolic rate but very slightly increased in three mild cases but in two severe cases the demand for oxygen was from 7 to 33 per cent above the normal average. The basal metabolism in pernicious anemia was lower than that of leukemia, but higher, as a rule, than that of simple anemias. The agreement between the direct and indirect calorimetry, as well as the respiratory quo- tients, indicates that the basal metabolism of pernicious anemia is qualitatively identical with the normal. The basal rate, when determined on a series of cases, shows no great difference from that of normal indi- viduals. Some are a little above, and some a little below, normal. Wilson (659) noted a tendency for the rate to be low during relapses. Tompkins, Brittingham, and Drinker (614) have made the most illumninating studies undertaken in connection with blood transfusions. A patient with pernicious ane- mia shows, after transfusion, an immediate fall in heart and respiratory activity, but no immediate fall in meta- bolic rate. Some days later, however, the metabolic rate invariably falls. Muscular activity reduction cannot ex- plain this diminution of energy output. These investiga- tors feel that there are two opposing factors operative on the metabolism of these patients. (1) There is a tendency to increased use of energy, perhaps occasioned by the ab- normal and increased marrow activity. (2) There is a tendency to decreased use of energy, caused by the patho- logical storing of fat not only in fat depots but as infiltra- tions in normally active tissues. The use of energy for blood maturation is brought to a stand-still by a blood transfusion, not all at once, but after a period of days, during which adjustment of some sort takes place. In other words, blood transfusion neutralizes the stimu- lation to blood formation. Hence transfusion really un- masks the actual metabolic state of the patient. When 194 PERNICIOUS ANEMIA thus unmasked, the metabolic rate is invariably found to be lower than it was before, regardless of its previous level. It is of interest that blood transfusion lowers the temperature if it has been previously elevated. The specific dynamic action of foodstuffs has not, so far as we are aware, been studied in patients with this disease. Mason and Mason (410) noted a depression in the metabolic rate following exposure to ultra-violet light in certain cases, a phenomenon possibly associated with the presence in the skin of bilirubin. Kabanow’s (330) sero-diagnosis of pernicious anemia has never received very wide recognition. Red corpuscles in this disease show an extremely high degree of reversi- bility of hemolysis (590). The use of foreign protein thereapy frequently does away with diarrhoea and fever and may apparently initiate improvement generally (183, 284, 514). CHAPTER VIII THE NERVOUS SYSTEM Nervous changes were not specifically remarked by the earlier observers, because the manifestations, except for marked neurotrophic and motor disturbances (which are not constant) tend to be largely subjective, and when objective, certainly not obtrusive. Addison (5) noted fatty changes in a portion of the semilunar ganglion of the solar plexus. Biermer (60) mentioned hemorrhages in the brain and retina. Little (381) construed most of the total general symptomatology as evidence for primary involvement of the nervous system, a construction which, though periodically revived (266, 390, 581), cannot now be sanctioned. Lichtenstern (373) in 1884 reported pos- terior column degeneration and pernicious anemia occur- ring in two cases diagnosed as tabes dorsalis. It is almost certain they were instances of true pernicious anemia. Lichtheim (374) in 1887 described a case of severe anemia presenting clinically stiffness and weakness of the legs, ataxia, parasthesia, and Rhomberg’s sign, and, post mortem, marked degeneration of the columns of Goll and Burdach, with foci of degeneration in the lateral and anterior columns. Lichteheim’s findings not only opened up a new aspect of pernicious anemia but stimulated neurological investigations in general. During the next thirty years, the reports of Putnam (504), Dana (137), Stewart (595), von Noorden (625), Eisenlohr (168), Minnich (437), Nonne (472, 473), Burr (85), Money (451), Taylor (608), Boedeker and Juliusberger (53), Russell, Batten and Collier (543), Lloyd (382), Colquhoun (127), Klein (341), Bastienelli (32), Clark (117), Petren (498), Campbell (97), Duck- worth (156), Brown, Langdon and Wolfstein (75), Bil- lings (61), Bramwell (65), the Déjerines, Crouzon, and [ 195 ] 196 PERNICIOUS ANEMIA Jumentie (140, 141, 142), Cadwalader (93), Schaller (550), and many others delineated the spinal-cord changes as a type of combined system disease, causing well-recog- nized symptoms and signs. Frequently enough, these were — taken to constitute a separate disease of the nervous system. During the past ten years (1917-1927), the report of Hamilton and Nixon (253) settled in the affirmative the question whether peripheral nerve degeneration occurs. Hurst and Bell’s (311) reports on achlorhydria in these cases constitute a very strong argument for refusing them the status of a disease distinct from pernicious anemia. Woltman’s (662) report demonstrated that the brain, as well as the cord and peripheral nerves, showed degenerative foci. The contributions of Hamilton and Nixon and of Woltman are of classical importance in pathology and ought to be studied in great detail. THE ANATOMICAL AND HISTOLOGICAL CHANGES The brain (662) on being exposed is normal in size, of a grayish white or pearly white apearance with, usu- ally, considerable edema of the pia-arachnoid, and some peri-vascular opacity in these membranes. The sinuses are usually practically empty. The ventricles are normal in size and their walls smooth and glistening. The vessels at the base of the brain may show slight thickening and stand open when cut, but do not present atheroma. The spinal cord appears large, in spite of the degener- ative process within it. This is because of the edematous nature of the process and the absence of neurogliar proliferation (125). Hemorrhages of a petechial nature may be found in the dura, both of the brain and cord, or in the paren- chyma of either, while, exceptionally, a considerable hem- orrhage may be found in any of these situations. THE NERVOUS SYSTEM 197 The characteristic lesion, essentially the same in the cord and brain, is the so-called Lichtheim plaque, which consists, in the early stage of its formation, of a small area in the white matter, of a darker and more translucent appearance than normal. In the cord, the plaque usually makes its first appear- ance in the lower thoracic region and in the centre of both posterior columns and soon afterward in the centre of both posterior columns as well. Later, small areas of degeneration may be seen scattered through almost the whole of the antero-lateral columns. These by coalescence eventually may involve the entire white matter of the cord in a degenerative process, the only portion to escape being the narrow zone of short internuncial fibres which lie next to the gray matter. In its most fully developed state, therefore, an almost complete transverse degener- ative blocking of the white matter occurs. It is only in the early stages or in moderately affected cases that the pro- cess is limited to the posterior or to the lateral columns. As Collier (125) points out, this annular degeneration of the lower thoracic portion of the cord is highly char- acteristic and occurs in no other disease. Progression upwards and downwards takes place by the occurrence of isolated plaques of degeneration in the posterior and anterolateral columns, and by extension of these and coalescence with areas already degenerated. In this way it does not resemble a system disease of the spinal cord. The process may extend upwards as high as the internal capsule in the pyramidal tract. The trans- verse area involved varies from being confined to the posterior and lateral columns, or, as previously indicated, to involvement of almost the entire white portion of the cord. Cavity formation may occur in the cord (34, 96, ol, 212); Two other types of change may be seen. (1) Secondary degeneration of the white columns both upwards and 198 PERNICIOUS ANEMIA downwards from the Leichteim plaques. (2) Retrograde changes, tigrolysis, vacuolization, shrinking and neuro- phagy in the nerve cells of Clarke’s column and in the Betz cells from which the pyramidal fibres originate. In the brain (662), the lesions of greatest interest are the plaques of degeneration in the medullary substance of the cortex, sometimes visible to the unaided eye, and equally often to be detected only by microscopic exami- nation. These plaques are usually smaller, fewer in num- ber, more widely scattered, and less readily enlarged by coalescence and secondary degeneration than those in the cord. There also occur small round areas about 0.1 milli- meters in diameter, most numerous in the medullary por- tion of the cortex, giving the appearance of a localized edema. Again, the gray matter in the margin of the gyri shows pyramidal cells in all stages of degeneration, sur- rounded by small areas of partial necrosis. Woltman thought these degenerations were caused by the same process as produced the plaques in the medullary sub- stance. Varying degrees of tigrolysis, vacuolization, nuclear swelling, and axonal reaction were observed. Satellitosis and neuronophagia were also seen. Woltman confirmed the observation of Henneberg that neurogliar reaction was practically absent. Woltman (662) from a review of the literature, and from his own studies, is inclined to attribute the nervous lesions to the action of some toxin. Blankenhorn (48) has suggested the possible role of bile salts in this connec- tion. The spinal fluid has been found negative on bacterio- logical and cytological examination (103). The mechanism by which degeneration is brought about has been the subject of much argument. One theory regarded petechial hemorrhages in the nerve tissue as the starting point (437). Another regarded those areas most liable to degeneration which received the largest blood supply and therefore presented the largest expos- THE NERVOUS SYSTEM 199 ure to toxin (401). Another merely reversed the latter theory, stating that areas of poorest blood supply would suffer most (68). The ‘“‘vascular theory” was abandoned because it was shown that hemorrhage did not always occur and that vessel changes did not correctly corre- spond to areas of degeneration (32, 322, 505, 543). A theory was advanced to the effect that the changes found in the white matter were secondary and but part of a cycle of degeneration which began in anterior horn-cells, whether or not these cells gave microscopic evidence of injury (539, 610). The theory of a true infectious myelitis of dissemi- nated type (53) had to be abandoned because of the lack of inflammatory reactions. Dana (138) noting that it is the peripheral ends of the axones of the pyramidal cells and of the posterior ganglion cells that chiefly show the destruction, considered this due to the distance of this portion of the nerve fibre from its trophic centre. Wolt- man (662) considers that lymph stasis is an important factor in the production of the Lichtheim foci, since plaques so frequently occur around the blood vessels. The earliest change is swelling of the medullary sheaths over a small area of the white matter (125). The swollen sheaths then break up by fatty degeneration, and the axis-cylinders become no longer recognizable. The degen- erate contents of the swollen medullary sheaths now gradually disappears, leaving nothing but the fine con- nective tissue of the spinal cord surrounding vacuolated spaces filled with fluid, of varying size, some of which represent the spaces originally occupied by the nerve fibres, but others are formed by the fusion of several such spaces (Collier 125). Hamilton and Nixon (253) show that marked degen- eration may occur in the anterior and posterior roots and in the peripheral nerves. 