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Pernicious Anemia *
PERNICIOUS ANEMIA* STEVEN O. SCHWARTZ, M.D. DEFINITION
PERNICIOUS anemia is a disease usually insidious in onset and protracted in course, manifesting itself as an involvement of the hemopoietic, gastro-intestinal and nervous systems with differing degrees of inte'nsity. Involvement of the hemopoietic systsem results in a megaloblastic bone marrow and varying degrees of anemia, leukopenia, granulopenia and thrombocytopenia. Prime manifestation of gastro-intestinal involvement is the atrophy of the gastric mucosa with an accompanying achlorhydria and achylia; while degenerative changes of the posterior and lateral columns of the spinal cord characterize the nervous system changes. The administration of liver induces a remission in the manifestations of the disease.· HISTORY
Thomas Addison is credited with the original description of pernicious anemia, though his concept of the interrelationship with suprarenal gland disease was incorrect, and several writers recorded the disease before him. His masterly description published in 1855 1 has well earned him the eponym, albeit in strict justice credit for priority should go elsewhere. Combe16 in 1822 is said to have been the first to report an authentic case, while others were published by Andral (1823), Hall (1837), Piorry (1841), Pearce (1845),31 Elliotson (1846)/9 and Barclay (1851).6 Channing as early as 1842/3 recognized a severe pernicious anemia-like picture in the puerperium and discussed the use of blood transfusions in its treatment. Biermer, 8 unaware of Addison's work, reported fifteen cases in 1871 and is often credited by German writers with priority, even though another German, Lebert, had published two cases previously. • From the Hematological Laboratory, Cook County Hospital. Aided by a grant from the Wilson Laboratories.
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By 1860 when Wilks pointed out the absence of an increase in the white blood cells, much interest was manifested in both the clinical and pathological aspects of the disease. Greatest progress, in retrospect, was made between 1874 and 1888. In 18? 4 Immennan called attention to the fever which accom~ panied the disease (an association also noted by Biermer) and attributed it to the anemia. In 1875 Pepper and a year later Cohnheim1.5 described accurately for the first time the changes in the marrow and suggested that these were responsible for the anemia. During the same year Quinke45 depicted the rich iron deposits in the liver, pancreas, kidneys and other organs and pointed out the difference in the size of the red blood cells, calling attention to their variations in shape, which he named poikilocytosis. The next year Bromwell was reporting favorable results in some cases following the administration of arsenic, and three years later Fenwick21 not only recorded that the gastric mucosa was. atrophic. but clairvoyantly expressed the view that the symptoms of the disease were the results of this rather than the secondary deficiency of the blood. Between 1880 and 1883 came Ehrlich's discovery of nucleated red cells in the circulating blood, Eichhorst's finding of the microcytes, and Laache's observation on the disproportionately high hemoglobin-red cell ratio and emphasis of the large, deeply colored red cell which he thought characteristic. Soon afterwards Lichtheim (1887) recognized the pathological, and resultant clinical, nervous system changes. Momentum was given the theory of parasitic etiology by the findings of Ankylostoma duodcnale by Baumler (1881) and Sahli (1883) and Dibothriocephalus latus by Rehber (1884) and Runcberg (1888) in cases of apparent pernicious anemia. But Hunter, basing his thesis on the increased stores of iron, the hyperplasia of the bone marrow, and evidences of blood destruction, postulated a toxic, hemolytic causation. There is little bf significance, excepting the increasingly widespread use of blood transfusions and the brief era of splenectomy, separating these early years from the "modern" era. Basing his observations on the efficacy of liver in relieving dogs made anemic by bleeding, Whipple66 suggested that there might be a scarcity of red cell stroma building material in pernicious anemia. Minot, prompted by this work and the knowledge that liver was of benefit in sprue, together with Murphy42 began
