THE RELATIONS BETWEEN CHLOROSIS, SIMPLE AN/EMIA, AND PERNICIOUS ANzEMIA, INCLUDING LEUCOCYTHEEMIA AND HODGKIN'S DISEASE. BY FREDERICK P. HENRY, M.D., PHYSICIAN TO THE PHILADELPHIA HOSPITAL. FROM THE MEDICAL NEWS, October 5 and 12, 1889, [Reprinted from The Medical News, October 5 and 12, 1889.] THE RELATIONS BETWEEN CHLOROSIS, SIMPLE AN /EMIA, AND P E R NIC10 U S A N /E MIA, IN- CLUDING LEUCOCYTH/EMIA AND HODGKIN'S DISEASE.1 By FREDERICK P. HENRY, M.D., PHYSICIAN TO THE PHILADELPHIA HOSPITAL. The title of the subject which I have the honor to discuss before this Association, viz., the Relations between Anaemia, Chlorosis, Pernicious Anaemia, etc., might be criticised on the ground that it as- sumes certain relations to exist between these various affections of the blood. To such criticism it might be replied that the selection of such a title is the expression of the universal medical belief that these affections are allied, and that it is in the highest degree improbable that such a practically unanimous verdict can be erroneous. Without stopping to mention any of the numerous historical instances in which the prevailing medical belief has been erroneous, I will begin by pointing out that in the discussion of this subject everything depends upon what is understood by the term Re- lation. 1 Read before the Association of American Physicians, Sep- tember, 1889. 2 HENRY, While we are justified in speaking of kindred dis- eases, there are no facts to warrant the belief that one affection can be converted into another, or that the cause of one disease can be so modified by its habitat and general environment as to excite another which is, by common consent, entirely different. The best example of kinship is afforded by the in- fectious diseases, which originate, not in the same, but in a similar manner. No nearer relation than this has yet been recognized in disease. In the remotest past there may have been one pathogenic organism, the source of all the ills to which flesh is heir, but at the present time there are many such, and their differentiation is complete and permanent. There are, therefore, three questions to be dis- cussed : 1. Are chlorosis, simple anaemia, pernicious anae- mia, etc., separate diseases? 2. Are they of kindred nature? 3. Are they different stages of one disease? I will first consider pernicious anaemia, because the determination of its status is of fundamental im- portance. It is admitted by those who argue most forcibly in favor of the independent nature of this disease, that its clinical features are common to a number of affections, particularly cancer and atrophy of gastric glands. They have also been repeatedly associated with the presence of parasites in the intes- tinal canal, such as anchylostomum duodenale and bothriocephalus latus. In these and other affections the blood has presented the characteristics of per- nicious anaemia, viz. : 1. Great diminution of vol- ANEMIA, CHLOROSIS, ETC. 3 ume. 2. Enormous reduction of the number of the red corpuscles, sometimes to ten per cent, of the normal-i. e., the blood may contain 500,000, in- stead of 5,000,000, of these bodies to the cubic millimetre. 3. Poikilocytosis-i. e., remarkable alterations in the size and shape of the red corpus- cles. 4. Microcytosis, by which is meant the pres- ence in the blood of numerous minute spherical, yellowish-red corpuscles, resembling oil-drops; these are not constantly present. 5, and most diagnostic, a relative richness in haemoglobin. The percentage of haemoglobin may equal, exceed, even double, that of the red corpuscles. 6. No absolute increase in the number of the white cells. By one set of writers it is argued that when, in the course of cancer, atrophy of the stomach, or other disease, the above-mentioned striking changes in the blood are observed, the case is not one of pernicious or idiopathic anaemia, as they term it, because a well-marked lesion is present. If, however, the same alterations of the blood are present, and at the autopsy no lesions can be found except those that are manifestly secondary to the blood-change, such as fatty degeneration of the heart and intima of blood- vessels, then the case is one of pernicious or idio- pathic anaemia. For example, in 1886,11 reported, in conjunction with Prof. Osler, a case of atrophy of the secreting structures of the stomach with every clinical feature of pernicious anaemia. About the same time I had under observation another patient, 1 Amer. Journ. of the Med. Sciences, April, 1886. 