200 PERNICIOUS ANEMIA THE OCCURRENCE OF NERVOUS INVOLVEMENT Five ill-defined types of pernicious anemia may be recognized, depending upon the time of appearance of nervous symptoms: (a) cases with blood changes preced- ing the nervous symptoms by some months. This is the most common order of appearance, the neurological mani- festations not being noted until nine or ten months after the establishment of severe anemia. Numbness, pares- thesia and motor phenomena may commence just at the peak of a first blood-remission. (b) Cases with blood changes beginning some months after the inception of nervous symptoms. These are the cases in which early diagnosis is possible without anemia. They occur, more- over, usually in persons over fifty years of age, and the anemia is likely not only to begin very suddenly, but to run an acute course. (c) Cases in which the blood-system and nervous-system changes begin together. The writer has seen two cases presenting initially the following find- ings: parasthesia and numbness of the extremities, glos- sitis, reduction in hemoglobin, greatly disturbed cellular morphology but no reduction in the number of the red blood cells. (d) Cases with blood changes occurring only terminally. These are the so-called “pure’’ examples of subacute combined degeneration of the spinal cord, and are responsible for the fact that the nervous changes were regarded as having an independent existence as a generic disease. More careful and prolonged blood exami- nations have shown not only that a simple anemia usually accompanies these cases, but that, near the end, even if for only a period of six weeks, a truly specific anemia occurs, not to be distinguished from that of pernicious anemia. (e) Cases without blood changes. These are rare instances of fulminating cord damage which terminate fatally before the blood system has become implicated. The nervous system is involved in eighty and six-tenths per cent of all cases diagnosed as pernicious anemia (663, THE NERVOUS SYSTEM 201 664). It is therefore somewhat less often involved than the blood system (in ninety per cent) and the digestive system (in nearly one hundred per cent). These facts, coupled with the almost invariable finding of achlor- hydria in association with subacute combined degenera- tion, bring out the essential unity of the whole Addisonian complex, which may be regarded as a triad of system changes in which only one system—the digestive—stands obliged to change, the other alterations—those of the blood and nervous system—being superstructures raised upon this basis. The nervous system is involved more frequently in elderly than in younger patients. The occurrence of remissions does not cause improve- ment in the nervous manifestation. Some slight disappear- ance of numbness and parasthesia may be observed, and probably depends on the small margin of recoverability possessed by nervous tissue. Foreign protein therapy and the administration of kefir and aciduric cultures may, for some reason not apparent, bring about some improvement of a similar nature. Objective phenomena do not improve even in liver-diet remissions. Spontaneous or other re- missions seemingly cause but a cessation in the extension of the nervous degeneration. In cases of subacute com- bined degeneration progressing slowly for years without specific anemia, periods of inactivity of the disease may be noted, during which the patient feels comparatively well. Whether specific glossitis occurs in cases of subacute combined degeneration without blood change is not espe- cially noted in the literature. In the writer’s two cases it did not occur. It is quite evident that the nervous changes cannot be due to the anemia. The occurrence of one without the other may indicate a greater susceptibility of the one tis- sue to the causal process. The hereditary influence may 202 PERNICIOUS ANEMIA play a part in deciding this, since the familial occurrence of subacute combined degeneration has been noted (702). The appearance of cord changes in a case already showing characteristic blood changes is believed to indi- cate an intensification, as well as an extension, of the disease process. In the latter half of the disease the degree of cord involvement is of considerable prognostic impor- tance. A remission is not likely to occur in a patient with very marked cord symptoms, or if it should occur, is not likely to be very satisfactory. It is for this reason that heretofore it was unusual to see a case in good blood remission with disabling residual cord change. Such a spectacle is becoming commoner since the liver-diet treat- ment has been used. As before stated the true condition of the patient is ultimately more related to the nervous changes than to the blood changes. THE SYMPTOMS AND SIGNS OF NERVOUS INVOLVEMENT Among the earliest, most persistent and commonest manifestations are sensory subjective phenomena—espe- cially numbness and tingling. Similar sensations may be present in simple anemia when profound, but they may occur as the first indications in this disease, frequently with little or no anemia. Other parasthesiae are quite commonly added—burning, coldness, griping, band sen- sations, dead sensations, twisted and cramping sensations. These begin ordinarily in the glove-and-stocking areas, extending up the legs, in severe cases, even upon the trunk where intersegmental division lines may be noted; although they may begin in the perineum, skin of the head or in the tongue. Girdle sensations occur usually in cases developing spasticity. Lightning pains, similar to those of tabes, have not infrequently been met and have caused suspicion of an abdominal lesion. Dull aching pains, sharp, shooting pains and soreness also occur. THE NERVOUS SYSTEM 203 Among objective sensory changes the one of greatest diagnostic importance is the diminution or loss of deep sensibility in the distal ends of the extremities with little or no loss of cutaneous sensibility in the same parts (525). Thus we may find loss of joint-position sense, diminution or loss of vibratory sense, astereognosis, acro-ataxia, proximo-ataxia, ataxia in locomotion, Rombergism, and loss of finer coordination of the fingers. The extremities may be hyperesthetic to light touch; and the contact of objects with the hands and feet may be painful. An intel- ligent patient described it as, “a feeling of exaggerated sensitivity.” Such hyperesthesia as well as shooting pains, sometimes likened to “electricity,” are found usually dur- ing periods of activity when the cord symptoms are rapidly progressing. During other stages, cutaneous hyperesthesia and anesthesia to touch, temperature and pain may occur. The special senses show diminished activity. The motor symptoms comprise muscular weakness in the legs, paraparesis, paraplegia, and weakness or paraly- sis in the arms, trunk, viscera and sphincters; ataxia in locomotion, ataxic paraplegia; spastic and flaccid paraly- sis in the legs. The condition of the reflexes depends upon the exact nature of the cord involvement in a given case. Trophic disturbance is shown in the muscular wasting and atrophy and the common occurrence of bed sores. The paraplegic signs ordinarily follow after the sen- sory changes but may, in exceptional cases, usher in the disease. Usually the patient has become only gradually consciousness of leg weakness, unsteadiness or incoordi- nation, and shows on examination slight rigidity of the lower extremities with weakness of certain muscle groups, with increased knee jerks, ankle jerks, foot clonus, and an extensor type of plantar reflex. In some cases, with implication of the lateral column of the spinal cord, the knee jerk is diminished or lost, and the picture is that of ataxia with flaccid weakness. 204 PERNICIOUS ANEMIA The clinical picture will depend in every case upon the transverse and longitudinal extent of cord involvement. When the posterior columns are alone involved, as they exceptionally are, a fairly rapidly developing paraplegia usually results. When the lateral columns are chiefly affected, spastic gait, increased reflexes, and some degree of paralysis result; when the posterior columns are chiefly affected, the tabetic symptoms appear and may progress to loss of sphincter control. Usually both col- umns are affected, the one more than the other. A rapid annular degeneration involving the whole white matter of the cord may present the clinical picture of a transverse myelitis. As the disease advances, paraplegia progresses upwards involving more and more of the trunk. Paraplegia may eventually become complete with great muscular atrophy, and ordinarily with disappearance of the spacticity. The paraplegia does not often proceed as high as the upper lim- its of the region supplied by the cervical cord enlargement. Although sexual impotence may be an early symptom in the male, bladder disturbances and loss of sphincter control are usually late manifestations. An easy excitability of the skin reflexes, remaining well through the disease, is highly characteristic. An en- tensor type of plantar reflex is usually the first definite sign of organic involvement and remains unchanged. The deep reflexes usually show an initial increase becoming later lost, with development of the paraplegia. The reappearance of deep reflexes after being lost indi- cates that the lesion was first confined to the posterior