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feeding large amounts of liver to patients and by 1926 had become satisfied with both the objective and subjective response to this therapy. Soon Cohn and Minot14 were able to show that oral extracts of liver were as efficacious as the whole organ, and not long afterwards Ginssle prepared the first practical parenteral extract. The next milestone is represented by Castle's experimentsl l, 12 showing that pernicious anemia is the result of a lack of the socalled "intrinsic factor," which is normally produced by the stomach and interacts with certain foods containing the "extrinsic factor" to produce the "anti-pernicious anemia principle." Sturgis and Isaacs61 (I 929) showed that stomach tissue had properties similar to liver, and since then these properties have been demonstrated in kidney, brain, placenta and other organs. Much has been written and many of the finer clinical and hematological details clarified in the intervening years, but with the exception of the concentration of the liver extract and attempts at the establishment of its chemical identity, with the view of synthesis, no further progress has been made. ETIOLOGY
Pernicious anemia results from the failure of the gastric mucosa to elaborate the "intrinsic factor" of Castle, which is normally produced in the pyloric portion of the stomach in man. B9 When the "intrinsic factor" is absent or markedly diminished/6, 29 no "anti-pernicious anemia principle" is formed by interaction with the "extrinsic factor."59 The "anti-pernicious anemia principle" is stored in the liver51 and thence supplies the functional needs of the bone marrow, the integument and its appendages, and the central nervous system. Occasionally destruction of the "intrinsic factor" producing portion of the stomach by disease,25 chemicals, 2 or surgery40 will give rise to pernicious anemia. Infrequently, diets abnormally low in "extrinsic factor" may have the same results.B,27 Pregnancy, Ankylostoma duodenale, Dibothriocephalus latus and many other infestations and conditions have been incriminated as etiologic agents, but considerable doubt exists whether these are truly etiologic agents or merely precipitating factors in latent cases.
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INCIDENCE
Although pernicious anemia occurs most frequently in Caucasians from the temperate regions,23. 24 exceptions are so numerous that one cannot rely on nationality as a diagnostic aid. It is said to be unusual in ·the Negro, but we have recently shown54 that its incidence has been much underestimated. The same is probably true for its rarity in Orientals, I myself having observed the disease in three Chinese. Seventy-five per cent of the cases occur between the forty-fifth and seventy-fifth years, but the age range is extreme. The occurrence in young children is debatable, though an occasional case is reported. Our youngest proved case was in a girl of seventeen. 53 We have noted a progressive increase in the rate per 100,000 beginning with 0.5 in the decade between ages ten and nineteen and reaching 553 in the decade between ages seventy and seventy-nine. There is a falling off of the rate above this but this falling off is probably more apparent than real (Tabulation). TABULATION INCIDENCE OF PERNICIODS ANEMIA ACCORDING TO AGE
Age Group Rate 10-19 .................. ,. . . . . . . . . . . . . .. . . . . . . .. . . 20-29 ........................................... 30-39 ........................................... 40-49 ........................................... 50-59 ........................................... 60-69 ........................................... 70-79 ........................................... 80-89 ...........................................