4 HENRY, a woman, whose symptoms and blood-changes were identical with those of the above-mentioned case. "After an illness of more than a year she died, and at the autopsy, at which I was present, no lesion was found to explain the profound alteration of the blood. Accord- ing to most authorities, the first of these cases, in which a lesion was found, to which the symptoms might be reasonably attributed, is, for that very reason, not a case of pernicious anaemia. The second case, on the other hand, is one of pernicious or * idiopathic ' anaemia, because a lesion, to which the symptoms might be attrib- uted, was not found."1 This kind of reasoning appears to me very un- scientific. In both cases there were the same blood-changes, viz., those universally recognized as pathognomonic of pernicious anaemia. In one, the cause of these changes was manifest, or, rather, be- came so after a careful microscopical examination of the stomach. In the other, it eluded the minutest investigation. The pernicious blood-change was a process common to a known and an unknown cause, and not a separate or independent disease. An independent disease is one which rests upon a constant anatomical basis, or is invariably produced by the same specific agent. Processes of disease, on the other hand, are common to a number of distinct and independent affections, the most widely distrib- uted of these processes being fever, inflammation, and anaemia. Anaemia may be either a disease or a process-a disease where directly dependent upon a lesion of one of the haematopoietic organs; a process 1 Ansemia. By F. P. Henry, M.D. Philadelphia, 1887. AN/EMIA, CHLOROSIS, ETC. 5 when not so dependent. From this point of view, the uniform blood-changes of pernicious anaemia are due to a disturbance of nutrition of the profoundest character, which may arise from a number of causes, some known and others unknown. It is, therefore, nothing more than a disease-process, and as such related both to anaemia and chlorosis. Let us now inquire more particularly as to the mode in which this profound anaemia is produced, whether by a defect of haemogenesis, an excess of haemolysis, or by a combination of both. The causes of anaemia have been divided by Coup- land into two classes: " deficiency of income and excess of expenditure," and, according to most writers on diseases of the blood, chlorosis is a typi- cal example of the former. In that affection there is a deficient assimilation of iron, which is accounted for in a more or less satisfactory manner by various theories. The most prevalent is that of Bunge, which has been practically adopted by Sir Andrew Clark. Until quite recently, no satisfactory expla- nation could be given of the efficacy of iron in chlorosis, and especially of the necessity of adminis- tering it in large doses, for it was well known that very little of this drug was absorbed. It was also known that our food, which, when in proper amount and variety, contains more iron than we need, does not contain this metal in inorganic form, but in an exceedingly complex organic union. Human milk, which contains the merest trace of iron, supplies all that is needed for the wants of the rapidly growing infant. Nearly all our food-substances contain iron, 6 HENRY, and there is probably no drinking-water in which traces of it cannot be found. Zander1 examined the water from three hundred springs, and found iron in every specimen. The same observer examined the feces of chlorotic patients before they had been placed upon any treatment, and found iron in them in considerable quantity-a sure proof that there was no want of this metal in the food. The conclusion, therefore, must be that there is, as already stated, something which interferes with the digestion and assimilation of the superabundant iron contained in the food ; and this something is believed by Bunge to be sulphur. In chlorosis, as is so emphatically insisted upon by Sir Andrew Clark, digestive disturbances are ex- ceedingly common. Abnormal fermentations and decompositions take place in the gastro-intestinal tract, and give rise to the formation of quantities of sulphides which decompose the iron contained in the food, and completely unfit it for the purpose of nutrition. By administering an inorganic prepara- tion of iron we simply offer a bait to these sulphides, which they seize upon and so allow the organic com- binations in the food to escape and to be absorbed. This theory explains also why it is often necessary to administer large quantities of iron, for in such cases the sulphides are supposed to be formed in large amount, and to need corresponding quantities of iron to saturate them. The blood of a healthy adult contains only about 1 Virchow's Archiv, Bd. 84, 1881. ANJEMIA, CHLOROSIS, ETC. 7 forty-five grains of iron (three grammes), and, there- fore, in severe cases of chlorosis there is only a de- ficit of about one scruple of this metal. Why then is it so often necessary to administer colossal doses of iron in order to cure a case of chlorosis? Evi- dently because the iron plays some other role than that of a food. The theory of Bunge, to which I have just alluded, offers the most satisfactory expla- nation of its mode of action.1 There are other theories of chlorosis supported with equal ingenuity, such as those of Zander2 and Landwehr,3 which, in accordance with the division of labor agreed upon between us, I leave