columns and later attached to the lateral columns. A disharmony between the clinical and pathological cord findings very often occurs, and is probably explained correctly by Hamilton and Nixon (253) on the basis of common lesions in the peripheral nerves. THE NERVOUS SYSTEM 205 ALTERATIONS IN THE PSYCHIC FUNCTION Quite apart from any definite psychic abnormalities which may attend the disease, a certain constitutional mental make-up has been noted in these individuals. “, . these patients are different in some way from other patients: they listen to what you say, they do not argue, they raise no objections; they are almost too good” (665). They have been regarded as extremely susceptible to their environment (31). Sometimes the very first manifestation of abnormality in cases eventually becoming pernicious anemia is an apprehensive neurosis. Langdon (353) went so far as to regard this and other premonitory mental states as mani- festations of “pre-pernicious anemia.” It required time for other alienists to become agreed with Langdon. Wolt- man now even suggests that a certain group of mental cases are really pernicious anemia without anemia (665). The psychic disturbances range from mild depression to violent maniacal outbursts (Lurie 388), from indiffer- ence, apathy and severe melancholia to irritability, hyper- kinesis, delusions and hallucinations. Barrett (27, 28) would place the psychotic manifesta- tions among the paranoid conditions which are sympto- matic of a toxic, organic process affecting the central nervous system. Sometimes a distinct psychosis, such as manic-depres- sive insanity may occur. These patients have, in the writer’s experience, usually given evidence previously of harboring a psychosis. It is the general experience of mental hospitals that these psychoses clear up during re- missions and return with relapses. Barrett could not regard the cortical organic changes found as being of specific type, resembling rather those which occur in chronic intoxications. Woltman did not regard the brain changes as the cause of the psychic dis- turbances but referred the latter to the operation of a 206 PERNICIOUS ANEMIA toxin. Lurie’s autopsies had all shown psychic disturb- ance in life, so that the constant finding of cerebral lesions did not indicate a causal relationship, which would obviously be proved only by negative brain findings in all cases without psychic involvement. Woltman, how- ever, found just as marked brain changes in cases with normal mentality as in those with mental disturbance. The coma which usually precedes death, especially in cases with definite nervous involvement, ordinarily lasts from twenty-four to seventy-two hours. In some cases it is a deep coma, the patient never rousing. In other cases the lodging of mucus in the pharynx may rouse the patient for a moment, even when voices or shaking have failed to do so. In cases with psychic confusion, coma seems but a deepening of the mental clouding, and such patients may rouse during the early stage of coma to make some mut- tering remark with regard to their favorite delusion. Cheyne-Stokes respiration can usually be detected for many hours before death, and even before the pulse gives any indication of weakening. Woltman regards the coma as evidence of the effect of a toxin on the cerebral cortex. CHAPTER IX CARDIOVASCULAR, RESPIRATORY, GENITO- URINARY AND OTHER SYSTEMS THE CARDIOVASCULAR SYSTEM Combe (128) noted the pale color of the heart at autopsy. Addison (5) mentioned the fatty change in the heart muscle and remarked on the easily excited pulse. Biermer (60) wrote on the cardiac murmurs, bruits in heart and great vessels, the clinical resemblance to endo- carditis, the occurrence of hemorrhages and the post mortem finding of fatty degeneration of the cardiac muscle. Most of the earliest observers, including Elliot- son (171) were impressed by the cardiovascular findings. It is difficult to distinguish cardiac symptoms from those due to the anemia. Dyspnoea, weakness, and faint- ness are probably to be attributed more to anemia than to the heart, especially in the early stages of the disease, although in the later stages the cardiac condition assumes an undetermined part in their production. Pre-tibial edema is not an infrequent occurrence but it is not clear in what degree it is to be attributed to the heart. There can be no doubt that increased permeability of the vessel walls, due to trophic disturbance secondary to the anemia, and possibly other unrecognized factors, play their parts. Williamson (665) was unable to decide in his unusual case of anasarca complicating the disease, what factors were most involved, for there were evidences both of cardiac insufficiency and impaired vascular vitality. Smith (582) noted the infiltration of tissues by serum in cases showing gain in weight without blood improvement after transfusion, and regarded this increase of tissue fluid as frequently indicative of a critical phase, to be followed either by improvement or death. The cardiac and vascular conditions, as well as the increased filterability [ 207 ] 208 PERNICIOUS ANEMIA of the plasma result, at any rate, not only in clinically recognizable edema (pre-tibial, pulmonary) but in in- crease of the serous fluids, and in mediastinal, perilaryn- geal and mesenteric infiltration in some cases (605). A moderate thickening of the radial arteries is some- times met with, but definite radial sclerosis must be a rare finding in this disease. The vessels at the base of the brain are sometimes moderately thickened but atheroma has not been observed (662). The widespread extravasations noted first by Biermer (60) were attributed by him to vascular weakness al- though the functional purpura which exists must be taken very thoroughly into consideration in this connection. Punctiform hemorrhages may occur in the retina, men- inges, brain surface, serous membranes, gastric mucosa, urinary and gall bladders, and pancreas. Intestinal hem- orrhage, sometimes of a severe character, is not really uncommon. Metrorrhagia, hematemesis and epistaxis also occur. The capillaries are sometimes found quite empty, and sometimes so unusually narrow as to suggest a constitu- tional hypoplasia (270). The macrocytes tend to loitre in the capillaries and this has been presented as a reason why these patients’ complexions are as good as they are (157). Cardiac pain was noted as a definite feature in perni- cious anemia by Herrick and Nazum (267). Coombs (130) by special attention to this point found cardiac pain in eight out of thirty-six patients. In two, there was sub- sternal pain on exertion. One had “heavy” pain over the chest and shoulders. Another had a painful constriction around the waist. Another had a tearing, pressing pain in the centre of the chest and in the arms. Another com- plained of midsternal pain during the examination. In all these, pain was brought on by exertion. One had atheroma of the aorta, while one died from severe precordial pain. Reid’s (519) enquiry indicated a note-worthy absence of sclerotic changes in the heart. SYSTEMS 209 Cardiac hypertrophy, sometimes very considerable, is often associated with the disease. In Cabot and Richard- son’s (88) series of nineteen cases, eighteen showed a definite hypertrophy or dilatation. In only three of these could possible causes for the hypertrophy be found in the heart itself, while in the other fifteen cases none of the usual causes or accompaniments of cardiac hypertrophy were present. Coronary sclerosis was found in but one case, while slight arteriosclerosis in the aortic arch and of the abdominal aorta were noted in several of the cases. Systolic murmurs, to some extent “hemic” in char- acter have been recognized for over fifty years as almost constant findings, heard at the base and in various valve areas. They may be heard in only a little over half the cases on first examination, since they may not be present at the moment the stethoscope is first applied. Needless to remark, valvular disease is not a part of pernicious anemia. In view of Cabot’s (87) demonstration of the rarity of true valvular insufficiency, such an explantion and the usual one had better be withheld. If murmurs are due to vibration of the valve cusps, then possibly the momentum of the blood with its reduced specific gravity does not furnish sufficient impact to hold the valves steady. The fatty change in the myocardium is conspicuous. In fact this is the only disease in which very marked fatty degeneration of the heart muscle occurs. The papillary muscles of the left ventricle usually present a yellow, striated appearance like a tiger’s skin, and in severe cases even wider territory may be involved. The mural muscul- ature never presents a normal red color and varies from a reddish-gray to a frankly yellow color. Microscopically, fat lies in scattered foci in the muscle fibres, replacing to some extent the contractile substance. Reid (519) takes the view that the infiltrated fat is brought to the heart by the blood in a normal physiological manner, and that the fatty change does not impair myocardial efficiency. This 210 PERNICIOUS ANEMIA view seems to be somewhat extreme. Much discussion has centred on the fatty changes in the heart, liver and kidney as well as in the medullary substance of the nervous sys- tem, but it is our duty to do little more than note its occurrence. In patients dying with symptoms of acute heart failure after blood transfusions, it is not clear that death can be attributed to the heart alone. Possibly it cannot be attributed to the heart at all. Reid’s (519) electrocardiographic studies revealed no abnormalities of any significance. The Q.R.S.T. inter- val was of normal duration, the inference being that the ventricular systole is not lengthened and that the increased output of the heart cannot be due to such a factor. The increased pulse rate is due, in part at least, to the heart’s effort to compensate for the anemia. The pulse is usually regular, full and easily compressible. The systolic pressure disproportionately low, with a resulting high pulse pressure. Addison and Elliotson both noted the stimulation of the pulse rate and force caused by exertion or emotion. Some observers have noted that individuals were hypertensive before the disease (495). THE RESPIRATORY SYSTEM Emphysema, noted in sixty per cent of cases, may par- tially explain the distressing dyspnoea, and is no doubt due to nutritional disturbances causing atrophy of the elastic tissue with consquent dilatation of the air vesicles (605). Hydrothorax, which occasionally occurs, may be attributed to associated myocardial weakness. Pleural effusion of less extent is not very uncommon. The chronic hacking cough characteristically seen in the last weeks of life is due to pulmonary congestion and moderate edema, the latter caused partly by circulatory weakness and partly by increased filterability of the blood. Pulmonary edema of marked degree is a common terminal event, the patient drowning, while comatose, in his own secretions. SYSTEMS 211 Symmer (605) suggests that the pulmonary edema may be due to disproportionate activity of the two ventricles, the left being relatively weak through fatty transform- ation, and cites Welch’s (639) experimental edema of the lungs produced by compression of the left ventricle. At autopsy the pleural fluid is increased in amount and tinged with bilirubin. Many cases show subpleural puncti- form hemorrhages, merely a local manifestation of the general condition of functional purpura. Many patients die of pneumonia. Tuberculosis of the lung is practically never seen. Mathias (408) would explain this by reduced oxygen tension of the tissues. THE GENITO-URINARY SYSTEM A trace of albumin is so commonly to be found in the urine in cases of pernicious anemia, that many have been temporarily diagnosed as nephritis, and the expression “the nephritis of pernicious anemia” has come into being, although into little use. Steiglitz (597) found evidence of mild renal damage, as signified by the presence of albumin or casts or both. On reviewing Cabot’s five hundred and six cases of whom forty-six per cent had albuminuria, fifty cases at the Johns Hopkins Hospital, of whom 62 per cent had albumi- nuria or casts or both, and one hundred cases at the Pres- byterian Hospital, Chicago, of whom fifty-seven per cent showed similar findings, this author finds a total of pre- cisely fifty per cent exhibiting evidence of renal damage. But in one hundred cases of secondary anemia at the last named hospital, only fourteen per cent showed albumin or casts and of these fourteen cases, four had definite nephritis or lesions of the urinary tract. Steiglitz there- fore concluded that disturbance of renal function was common in pernicious anemia. Histological examination of the kidneys revealed de- generation of the tubular epithelium due probably to the 212 PERNICIOUS ANEMIA evident deposition of iron pigment in the convoluted tubules. Iron in these cells inhibited the passage of water and total solids and reduced the specific gravity of the urine. Steiglitz also found that fixation of the specific gravity and increase of night over day volume was char- acteristic. While the tendency is thus to attribute to hemosiderosis rather than to anemia the renal manifesta- tions in this disease, it must not be forgotten that all parenchymatous, active tissue is probably involved meta- bolically by the fundamental, though as yet unascertained, causative process. Christian (110) considered the kidney was affected by a nutritional or toxic disturbance in the renal cellular activity. Using renal dietary tests he found that pernicious anemia was accompanied by impairment of renal function similar to that found in patients with advanced nephritis. But in pernicious anemia no other evidence of chronic nephritis exists and the disturbance appears due to the anemia, decreasing with subsidence of the severity of the anemia unless the anemia is maintained so long that per- manent disturbance of renal functions ensues. Percy (495) has noted pernicious anemia occurring in individuals with chronic nephritis and hypertension, and has remarked on the fact that hypertension is maintained, even in the presence of severe anemia and adynamia, until — the terminal stage of the disease. The urine may be dark, during severe stages of the anemia, from the presence of urobilin. Pigment granules, intracellular or free, in the urine indicate siderosis of the kidney (540). Bladder symptoms—difficulty in micturition and reten- tion—result from disturbed innervation secondary to degeneration of the spinal cord. Woltman (663) found that of one hundred and twenty-one patients with cord involvement, eight per cent had partial incontinence and eight-tenths per cent had complete incontinence, that SYSTEMS 213 retention was partial in four per cent and complete in eight-tenths per cent. Hamilton and Nixon found among forty-one patients, six with urinary incontinence on admission. These symptoms may improve with remissions and recur with relapses (580 A). “Cord bladders” ordin- arily occur late in the disease. In exceptional cases where rapid cord degeneration preceded the anemia, urinary incontinence has been the initial complaint for which the patient sought relief. In elderly men the occurrence of prostatic obstruction may lead to an erroneous diagnosis of “cord bladder.” Sexual vigor in the male suffers very early in cases where the spinal cord degenerates. Menstruation frequently ceases during severe anemia and may reappear during a remission. When it does not reappear it is an open question whether pernicious anemia has caused the menopause or whether the menopause has merely coincided with the disease. Certainly, the fact that the disease is commonest at the ages when the menopause most frequently occurs would rob an etiological theory based on the gonads of all probability of correctness. THE EYES The description by de Schweinitz (147), the first to appear on this subject in America, was discussed by Knapp and covered the subject completely. Earlier reports had appeared in England and on the continent (400, 513, 547, 615). The ophthalmoscopic picture comprises the following changes: (1) pallor of the disc; (2) cloud-like edema of the retina, most marked in the retinal periphery; (3) exudates or plaques; (4) flame-shaped and irregular hemorrhages in the neighborhood of the papilla; (5) hemorrhagic areas containing a yellowish centre, or iso- lated yellowish-white spots which probably correspond to hypertrophied and degenerated nerve fibres. 214 PERNICIOUS ANEMIA The microscopic histological changes include: (1) hemorrhages in the various strata of the retina but most marked in the nerve-fibre layer; (2) marked peripheral edema of the retina. There is no ground for considering these changes to indicate an infectious retinitis, since inflammatory signs are absent. Retinal changes showing some or all of the features described—especially hemorrhages—occur in from forty- four to sixty-two per cent of all cases at the height of the disease. Woltman found them in thirty-three per cent (of low grade) and thirty per cent (with hemorrhages) in a series of one hundred and fifty cases. These retinal hem- orrhages are indicative of the functional purpura exist- ing, and since they may be found in severe anemias of known etiology (for example, that of D. latus infection, 121) and in chlorosis, they are not of great diagnostic value. Goss (233) has shown that blood transfusions produce no immediate effect on the retinal changes, do not prevent further occurrence of hemorrhages, and do not cause the hemorrhages to be any more rapidly absorbed, although a remote effect of transfusion is a gradual lessening of retinal edema, and a decreased tendency to hemorrhages. THE EAR While it is now well recognized that noises in the ears occur with great frequency not only in pernicious anemia but other anemias as well, and that in pernicious anemia they seem related quite definitely to changes in the blood volume, the report of Schwabach (566), which reviewed the literature, indicates that deafness may occur from hemorrhages interfering with either the sound-conducting or sound-perceiving apparatus. CHAPTER X DIAGNOSIS AND PROGNOSIS While it is a truism to state that the more intimate one’s knowledge of pernicious anemia becomes, the fewer will be the diagnostic difficulties encountered, the statement may nevertheless be pardoned in view of the many fea- tures presented by this disease. Early diagnosis is becoming increasingly desirable in view of the recently demonstrated success of the liver- diet in treatment, and it is precisely in early cases, before the blood picture has become fully developed, that most of the perplexity arises. Again, so many systems are involved, that great oppor- tunity exists for suggestions of other disease to creep in, particularly in view of the fact that certain other anemias have somewhat similar blood pictures. EARLY DIAGNOSIS We are beginning to recognize a fairly well-defined condition which precedes this disease and which, in its several variations, might be referred to as “pre-pernicious anemia.” The chief characteristic of this condition is achlor- hydria—the one obligatory feature. Achlorhydria alone does not constitute the condition but only when it is asso- ciated with one or more of the following features—spinal cord involvement, glossitis, and the earliest blood changes. These early blood changes are to be understood as those which appear before any actual oligocythemia is present and consist of the following: increased volume index and anisocytosis. A patient complaining of glossitis, or of numbness and tingling in the extremities, or both, may be regarded— provided he has achlorhydria—as a potential case of [ 215 ] 216 PERNICIOUS ANEMIA pernicious anemia, even if his blood showns no change whatever. The suspicion is rendered certain if he has, additionally, an increased volume index or anisocytosis, or both. The least positive evidence which could place a patient in this early suspected group is a combination of achlor- hydria and increased volume index. There is also an apprehensive neurosis very commonly met with in this pre-pernicious anemia state, which ap- pears to be a specific early involvement of the psychic function and may be regarded as part of the disease. It may occur in patients whose mental histories, personal and family, are negative. Early diagnosis is facilitated by bearing in mind the fact that pernicious anemia is not a disease of the blood alone but affects also the digestive and nervous system (439). It is quite justifiable to diagnose the disease in the absence of anemia, when other systems present incrimi- nating evidence. The specific anemia with disturbed corpuscular mor- phology and high color index, characteristic of the full- established blood picture may, in some cases, supervene rather suddenly upon a blood condition seemingly normal. In other words, disturbed morphology is obvious as soon as any anemia occurs and we may say that the specific anemia appeared “out of a blue sky.” In other cases, the patient has had a simple anemia with low color index for some time previously. This has been due, in some instances, to focal infection, to intestinal indigestion, or other rather obvious causes. It has been due, in some cases, apparently to achlorhydria, for it has been well demonstrated that achlorhydria itself