to the con- sideration of the co-referee in this discussion. Suf- fice it to say that they all unite in referring the cause of chlorosis to a defect in hsemogenesis. I have entered into these details concerning chlo- rosis because it is universally conceded to be a typical example of defective haemogenesis, and be- cause I wish to compare it with another disease- pernicious anaemia, which is now generally attributed to excessive haemolysis. This opinion, now preva- lent, of the nature of pernicious anaemia, is largely due to the elaborate investigations of Dr. William Hunter.4 This observer not only believes that the blood-changes of pernicious anaemia are essentially haemolytic, but that " haemogenesis is so little inter- fered with that it is generally in excess of the nor- 1 Zeitschrift fur physiologische Chemie, 1885. 2 Loc. cit. 3 Archiv fiir die gesammte Physiologic, 1886, Bd. 39, S. 193, and Bd. 40, S. 21. 4 Lancet, Sept. 22 and 29, Oct. 6, 1888. 8 HENRY, mal." The arguments of Hunter in favor of the independent nature of pernicious anaemia are the most powerful that have yet been advanced. They may be summed up in the concluding paragraph of his valuable paper: "In pernicious anaemia the seat of disintegration [of the red corpuscles] is chiefly the portal circulation, more especially that portion of it contained within the spleen and the liver, and the destruction is effected by the action of certain poisonous agents, probably of a cadaveric na- ture, absorbed from the intestinal tract." Hunter admits that the clinical features of per- nicious anaemia are often associated with various gastro-intestinal lesions, especially cancer of the stomach and atrophy of the gastric glands, and with intestinal parasites, but believes such association to be accidental: " This conclusion is based chiefly on two considera- tions: (i) that similar anatomical changes, sometimes even more marked, are constantly to be met with in cases presenting none of the features of pernicious anaemia ; and (2) that cases of pernicious anaemia are constantly met with in which no such gross anatomical changes are to be found." Atrophy of gastric glands has often been observed in association with the clinical features of pernicious anaemia, and it is believed by some, myself among the number, to be a cause of that disease-process. The same gastric lesion has existed without the clinical features of pernicious anaemia, and this is one of the reasons why Hunter regards the latter as representing a distinct and independent disease superadded to the former. When closely looked ANEMIA, CHLOROSIS, ETC. 9 into, this argument loses much, if not all, of its force. The function of the stomach is very complex, and may be largely supplemented by that of the intes- tine. In fact, in the opinion of some of the best authorities, gastric is merely preparatory to the more perfect intestinal digestion, the office of the stomach being chiefly to coagulate milk and liquefy albu- minous bodies. It has been found that a dog whose stomach has been excised may be nourished for an indefinite period by placing food in its duodenum, and there would, I think, be little difficulty in proving that of the various functions of the stomach, the motor is of paramount importance.1 As I have remarked elsewhere : " The important part assigned by nature to intestinal digestion, coupled with the fact that it may entirely sup- plement the action of the stomach, has led Jaworski to attribute a subordinate role to the stomach, which he regards as a species of warm chamber, in which the food is detained for a time prior to its delivery to the intes- tine. This view reminds one of the Hippocratic theory of the coction of food by animal heat."2 These well-known facts offer one explanation why atrophy of the gastric glands is sometimes associated with the symptoms of pernicious anaemia; at others not so associated. The difference depends upon the preservation or impairment of the motor function of the stomach. The fact that "cases of pernicious anaemia are constantly met with in which no such 1 Vide Klemperer: Ueber die motorische Thatigkeit des Ma- gens. Deutsche medicinische Wochenschrift, Nov. 22, 1888. 2 American Journal of the Medical Sciences, Nov. 1888, p. 498. 