is accom- panied, more often than not, by a simple fluctuating anemia with red corpuscles usually smaller than normal (56, 187). All patients in these simple anemia groups may develop pernicious anemia, in which case the specific DIAGNOSIS AND PROGNOSIS 217 morphological features are merely superadded to an al- ready existing simple anemia. A physician ought to be particularly suspicious of a simple anemia occurring in connection with achlorhydria, and to look for glossitis and disturbances of sensation even though the smear picture indicates no morphological abnormality. The earliest appearance of anisocytosis will usually be accompanied by reduction in the hemoglobin percentage, even though the red blood cells are not as yet reduced in number. In the early stages of the anemia a color index less than one per cent ought not to forbid the diagnosis pro- vided this is the only consideration against it. Furthermore, leukopenia and reduction of the blood platelets may not be striking in early cases, because these features indicate a more intense marrow involvement than usually occurs at first. The power of the marrow to sustain even a mild leukocytosis, in the presence of infec- tion, is particularly to be remembered in early cases, for the diagnosis is justifiable where, in an early case, a white blood count of thirteen thousand per cubic millimeter is found as a result of some recognizable infectious complication. Inasmuch as patients with achlorhydria are somewhat prone to infections such as cholecystitis, pyorrhoea alveo- laris, apical abscess, and appendicitis, and inasmuch as achlorhydria is always associated with gastritis and may be associated with exophthalmic goitre (450) and with arthritis deformans, it follows that every anemia occur- ring in connection with any of these conditions should be intensively studied from the standpoint of tongue changes, cord changes, and morphological blood changes. Such a study will be rewarded quite frequently by an early diag- nosis of pernicious anemia. 218 PERNICIOUS ANEMIA Certain of the constitutional peculiarities of the patient should be kept in mind, especially prematurely gray hair, and the feminine bodily characteristics of the male pa- tients previously referred to. There is no doubt that if all the facts of pernicious ane- mia are kept constantly in mind, the early detection of characteristic symptoms, and of pathognomonic symp- tom-groups, will become a much more common accom- plishment. DIAGNOSIS AFTER THE ANEMIA IS ESTABLISHED Real difficulty is occasionally encountered in differenti- ating this disease from the following diseases in particu- lar—cancer of the stomach, syphilis, sprue, the chronic hemolytic anemia of pregnancy and dibothriocephalus anemia. These various conditions will be briefly described with emphasis on the points of difference from perni- cious anemia. Cancer of the stomach (67, 255, 256, 348, 527, 585, 644). In all cases of cancer of the stomach the gastric acidity is reduced, while achlorhydria occurs in fully 50 per cent, as judged by the fractional test meal. Therefore in half the cases, the one fundamental physiological fea- ture of pernicious anemia is present. It is unusual for gas- tric carcinoma not to be accompanied by anemia of some type and of some grade, at some stage. In by far the great majority of cases this anemia is of a simple type—low color index and regular cellular morphology. This simple anemia may, however, be very severe. There are three or four possible factors which may be considered as causing this simple anemia—disturbance of nutrition consequent upon anorexia, obstruction and fermentation, septic in- fection in and around the cancerous area; loss of blood by hemorrhage or constant oozing from the ulcerated growth or from a polypoid growth, and, finally, a factor upon which sufficient emphasis has perhaps not been DIAGNOSIS AND PROGNOSIS fag) placed, viz., the absorption into the blood of hemotoxic autolytic products of the cancer itself. However it may be caused, this simple anemia of varying severity is usu- ally the type present and the type which remains until death. There is a second type, more severe, which occurs in a lesser number of cases, characterized by features common to both simple and pernicious anemia. The color index is low, achromia is prominent; but, on the other hand, ma- crocytosis is present. The macrocytes, however, are defi- nitely circular in outline and show achromia, whereas in pernicious anemia the macrocytes are nearly all oval in outline and never show, during active phases, any achro- mia of importance. Finally, there is the third type, the cases being few in number, which resembles Addisonian anemia sometimes very closely—high color index and oval macrocytosis. Even in these cases, there does not occur so much reduc- tion in the leukocytes, and this is a ready point in differ- entiation. The remarks that apply to this form of anemia apply equally to the “pernicious-like”’ anemia which occa- sionally accompanies carcinoma of the colon. In both, besides this macrocytic anemia, glossitis sometimes occurs and makes distinction from pernicious anemia very diffi- cult. But the lack of myeloid depression, as evidenced by lack of leukopenia, is a point to be repeated and empha- sized. Another diagnostic point of importance is a low icterus index. So far as critically reported, the degree of bilirubinemia in these severe anemias of gastric cancer is within normal range, whereas in pernicious anemia it is considerably increased in the vast majority of cases. This difference in the bile pigment distribution, if it con- tinues to be reported, should do much to differentiate this “cancer anemia.” When metastases form in the bone marrow a similar pernicious-like anemia develops, although here again 220 PERNICIOUS ANEMIA marked leukopenia seldom occurs. During life, pain over the bones involved may suggest this condition. At autop- sy cases of this severe anemia of gastric carcinoma fail to show characteristic hemosiderosis of the liver. Cancer of the stomach not infrequently complicates an already existing pernicious anemia. The presence of true Addisonian anemia is indicated by spinal cord involve- ment and increased icterus index, neither of which are likely to be present with gastric cancer. Marked loss of weight may occur in pernicious anemia and is therefore an unreliable criterion in diagnosis. If the presence of a gastric cancer has been proved, then the problem of whether the anemia is due to this cancer or due to associated pernicious anemia is often one to tax the resources of the clinician. In some cases a double diagnosis is quite justifiable. Syphilis (208, 271, 512, 592). The statement is occa- sionally seen in the literature that the blood of patients with pernicious anemia often gives a positive Wasser- man reaction in the absence of syphilis. The writer recent- ly did blood Wasserman tests on sixty-four consecutive patients with true pernicious anemia. The cases were all derived from the rural parts of Ontario where syphilis is uncommon. The tests were carried out first by the modi- fication of the original Wasserman as employed at the Johns Hopkins Hospital, using their antigen, and checked by the Kolmer Wasserman method at the Ontario Public Health Laboratories, Toronto, through the co-operation of Anderson. The results were consistently negative by both methods. The patients from whom these blood sam- ples were taken were in various stages of the disease from perfect remissions to coma. The reactions were carried out within twenty-four hours of the time of taking the samples. We are persuaded that a positive Wasserman is uncommon in uncomplicated Addisonian anemia. DIAGNOSIS AND PROGNOSIS 221 This means, we believe, that when a positive Wasser- man is obtained on a fresh sample of pernicious anemia blood, the question of syphilis should be seriously con- sidered. Cases of severe macrocytic anemia very strongly sug- gestive of pernicious anemia may be encountered in indi- viduals with tertiary syphilis, especially during the late period of the disease when cachexia is evident. If the anemia can be entirely and permanently cured by anti- syphlitic treatment, it is fair to believe that it was due to syphilis, since such treatment cannot cure pernicious anemia. Clinical distinction must rest on finely drawn micro- scopic evidence—the shape of the macrocytes, the degree of myeloid depression—on the icterus index and associat- ed signs in the tongue and nervous system. Post mortem it may be possible to judge from the bone- marrow reaction and liver siderosis which disease caused the anemia. In urban centres where syphilis is common, the two dis- eases may co-exist, and, where justifiable, the double diagnosis should be made. These cases with syphilis do cause great perplexity and it must be admitted that syphilis of itself can cause a very severe macrocytic, pernicious-like anemia, and even, at times, characteristic cord changes. The etiological dilemma thus arising has already been sufficiently discussed. Sprue (1, 66, 169, 207, 465, 471, 517, 622, 661). The anemia of sprue resembles that of pernicious anemia, al- though in the great majority of cases the Price-Jones graph in sprue shows less shifting of the curve to the right. It is nevertheless true that the smear picture bears a striking resemblance to that of pernicious anemia. Marked oligocythemia, high color index, and a delayed Van den Bergh reaction are other points of resemblance. 222 PERNICIOUS ANEMIA Finally, the common occurrence of glossitis in sprue adds a feature which renders confusion with pernicious anemia inevitable. In a large proportion of sprue cases, however, the dif- ferentiation can be made by several points. The gastric contents contain free HCl, the degree of anisocytosis is not so great, and the diarrhoea tends to be of a fermen- tative type and to occur chiefly in the morning. Cord symp- toms are usually absent and the dorsum of the tongue shows central rather than peripheral fissuring, and atrophy of filiform papillae near the tip rather than gen- eral papillary destruction. Where achlorhydria appears it can often be followed in its development during the disease, and it is therefore not a pre-existing condition as it is thought to be in per- nicious anemia. But difficulty of a very perplexing nature arises in some cases, for sprue sometimes presents so faithful a picture of pernicious anemia, even to the gastric, tongue, and cord symptoms, that differentiation is practically im- possible and either diagnosis may be made with equal justification. Wood has brought this dilemma very forci- bly to the attention of the profession. He has sent the writer smears from such cases which would certainly be accepted as smears from pernicious anemia. He found the monilia psilosis in the stools, tongue, or gums of all these difficult cases, as well as in frank cases of sprue, but not in cases who had neither sprue nor pernicious anemia. Complement fixation reactions on the blood, using anti- gens prepared from the M. psilosis were found to be use- less for diagnostic purposes, since positive reactions may occur in any individual who harbors the monilia, whether the individual is well, has sprue or has pernicious anemia. While most cases of sprue can easily be differentiated from pernicious anemia, a few cases present so close a re- semblance that either diagnosis is permissable. Pernicious DIAGNOSIS AND PROGNOSIS 2S anemia has hertofore been almost invariably fatal while sprue has by no means been invariably fatal. The chronic hemolytic anemia of pregnancy (38, 118, 154, 174, 175, 200, 201, 216, 228, 250, 261, 329, 443, 478, 541, 548, 558, 565, 577, 626). No perfectly satisfactory classification or systematic description of the anemias oc- curring in pregnancy has been made. But it is recognized that a simple anemia is likely to occur in the early months of gestation and improve toward term; it is also evident that simple anemia may result from uterine hemorrhage, either sudden and extensive, or prolonged and moderate; also there‘is no doubt that puerperal sepsis may cause a severe simple anemia. None of these forms should be mis- taken for another and rarer form, the so-called “perni- cious anemia of pregnancy’’, or better, “the chronic hemo- lytic anemia of pregnancy.” For some reason the obstetri- cians do not seem as familiar with this form as the inter- nists, probably because this anemia usually comes on near or after term and patients are transferred to the medical wards of hospitals. In Maryland, Williams has seen only two cases, while among the hospitals of Ontario the dis- ease is not very uncommon. It might be briefly described as pernicious anemia associated with pregnancy, but this description is fallacious since differences exist. The chief differences are as follows: absence of glossitis and cord changes, an average red blood cell diameter of less than normal in spite of the presence of macrocytes, the presence of marked achromia, higher reticulated cell counts, and increased fragility of red corpuscles to hypo- tonic salt solutions. Minot regards this disease as a variety of chronic hemolytic jaundice. Its cause is pregnancy, and when pregnancy is past, many patients permanently re- cover. So far as critically reported, achlorhydria has been present, although reports on this point are few. Usually there is not so great a degree of leukopenia as in perni- cious anemia and the blood platelets may be normal in 224 PERNICIOUS ANEMIA number. At other times there is evident marrow depres- sion and retinal hemorrhages are present. As a working principle, one is justified in placing a patient in this group when the blood findings are somewhat atypical and when tongue and cord symptoms are absent. A point of distinc- tion is the fact that these cases may recover permanently. Dibothriocephalus latus anemia (36, 121, 193, 405, 546, 552, 551, 606, 607). While the writer is not familiar with this form of anemia in practice, it appears from the continental literature and from sporadic reports in Ameri- ca that very occasionally the fish-tapeworm infection is capable of producing an anemia indistinguishable from that of pernicious anemia. The incidence of glossitis, achlorhydria and cord change is not exactly reported. The stools should be examined for the ova or the worm itself, especially in worm-infested populations, and where these are found the diagnosis of bothriocephalus anemia is justified. If the worm is expelled sufficiently early, com- plete recovery takes place. While the above mentioned five diseases present the in- stances where differential diagnosis is very difficult, and sometimes impossible, there are still other diseases which may be confused with pernicious anemia for various reasons. Anemia from acute or chronic sepsis may at times pro- duce a somewhat similar blood picture, especially infec- tions with hemolytic streptococci and the malaria plasmo- dium. Differentiation rests on the finding of a sufficient cause, on strict microscopic evidence in the blood, and the absence of associated signs in the tongue and spinal cord. In these cases, marked bone-marrow regeneration may cause a flooding of the circulation with immature white blood cells, a condition which has been unhappily called leukanemia. Chemical poisoning with anilin derivatives, and nitro- and benzol products may be confusing, but the clinical pic- DIAGNOSIS AND PROGNOSIS 225 ture is not that of pernicious anemia. Hemolytic anemia is often seen following the intensive treatment of syphilis with benzol derivatives. Aplastic anemias, both idiopathic and those produced by radium and mesothorium (209, 395, 520, 643) or by osteosclerosis, may usually be differentiated by the smear picture, and almost always by the low icterus index and absence of the cardinal clinical signs of pernicious anemia. In the aleukemic phase of leukemia, a blood picture like that of pernicious anemia may occur, but should not present great difficulty when reference is made to other features (76). Secondary cancer metastases to the bone marrow may also produce a blood likeness. Some cases of polycythemia, in the terminal stages, may resemble the pernicious anemia blood picture, but should be readily differentiated (113). The symptom—purpura—may confuse, since it is com- mon to severe aplastic anemia, purpura hemorrhagica, and the bone-marrow exhaustion stage of pernicious ane- mia, and because, especially, any marrow involvement sufficient to cause thrombocytopenia may produce a ma- crocytic anemia. Associated signs must be here kept in mind. Endocarditis, especially when due to hemolytic strep- tococci, may confuse because of cardiac murmurs, en- larged spleen, fever, and toxic involvement of the mar- row. The history of the case, blood cultures, careful evalu- ation of the blood picture and the degree of illness of the patient will usually help to decide the diagnosis. Addisons’ disease, nephritis and nephrosis, and arteri- osclerosis may present superficial resemblance. Tabes dorsalis or multiple sclerosis may be incorrectly entertained because of the subacute combined degenera- tion of the spinal cord. Chronic hemolytic jaundice may confuse because of the icterus but the blood picture is different in the ma- jority of cases. Macrocytosis is less and the macrocytes 226 PERNICIOUS ANEMIA are circular rather than oval, the icterus index is higher, there is not so great a degree of bone-marrow depression as indicated by the presence of more leukocytes and blood platelets, while immature forms, especially reticulocytes, are more plentiful. The gastric secretion is usually nor- mal. Exceptional cases, however, in which the marrow is greatly involved may present a striking likeness to the middle type of pernicious anemia, in which rapid regener- ation is a continuous feature. Splenomegaly, a feature of many diseases, is rather an uncommon feature of pernicious anemia, but it does oc- cur. Chronic hemolytic jaundice, Banti’s disease (the identity of which seems uncertain), Gaucher’s disease, the enlarged spleen of syphilis, chronic sepsis, tubercu- losis and malaria, idiopathic splenic anemias, and the en- larged spleen of polycythemia and of splenomyelogenous leukemia, may all at times cause trouble, but should not present great difficulty if the cases are thoroughly studied with special reference to the gastric secretion, tongue changes, cord changes, and minute blood changes, and if it be borne in mind that enlargement of the spleen— sometimes to great dimensions—occurs in an occasional case of pernicious anemia. The abdominal crises sometimes seen in pernicious ane- mia, as a result of spinal cord disease, as well as the epigastric pain which is sometimes a part of the disease, may frequently lead to a diagnosis of an acute abdominal pain, but this mistake can usually be avoided by a thor- ough study of the case from every angle. Myxedema may very occasionally give rise to a con- fusing blood picture and might be very difficult to recog- nize as such unless a complete critical study.of the blood of the gastric secretion, and the basal metabolic rate were made (443). Prognosis (54, 72, 86, 213, 391, 584, 671). Heretofore the average length of life from the first symptoms was a little over two years, in treated and untreated cases. The DIAGNOSIS AND PROGNOSIS 227 liver diet has already brightened the prognosis as to length of life, but it would be premature to form a judg- ment. It may be said that the prognosis as to length of life is better in cases from which all possible sepsis has been eradicated and in patients without spinal cord symptoms. As has been stated before, remissions of five years dura- tion are not as uncommon as once thought. Spontaneous cure is not proved, but in a very few cases normal life ex- pectancy has been realized. Prognosis with regard to the likelihood of a spontane- ous remission can only be judged by signs indicating ces- sation of disease activity (fall of the icterus index and fever), and by signs indicating bone marrow stimulation (polychromatophilia, nucleated red blood cells in moder- ate numbers accompanied by an increased percentage of reticulated forms, increase in polymorphonuclear leuko- cytes and blood platelets). Prognosis with regard to the nearness of a relapse can only be judged by signs indicating increased disease activity, and by signs indicating a deepening of the bone- marrow involvement—lack of regenerative forms, in- creased disturbance of cellular morphology, decrease in polymorphonuclear leukocytes and blood platelets. Grave signs with regard to life are marked blast crises without considerable reticulated cell increase, ex- treme leukopenia and platelet reduction, and rapid exten- sion of the spinal cord involvement with loss of control of sphincters. Extremely grave signs with regard to life are the presence of macropolycytes in the circulation, the pres- ence in the blood of the ether soluble pigment described by Broun et al., and the appearance of coma. It would appear from the report of Minot and Mur- phy (447) that with the use of liver diet prognosis for a remission was 100 per cent good, if the treatment is prop- erly taken. CHAPTER XI PROPHYLAXIS AND TREATMENT It seems a self-evident proposition that if all cases of achlorhydria were placed upon the best treatment known for pernicious anemia that fewer (and perhaps very few) of the individuals would progress to the disease. Leake (358) has