10 HENRY, gross anatomical changes" (as those of cancer and atrophy) "are to be found" affords no proof what- ever, as Hunter seems to think it does, of the inde- pendent nature of pernicious anaemia. On the con- trary, it rather tends to prove that there are two kinds of pernicious anaemia, a structural and a func- tional. I have just shown that a motor insufficiency of the stomach may be one of the causes of pernicious anaemia. This is generally associated with gross anatomical lesions, such as cancer, atrophy, fibroid thickening, etc. A pernicious anaemia arising under such circumstances may be called structural or or- ganic. There is good reason to believe that a chemical insufficiency of the stomach, long con- tinued, especially if associated with intestinal indi- gestion, may also give rise to the symptoms of per- nicious anaemia. Under these circumstances it would be of the functional variety. Recent observations have shown that the gastric juice has other functions besides those of curdling milk and liquefying albuminous substances.1 Al- though proved by Spallanzani, more than a hundred years ago, to be possessed of antiseptic properties, it is only quite recently that its destructive action upon various microorganisms has been rigorously demonstrated. The facts thus established have an important bearing upon Hunter's theory that the blood-corpuscles in pernicious anaemia are destroyed 1 De 1'Action du Sue gastrique sur quelques Microbes patho- genes. Par MM. J. Straus et R. Wurtz. Arch, de M6d. Exp. et d'Anat. Path., i Mai, 1889. ANEMIA, CHLOROSIS, ETC. 11 in excessive numbers by a cadaveric poison absorbed from the gastro-intestinal tract. In cancer and atrophy of gastric tubules the gastric juice is notor- iously of defective composition, and a deficit of hydrochloric acid has also been observed in certain neuroses of the stomach. With the two first-men- tioned conditions the clinical features of pernicious anaemia are often associated, and they have also in a number of instances been clearly of neurotic origin. Several typical cases of pernicious anaemia have been reported by Stephen Mackenzie, of London; R. G. Curtin, of Philadelphia, and others, which had their origin in a profound shock to the nervous system. Probably in all these cases, certainly in the two first- mentioned classes, the antiseptic influence of the gastric juice has been withdrawn from the gastro- intestinal tract and the formation of ptomaines has proceeded therein to an abnormal extent. In this manner the origin of the supposititious cadaveric poison of Hunter may be accounted for. I will now point to what seems to me another im- perfect link in Hunter's chain of reasoning. In his article in the Practitioner? in which he discusses, and answers in the affirmative, the question whether pernicious ansemia is a special disease, he acknowl- edges his adherence to the general opinion that chlorosis is caused by defective hsemogenesis, and attributes this defect to a cadaveric poison which destroys the iron contained in the food we eat. This, as is well known, is the theory of Bunge. 1 The Practitioner, August, 1888. 12 HENRY, Now it seems to me illogical to attribute to one hypothetical ptomaine, that of chlorosis, a power of interfering with haemogenesis, and to another, that of pernicious anaemia, a power of increasing haemo- lysis. Haemolysis is increased in pernicious anaemia. This is proved beyond doubt by the able researches of Hunter; but it is, in my opinion, because of defec- tive hcemogenesis. The red corpuscles in this affec- tion are abnormally weak and perishable, as is proved by the fact observed by Copeman1 that their haemoglobin crystallizes out of them with great readiness. I am not alone in this opinion. In a recent discussion of a case of haemoglobinuria in the London Medical Society,2 Dr. Stephen Mac- kenzie "insisted upon the fact that in essential or pernicious anaemia there appeared to be some defect in the formation of the corpuscles, in addition to their rapid destruction." I trust that I have made it plain that, in my opinion-1. Pernicious anaemia is not an indepen- dent disease. 2. It is closely related to chlorosis. 3. It may be the terminal stage of other diseases, and especially of cancer of the stomach and atrophy of the gastric tubules. The grounds on which I believe pernicious anaemia and chlorosis to be related are not merely theoretical, for I have seen several cases and published one3 in which a transition between the two affections was, in 1 Lancet, May 28, 1887. 2 Brit. Med. Journ., May 4, 1889. 3 The Medical News, July 3, 1886. ANEMIA; chlorosis, etc. 13 my opinion, plainly evident, and Trechsel1 has ob- served two similar cases. The transition from per- nicious anaemia to chlorosis may be observed in any case of the former disease in which marked improve- ment occurs. Under such circumstances the red corpuscles lose their irregular contours and become circular in outline ; they increase in number, and, most important of all, their percentage of haemo- globin, which may have been equal, or superior, to that of the number of the corpuscles, is now much below the latter. The change is so marked that the case which, seen at its worst stage, would have been unhesitatingly set down as pernicious anaemia, would now, with equal certainty, be regarded as one of chlorosis. The constant presence of fever in pernicious anaemia can no longer be regarded as a point of distinction between that affection and chlorosis, for hyperpyrexia has been frequently observed in the latter, and would, according to Jaccoud,2 be more often found if looked for. In fact, Trazit3 devotes his thesis to the consideration of febrile chlorosis. The origin of pernicious anaemia has been attrib- uted to microorganisms by Frankenhauser,4 Planch- ard,0 and others. The former describes certain minute bodies supposed to be micrococci which he 1 Rev. med. de la Suisse Romande, June 20, 1888. 2 La Semaine medicale, August 8, 1888. 3 Journal de Med. et de Chir., November, 1888. 4 Centralblatt fur die med. Wissensch., 1883, p. 49. 5 De 1'Anemie dite pernicieuse progressive. Thfise de Paris, 1888. 14 HENRY, has observed in the blood of several cases of per- nicious anaemia. In the liver cells of the same cases he detected threads resembling those of leptothrix buccal is. All of Frankenhauser's patients had carious teeth, and these he believed to be the source of the microorganism of pernicious anaemia. This theory has found very few adherents, and it is worthy of remark that the latest work on patho- logical histology,1 by a countryman of Franken- hauser, makes no mention of it. In an earlier part of this article I defined an inde- pendent disease to be one which rests upon a con- stant anatomical basis, or is invariably produced by the same specific agent. If this definition is ac- cepted, pernicious anaemia cannot be regarded as an independent disease. Hunter and others have found, in this affection, a constant and decided increase in the amount of iron in the liver, and regard this as its essential anatomical feature. Without any wish to detract from the value of this observation, it seems to me unquestionable that this increase of iron in the liver is a consequence of defective haemo- genesis, and therefore to be classed with fatty de- generation of heart and other secondary changes. It is, in my opinion, plainly evident that the blood corpuscles of pernicious anaemia have undergone a marked degeneration. As I have elsewhere re- marked,2 the facts with reference to the blood of pernicious anaemia are such as to demonstrate a re- version to the type of the cold-blooded animals. 1 Practicum der pathologischen Histologie, von Dr. Oskar Israel, 1889. 2 Philadelphia Medical Times, April 3, 1886. ANEMIA, CHLOROSIS, ETC. 15 This theory might justly be regarded as fanciful, if it were based upon a resemblance of the blood of pernicious anaemia to that of the lower animals, fishes, and reptiles, in any one particular, but the facts show that the corpuscles of pernicious anaemia resemble those of the said animals in their number, their size, their shape, and their percentage of haemo- globin. In well-marked cases of pernicious anaemia we observe: 1. A reduction of the number of red corpuscles to a degree that is normal to the cold-blooded animals. It is not at all uncommon, in this dis- ease, to find less than one million red corpuscles per cubic millimetre. Figures such as these are normal in the cold-blooded animals. 2. Many of the corpuscles are much increased in size, so much so that they have received the name of megalocytes. Many of them are quite as large as the corpuscles of the lizard and eel. 3. They often show a tendency to assume an oval outline. The great increase in the size of the diseased corpuscles and their oval shape are very remarkable. The patient from whom the blood was taken was a typical case of pernicious anaemia. 4. To make the resemblance complete, nucleated red corpuscles have often been observed in the blood of pernicious anaemia. It is a most significant fact, in connection with the relations of the various affections under discus- sion, that the term "idiopathic" has never been 16 HENRY, applied to leucocythaemia. This disease was no sooner described by Bennett and Virchow1 than its association with structural changes in the blood- making organs, especially the spleen, was recog- nized. It corresponds, therefore, to our definition of an independent disease in being one which rests upon a constant anatomical basis. The blood-changes of leucocythaemia are so re- markable that they would warrant the separate classification of this disease, even if there were no other constant anatomical lesions associated with it. In the first place, the volume of the blood, which is diminished to such an extraordinary degree in per- nicious anaemia, is, in leucocythaemia, not only maintained, but sometimes augmented. In typical cases of this disease there is a condition of plethora, concerning the nature of which there has been some discussion. In the most minutely studied case of leucocythaemia with which I am acquainted-that of Sticker2- " The increased tension of radial and carotid arteries, the loud aortic-valve sound, and the fulness and tor- tuousness of retinal arteries and veins, pointed unmis- takably to a condition of plethora which Sticker considers hydraemic. On the other hand, von Bamberger,2 who has often observed dilatation of the heart cavities and abnormal fulness of the vessels in the bodies of those who have died of leukaemia, is doubtful as to the hydrae- mic nature of this plethora." 