already emphasized this point. It is to be hoped and expected that in the near future a frac- tional test meal will become almost as routine in exami- nation as the estimation of the blood pressure. This simple procedure followed by cautious periodical scrutiny of achlorhydric individuals will constitute a prophylactic duty of the physician, which, through the use of the liver diet in very early cases, may conceivably bring about a considerable prolongation of the period of life expectancy. The various methods of treatment which have been given extensive trial in pernicious anemia form an im- posing list. Among drugs may be mentioned iron, colloidal iron, arsenic, benzol combinations of arsenic, phosphorus, quinine, calomel, perchloride of mercury, mercurochrome, germanium dioxide, antimony, thorium, iodin, salol and other intestinal antiseptics such as dimol and gentian violet. Among organic and biological products may be noted human blood, antistreptococcus serum, B. welchii antitoxin, streptococcus vaccines, B. coli vaccines, choles- terol, hydrochloric acid, thyroid, marrow, spleen, liver, and parenteral protein injections. Surgery has been used for the eradication of foci of infection everywhere in the body, for iliostomy, splenectomy, ligation of the splenic artery (630), removal of bone-marrow (33,57), resection of the proximal colon, and heterogenous suprarenal trans- plantation (591). Other procedures are lavage, enemata, bile drainage (227), the withdrawal of small amounts of blood (490), heliotherapy, ultra-violet light therapy, hy- [ 228 ] ERO PEOEAxXIS AND TREAT MEN? | 229 drotherapy, and the use of X-Rays and radium. Diets of various descriptions, cultures of aciduric bacteria, butter- milk, kefir, alone or in many different combinations with other forms of treatment, have been employed. Arsenic was employed first by Bramwell (62,64) in the form of Fowler’s solution in gradually increasing doses on a case in the Newcastle-on-Tyne infirmary in 1877. Bramwell apparently used the drug empirically and ob- tained a strikingly good remission. Not without reason he later strongly recommended this form of treatment. It was immediately taken up by those members of the pro- fession who were familiar with the disease, and yet, dur- ing the next fifteen years, many physicians had encoun- tered numerous cases in which arsenic produced no appar- ent benefit. The theories of its action (49,599) are sev- eral—hemopoietic stimulant, anti-hemolytic agent, anti- septic agent directed especially against protozoa and streptococci (544,328) and, finally, a drug which has a “preservative” action on the red corpuscles (242,243). McPhedran’s (423) patient with an eighteen year remis- sion was kept constantly on 45 minims of Fowler’s solu- tion per day, but others have died taking similar doses. No one knows why arsenic benefits some cases any more than why it fails to benefit others. The use of sodium ca- codylate has attained considerable vogue, and so also has the use of antisyphilitic arsenical preparations. The use of benzol derivations cannot be recommended in view of the acute hemolytic anemia which occasionally follows their use (653). Fowler’s solution in gradually increas- ing doses by the mouth is the method of choice for it has never been shown that better results were obtained by any other preparation or method of administration, (344, 635). The use of “shock” doses of arsenic seems unjusti- fiable (108). Arsenic had better never be given than given to the point of gastro-intestinal intolerance or to the point of causing peripheral neuritis or melanodermia (455). 230 PERNICIOUS ANEMIA Strictly there is no reason to explain the perennial popu- larity of arsenic (403), yet it seems fairly certain that the drug will continue to be used in some form or in combi- nation with other methods of treatment. Iron was the first drug, in fact, the first form of treat- ment, used in pernicious anemia (171). This was sug- gested by the benefits of iron in chlorosis. Clinical ex- perience immediately branded inorganic iron as useless. Ferrous salts have recently been considered as even harm- ful (464, 579). The question of food iron will be presently considered. No encouraging results have followed the use of colloidal iron (15, 18, 639). Neither phosphorus nor quinine have any apparent beneficial effect. Germanium dioxide was found to exert no more bene- ficial effect than arsenic, though it was more easily toler- ated (251,461). | Preparations of mercury have ardent supporters. Fer- rier’s (198) case of long remission on calomel (and this patient is still living and well) is interesting, but one case proves nothing. Nor is there any convincing evidence that intestinal antiseptics such as salol or dimol exert any cur- ative effect. McLaughlin (418,419) does not consider in- travenous injections of mercurochrome a cure, but notes that remissions can be produced rather readily by this method. Fist (203) considers mercurochrome of doubt- ful value and thinks it may exert an effect analagous to that of the parenteral injections of foreign protein. Thorium X (206), antimony (118), and iodin (272) have given no evidence of benefit. The administration of gentian violet is of doubtful value since the report of its use indicates that other (dietary) methods were used which in themselves may have been responsible for the improvement (129). Among organic and biological products, it may be con- fidently stated that antistreptococcus serum (55, 632), B. PROPHYEA IS AND TREATMENT + 231 Welchii antitoxin (132), vaccines made from streptococci and B. coli (631), exert no beneficial influence and pro- duce at most a foregn protein effect. Parenteral protein therapy with milk (284), caseosan (260), or other agents will frequently bring on a remis- sion (514), and an interesting feature of this treatment is a not infrequent improvement in the patient’s subjec- tive sensory symptoms. A very similar effect was obtained by the writer (132) by the use of whey cultures of B. acidophilus. Usually these patients experienced a decided lessening of the numbness in the extremities within a week from the time of beginning treatment. Gram has compared the effect of kefir feeding to that of foreign protein therapy. Hurst noted aggravation of parasthesiae after each dose of autogenous streptococcus vaccines. None of these methods are curative. Organotherapy by the use of bone-marrow (210, 285) and spleen has received considerable trial, first by Fraser with bone-marrow, and recently the dried products of both have been investigated by Leake and others (362, 363, 356, 357, 360, 359, 361), not without beneficial ef- fect. Thyroid medication in the form of thyroid residue tablets has not proved encouraging although large doses could be given by MacBride (389) without intoxication. Organotherapy with whole calf’s or beef liver will be considered in connection with dietary treatment. It is doubtful if cholesterol in the diet or by subcutaneous ad- ministration in olive oil solution has any curative effect although it has been used because of its general antihe- molytic properties (176). The administration of dilute hydrochloric acid as a form of replacement therapy, while not constituting a cure, unquestionably is of benefit, especially in helping to control gastric symptoms and diarrhoea, and may be re- garded as a perfectly rational form of treatment to be recommended in connection with any other form of treat- 232 PERNICIOUS ANEMIA ment (501, 574, 152). From 1 to 2 drams of the dilute acid, in water, orange juice, or milk should be taken in sips during meals. Hurst gives, in addition to this, animal charcoal for its adsorptive effects in the control of flatu- lence. Blood transfusion may be regarded as a form of organotherapy. As a method of treating pernicious anemia it was employed quite early in the history of the disease (589, 104), and has been in continual extensive use for the past twenty years, having been made more feasible by modern methods of blood matching. Several references have been made already to the metabolic effects of blood transfusion. It is not proposed to consider here the extensive literature of the subject. The final judgment of blood transfusion in pernicious anemia is that it does not cure the disease, does not prolong life, may or may not induce a remission, but that it will always reserve for itself a place in treatment since it can be employed at times of emergency when a patient is too ill to receive any other form of treatment now available. Methods of blood typing, blood matching, and of transfusion, as well as descriptions of reactions to transfusion (58) may readily be obtained from many sources (441). The eradication of foci of infection, is, on general principles, just as rational a procedure in pernicious anemia as in any other disease. It is perhaps even more urgent than in some diseases owing to the fact that sepsis of itself may be responsible not only for a considerable proportion of the symptoms, particularly the gastric symptoms, but also for some degree of the anemia. Hun- ter (305) has well indicated that the eradication of infec- tion where possible somewhat ameliorates and lengthens the course of the disease. In all cases, however, the strength of the patient must be carefully balanced against the benefits to be derived from the treatment, and where the latter consists in opening the abdomen, due dis- PROPHYLAXIS AND TREATMENT) 233 cretion should be used. It seems questionable whether abdominal surgery, except for emergency purposes, is permissable in pernicious anemia (263). As a practical point, diseased teeth ought not to be removed at one sit- ting but at several sittings at sufficient interval to allow the patient to recover from shock, and particularly to pre- vent the gum tissues from being suddenly subjected to an extensive infection. Ileostomy (84), for some unknown reason, almost invariably produces improvement so long as the bowel remains open. Resection of the proximal half of the colon has not been found to be a justifiable procedure (412). Excochleation of bone-marrow from the long bones has been tried and is certainly to be strongly condemned in view of the results (633, 617). Splenectomy in pernicious anemia was advised by Eppinger (173) upon the theory that the spleen played a primary etiological role in the disease. Various effects of splenectomy on the metabolism and blood picture have already been mentioned. The operation does not cure the disease and seldom prolongs life. Splenectomy, however, is usually followed by a remission, and by improvement in the bile-pigment condition. The limited group of cases which show splenic enlargement are the only one upon which this operation is