3 1 Zeitschrift fur klinische Medicin, Bd. 14, 1888. 2 Wiener klin. Wochenschrift, No. 14, 1888. 3 F. P. Henry : Annual Univ. Med. Sci., vol. iv. 1889. ANEMIA, CHLOROSIS, ETC. 17 He withdrew, by venesection, a small quantity of blood from a leukaemic patient, and analyzed it, with the result of proving that its solid residue was greater than that of normal blood. He, therefore, proposes for this condition the term leukaemic plethora. The facies of a leukaemic patient is entirely differ- ent from that of a case of pernicious anaemia, and of itself shows that the vessels are well filled with blood. Sticker's patient is described as having a bright color-eine lebhaftere Far bung; and Delafield1 reports the case of a man whose lips and skin were of "good color." I, myself, was surprised at the rosy color of the first leukaemic patient whose blood I examined. In addition to this plethoric state of the blood, the increase in the number of the white corpuscles, from which the disease derives its name, the more marked tendency to hemorrhage, and the new formations of lymphadenoid tissue in various parts of the body, all suffice to separate this affection from simple anaemia, chlorosis, and pernicious anaemia. It remains, therefore, to be considered whether there is any relation between leucocythaemia and Hodgkin's disease. Without pausing to consider the appropriateness of the term, I may say that by Hodgkin's disease we understand an affection of which the most prominent features are an enlarge- ment, more or less general, of the lymphatic glands, enlargement of the spleen chiefly due to hypertrophy of its Malpighian follicles, new formation of adenoid 1 Philadelphia Medical Times, Feb. i, 1889. 18 HENRY, tissue in various parts of the body, and a high, though usually not an extreme, degree of anaemia. From this description it is evident that the lesions of Hodgkin's disease are very similar to, if not identical with, those of lieno-lymphatic leuksemia. In fact, the only material point of distinction be- tween them is the excess of circulating leucocytes in the latter. If, then, we can point to any cases of Hodgkin's disease in which the circulating leuco- cytes, at first normal or subnormal, subsequently increased in number to an inordinate extent, we are justified in regarding them as instances of transition from the one affection to the other, and in assuming a close relation between them. Fleischer and Penzoldt1 hold that there are cases of lymphatic pseudoleukaemia which represent the initial stages (vorstufen) of a genuine lymphatic leu- kaemia, and report one in which the transition from the former to the latter was demonstrated. The pa- tient was a male, set. forty-two, who presented ex- tensive glandular swellings in the neck on both sides and in the left axilla, which slowly enlarged while the condition of the patient became gradually worse. The blood was repeatedly examined, but it was not until about fourteen days before death-i. e., nearly a year after the first blood examination-that the pro- portion of white cells to red had increased to such an extent (i : 9) as to warrant the diagnosis leuksemia. Mosier2 reports a case of pseudoleuksemia (Hodg- 1 Deutsche Archiv fur klinische Medizin, B. 26, 1880, S. 368. 2 Virchow's Archiv, Bd. 114, 1888, S. 461. ANEMIA, CHLOROSIS, ETC. 19 kin's disease) in a boy, fourteen years old, who, when first seen, had enlarged glands in both axillae, both supra-clavicular regions, and in the cervical and infra-maxillary regions. Neither spleen nor liver was enlarged at first, and there was no increase in the number of white corpuscles. There was mod- erate fever. The disease, under treatment by arseni- cal injections into the glands, came to a standstill for sixteen days, the examination of the blood still giving a negative result, so far as concerns the num- ber of the white cells. The patient then returned home. Eight days later severe fever set in ; the ex- isting glandular tumors enlarged and new ones made their appearance. It also became evident, on physi- cal examination, that the spleen and liver were decidedly enlarged. On microscopic examination the white corpuscles were now found to be increased in number to such an extent that Mosier estimated them to be equal to the red. The case ran the usual fatal course of leukaemia, but was unusually acute, its whole duration being less than two months. Mosier concludes that too sharp a distinction has been hitherto made between so-called pseudoleukae- mia and leukaemia, notwithstanding the fact that this is the first case, in his large experience, in which he had observed a transition from the former to the latter affection. The rarity of such observations as the above is undoubtedly great, but, according to Fleischer and Penzoldt, may be explained in three ways: i. The transition is overlooked because the blood is not examined with sufficient frequency. 