justifiable. Cases with splenome- galy, high icterus index, marked increase of bile pigments in the duodenal contents, and showing an acute course, are frequently very decidedly benefited by the operation, but splenectomy must be done in as early a stage of the disease as possible, before cachexia has begun to appear and even before any marked degree of marrow exhaustion is in evidence. Life is prolonged by splenectomy in such cases, and the operation should be reserved only for such cases. The use of ultra-violet rays (613), X-Rays, and radium are all very disappointing in themselves (239), but it is 234 PERNICIOUS ANEMIA possible that the use of the mercury vapor lamp may be of assistance in association with other forms of treatment. The diets which have been recommended for pernicious anemia have been devised upon various observations of the symptoms and findings. Fenwick (199) recommended a diet relatively rich in protein and sparing in farinaceous foods. Hunter (296) advised the use of farinaceous foods in preference to proteins, with the idea of lessening intes- tinal putrefaction. Others have advised various kinds of diets with several empirical ideas in mind. Foods contain- ing iron in largest quantities, especially vegetables, have been recommended and commonly used, in spite of the fact that most physicians knew that inorganic iron was prac- tically useless. The treatment of the disease by Barker and Sprunt (25), in which over-feeding was practised as a part of the treatment, caused more interest to be taken in the subject of diet as a means of treatment. Mosenthal (454) and later Peppard (491) found that by overfeeding they could readily obtain positive nitrogen balances in pernicious anemia. The important experimental work of Whipple, Rob- scheit-Robbins (648, 651, 652), and their associates on the effect of various kinds of foods on blood regeneration, begun in 1920 and still being pursued, has exerted a pro- found effect, indirectly, upon the treatment of clinical anemias. They found that dogs, rendered anemic by hemorrhage, regenerated their blood much more rapidly when fed certain kinds of food, particularly liver. The high amount of food-iron contained in liver was consid- ered the chief reason for its beneficial influence. In 1921 Fenlon (195) recommended for pernicious anemia a diet high in animal liver because of the con- tained nucleoprotein. Gibson and Howard (223) were the first, judging from the literature, to apply the experimental findings of Whipple et al. to the treatment of pernicious anemia, in PROPHYLAXIS AND TREATMENT 235 an attempt “‘to test the efficiency of Whipple’s high iron diet when given to patients suffering from idiopathic anemia.” The diets they used contained “fruits, green vegetables, lima beans, sweet potatoes, egg yolk and liver (daily), the constituents being selected to provide a ration rich in iron and relatively low in fat.” The caloric and protein values were also relatively low. The beneficial effects of this diet have already been referred to in Chap- ter VII in connection with the metabolism of nitrogen and iron. It is to be noted particularly that liver formed a constant daily part of this diet, and that metabolic and clinical as well as hematological improvements were noted as constant results in a series of very carefully controlled experiments on eleven patients with this disease. Gibson and Howard felt that, while due allowance was to be made for spontaneous remissions occurring, this high food-iron diet was to be strongly recommended in treatment. The special diet used by Minot and Murphy (447) was devised as a result of many observations. The main ele- ment was food rich in food-iron and complete proteins, particularly liver. In addition to this, the fat and carbo- hydrate were reduced, and vitamine containing fruits and vegetables added. They had previously tried out clin- ically the high food-iron diet found by Whipple et al. to be beneficial in blood regeneration after experimental anemia from hemorrhage, and had concluded that this diet was of clinical value. Fat was reduced because of the hemolytic effect of unsaturated fatty acids, because lipoids are growth-inhibiting, and because many patients with per- nicious anemia gave a history of having eaten an abnor- mal proportion of fat in their routine diets over years. Gibson and Howard (223) previously noted a less favor- able iron balance in two of four patients who received a larger ration of fat than the others, and advised that a further study of fat ingestion in pernicious anemia should be carried out. 236 PERNICIOUS ANEMIA Minot and Murphy tried their diet on forty-five pa- tients with the result that all their patients showed a prompt, rapid and distinct remission of their anemia. This, incidentally, is the first and only instance in the his- tory of the disease, in which any form of treatment has produced invariable remission in so large a series of pa- tients. The average red blood cell counts for the whole group rose from 1,470,000 per cubic millimeter before starting the treatment to 3,400,000 at the end of the first month ; and for twenty-seven cases observed from four to six months after the diet was begun the average had risen to 4,500,000. The first signs of blood improvement were early decrease of the icterus index and early temporary increase of the reticulocytes. Constipated patients and patients with diarrhoea soon came to have normal bowel movements. Marked clinical improvement accompanied the blood improvement. None of the patients who re- mained on the diet had relapses, although two years had elapsed in a few of the cases since beginning the treat- ment. They noted no improvement in marked objective spinal-cord changes. The following instructions, issued by these investigators, give a concise and practical conception of the special diet recommended and used by them (462): The daily requirements of the diet in order of assumed importance are: (1) Liver (calves, beef, chicken) or kidneys (lamb) freshly cooked. At least one hundred and twenty, preferably two hundred or more, grams (cooked weight). Cook without fat; broil, bake, boil, mince or make into soup. (2) Fruits, preferably fresh—especially peaches, apri- cots, pineapple, strawberries, oranges, and grape- fruit—about four hundred grams. Raisins are de- sirable; allow them to be eaten freely. (3) Red muscle meat, trimmed free of fat, freshly cooked; one hundred and twenty-five grams or more. Beef heart is desirable. PROPHYLAXIS AND TREATMENT = 237 (4) Vegetables containing one to ten per cent of car- bohydrates, preferably fresh; cooked or raw. Not less than three hundred grams. Lettuce, spinach, asparagus, cabbage, and tomato are especially desirable. (5) Fats restricted, not over seventy grams. Avoid cheese, bacon, fried food. Allow but little cream and butter and not over one egg. Use mineral oil for salad dressings. (6) Avoid grossly sweet foods, yet allow sugar sparingly. (7) Starchy foods, as cereals, potato, breads, add to suit individual desires, but not to the exclusion of the requirements given above. The starchy foods are best crusty or dextrinated. Whole wheat toast is desirable. (8) Milk is best limited to about two hundred and forty grams. (9) Avoid excess of salt. Tea and coffee as desired. Ideally all food should be weighed. The liver is essential and must be weighed at first. After the patient under- stands the approximate quantity of the different foods to be taken their amounts may be estimated. The food must be palatable and as attractive as possible. The art of fine cooking and serving combined with per- suasion will often be necessary to get the patient to eat the food desired. Several small meals a day rather than three may be found suitable. The exact condition and desires of each patient must never be neglected; for instance, a persistent diarrhoea may necessitate that less fruit be eaten and that vegetables be pureed; allowing the patient his choice of the form or type of required food may enhance his progress. When the patient is unable to take much food, it is important that he eat some liver or kidneys (chicken giz- 238 PERNICIOUS ANEMIA zards may be substituted) and fruit, even if no other food is taken. Then gradually add meat and green vegetables. The starchy foods are to be given in accordance with the amount of the other foods eaten. The patient should be expected to take the full diet within about two weeks after commencing it. Present information suggests that the patient should continue with this sort of diet even though his red blood cell count remains high. The full diet should contain for the average person about two thousand five hundred calories, the protein being about one hundred and thirty-five grams, the car- bohydrate about three hundred and forty grams, and the fat not over seventy grams. This is the approximate com- position of the food given in the sample menu below. BREAKFAST Approximate weight in grams Liver or kidneys, broiled... 100 Oatmeal, 2 heaping tablespoons cooked, or dry meal...............- 18 Milk, '3) tablespoons... 00. tn ee 45 Sugar, 2 level teaspoonss../..-).0.002..0. 10 Toast, 3 slices (each slice 4 x 2 x,34 inches)... 30 Butter, 1 level teaspoon or a piece l x1x¥&% inches Meee |, 5 Fruits, choice of (a) Orange, average ‘sizéeinic. 0 120 (b) Strawberries, 534 tablespoons...-...2..-. eee Pi) (c) Grapefruit, 4 of one very large one... 200 (d) Peach, 1 large one)..e2..) eh 120 DINNER Beef, steak or roast, trimmed of fat; a very large serving........ 120 Vegetables, freshly cooked, as spinach, string beans, cabbage, tomato, etc., 2 average portions or 5 to 8 tablespoons............ 250 Potato, baked, medium size...) .020. le LAZO Bread, 2 slices (each slice 3 x 4.x 14 inches)... eee 70 Salad, pineapple, 214 slices, of size In Cans..071..20 1.23 eee 140 ettuce, big “helping...02/0..0 a 75 Pudding made of (1) Gelatine, 1 teaspoon, dry) weight. 2:../2.75. 2 eee 2 (2) Rice, boiled, 2 heaping tablespoons...1..2.-...2 22 eae 160 (3) Raisins, 20 large omes.(20 6.2 50 PROPHYLAXIS AND TREATMENT 239 (CRU Fs 2402212) CC 0°09) 0 ee 30 (Fruits may be put into such a dessert and raisins eaten separately.) SUPPER Liver soup, composed of (Tp TLANWE ESTAR EG Ie SEE Ee eee ee Sen 100 (A) WI 152 51g gb) 517211) 85 | UE A eee en SCE CARO EP 220 oie atte eC volte ih TEASPOON. anna oe k o ee cece ch ce cee + (4) Butter, 1 rounded teaspoon or a piece 1 x 1 x % in....... 10 Lamb, roast, without fatty parts, 2 small slices....................-.---- 60 JING oy ii oor era AS fh £15) (cS 0.010) 1 Ye Rea ne 150 or Potato, a small one, or rice, 1 heaping tablespoon.................... 80 Vegetables, fresh, 2 average portions, 5 to 8 tablespoons........ 250 RPE DISCINE OF EFISCUIL, Ae i