2. A certain 20 HENRY, time must elapse before the transition is accom- plished, and death generally occurs during the pseudoleukaemic stage. For example, in Fleischer and Penzoldt's case the stage of leukaemia was not reached until eight months after the first examina- tion of the blood, and, therefore, if death had oc- curred from any accident or complication within that period, the case would have been reported as one of pseudoleukaemia. 3. There may be cases of multiple lymphatic tumors which have no relation whatever to leukaemia, but belong to an entirely different species. As a rule, there is no absolute increase in the num- ber of circulating leucocytes in Hodgkin's disease, and, as just stated, instances of transition from this affection to leukaemia are rarely observed, but cases are not so uncommon in which the number of the white cells, while greater than under normal cir- cumstances, is scarcely great enough to warrant the diagnosis of leucocythaemia. Laache1 reports such a case-one in which the blood was repeatedly examined-the proportion of white to red corpus- cles varying between 1 : 70, the highest point, and 1 : 339, the lowest. I am inclined to regard an excess of white cells in the blood as the expression of a form of defective haemogenesis which maybe the terminal stage of any profound anaemia. In Fleischer and Penzoldt's case, leucocythaemia did not set in until fourteen days before death. In a case of pernicious anaemia 1 Die Anamie, p. 273. ANzEMIA. CHLOROSIS, ETC. 21 reported by Litten,1 the blood, previously without an excess of white cells, was found to be leukaemic (i : 15) four days before death, and this condition continued to increase until the day before death, when the proportion of white cells to red was as one to four. In a case reported as pernicious anaemia by J. H. Musser,2 the term leucocythaemia would, at one stage, have been more appropriate, for the white cells were to the red about as one to four. I recently examined the blood of a profoundly anaemic patient at the time of her admission to the Philadelphia Hospital-two days before her death-and found such an enormous increase in the leucocytes that, at the autopsy, which revealed a large perinephritic abscess, I made a careful, though fruitless, search for some communication between the abscess and a venous trunk. The woman had been in the hospital a short time before, in another ward, and had been regarded as a case of pernicious anaemia. The leu- cocythaemia was undoubtedly a late manifestation of her cachectic condition. The foregoing facts lead me to accept the first and fourth conclusions of a paper on the " Relations of Leucocythaemia and Pseudoleukaemia," published many years ago by H. C. Wood : 3 " 1. Clinically, the so-called true and false leukaemia are the same, save only in the matter of the white blood- corpuscles. 4. There are cases which, at one period of their course, represent pseudoleukaemia; at another, leukaemia." 1 Berliner klinische Wochenschrift, Nos. 19 and 20, 1877. 2 Proceedings Philadelphia County Medical Society, 1885. 3 American Journal of the Medical Sciences, Octooer, 1871. 22 HENRY, ANEMIA, CHLOROSIS, ETC. I am also inclined to agree with the opinion of Pepper,1 in so far as it applies to leucocythaemia and Hodgkin's disease, that " a condition so inconstant and irregular as the increase in the proportion of white corpuscles should not be made a ground of distinction between groups of cases identical in all other respects." In this paper I have endeavored to confine myself strictly to the question of the relations of these various forms of anaemia, avoiding, as far as pos- sible, any discussion of their nature. All the time at my disposal would have been occupied in the attempt to enumerate and criticise the different views concerning the pathogeny of leucocythaemia alone. I have tried to impart and illustrate my belief that the circumstances under which chlorosis and pernicious anaemia arise are so numerous and diverse as to forbid our regarding them as independent dis- eases. They are, in my opinion, neither more nor less than closely related processes of defective haemo- genesis. Leucocythaemia and Hodgkin's disease, in that they are always associated with lesions of the blood- making organs-spleen, lymph-glands, bone-marrow, etc.-are independent diseases, or, rather, different stages of the same disease, for such cases as those of Fleischer and Penzoldt, and Mosier, prove their relations to be of the most intimate nature. They also show the fallacy of the view that the local gland- ular affections of leukaemia are secondary to the accumulation of leucocytes in the blood. 1 Ibid., October, 1875. THE MEDICAL NEWS. A N ationalWeeklyMedical Periodical, containing 28-32 Double- Columed Quarto Pages of Reading Matter in Each Issue. $5.00 per annum, post-paid. Uniting in itself the best characteristics of the magazine and the news- paper, The Medical News renders a service of exceptional value .to the profession. 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