per 100,000 OS 405 21.0 66.0 157.0 310.0 553.0 191.0
In our experience males and females have been about equally affected (495 males and 505 females). Heredity is not of great significance, yet there is a distinct familial incidence, about 18 per cent of the patients24 having relatives with the'disease. Five proven cases in one generation, 50 occurrence in twins and in successive generations5 • 57 have all been reported, and I am aware of a family where three successive generations of daughters are affected. The finding of hypoclrromic anemia and achlorhydria in the families of patients with pernicious anemia is too frequent to be dismissed as pure coincidence. Draper18 has described the pernicious anemia "type" as a
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person having medium to tall build, broad face, large mandibular angle, short nose, long thin ears, wide, deep and short chest, wide subcostal angle, highly placed umbilicus, long abdomen, relatively wide pelvis and long lower extremities, eunochoidal habitus, and feminine quality of the secondary sex characteristics in the male. To this description we may add the broad spadelike hand and the usually massive bony structure, as well as the light eyes and light hair, which turns gray at an early age. 24 SYMPTOMS
The symptoms of pernicious anemia usually appear so slowly that the patient cannot date the onset of the illness or its first manifestation with any exactitude. For the most part the symptoms may be divided into four groups: (1) general complaints, (2) those referable to the cardiovascular system, (3) those to the gastro-intestinal tract, and (4) to the nervous system. This arbitrary division, though highly artificial since close interrelation and interdependence exists among the expressions of the disease, is justified by convenience for descriptive purposes. General Complaints
Most frequent complaints are weakness and a sense of being unwell-one or both of these being present in almost every case. The degree of weakness is variable and may be so mild as to manifest itself only as slight lassitude or may be severe enough to cause total disability. When extreme, the slightest exertion becomes impossible-the profound "languor" of which Addison spoke almost a hundred years ago. With the weakness go also the symptoms due to the anoxia of the central nervous system such as faintness, dizziness, inability to concentrate, loss of memory, ringing in the ears, spots before the eyes, occasional blurring of vision and a sense of coldness. As a rule the development of the general symptoms parallels the fall in the hemoglobin level. Cardiovascular Symptoms
The symptoms referable to the cardiovascular system follow even more closely the level of the blood. Few cardiovascular manifestations are noted while the hemoglobin is above 50 per cent (8 gm.), and in the slowly developing cases the paucity of complaints even with the hemoglobin level at 20 per cent (3 to
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4 gm.) or less is astonishing. It is to be remembered in this connection that it is the hemoglobin and not the red. cell level that is of importance here since the individual cells contain more than their normal complement of hemoglobin and this determines the oxygen carrying capacity of the blood. Dy spnea, appearing at first only after exertion and later with increasing ease, occurs in the majority of patients by the time they present themselves for examination. Edema is the second most important symptom and depends for its development on cardiac dilatation and subsequent relative failure, on tissue anoxia, on lowered blood proteins, and the anemia itself. It is usually confined to the legs but may be more extensive. Palpitation is almost as frequent a complaint as dyspnea, and is at first also noted particularly after exertion, though occasionally there is a constant awareness of the heart "pounding" even when lying down. With severe anemia, especially in the presence of changes in the coronary vessels, such as arteriosclerosis, where the blood supply of the heart muscle is already impaired, angina pectoris may be a complication. 63 With the amelioration of the anemia the pain disappears in most instances. Gastro-intestinal Symptoms
Most prominent among the gastro-intestinal symptoms is the loss of appetite. This may vary from a mild distaste for certain foods to anorexia so marked that little besides milk and cereals are eaten. To aggravate matters, the most essential food substances are the first ones eliminated. Dairy products, cereals and starches constitute the diet in the average case. Aversion to meat is so common as to bear special mention, the usual reason given being the "inability to digest it" and the "loss of taste for it." Frequently much patience and persuasion are required to reeducate the patient to eat a balanced diet, and meat in particular, even after the therapeutically induced remission. Epigastric distress-usually described as "pains in the stomach" -and nausea and vomiting are the symptoms next in importance. D!arrhea is one of the "text-book" symptoms, but in our experience occurs in no more than a tenth of the cases, while alternating diarrhea and constipation is seen only in about 5 per cent. We have, on the contrary, found constipation to be the rule, occurring in well over half the cases.
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The intensity of gastro-intestinal complaints roughly parallels the tongue changes, since in general the more extensive the atrophy of the tongue the more marked the atrophy of the upper gastro-intestinal mucosa. 33 • 38. 52 The tongue symptoms in turn follow the atrophic changes seen in the papillae. Varying degrees of tongue changes occur in almost all cases but tongue symptoms will be volunteered by only about a fourth of the patients. They are variously described as "burning," "smarting," the sensation of "acid" on the tongue, or as intolerance to sour, salty, hot and occasionally rough foods. Sometimes these sensations extend to the oral mucous membranes and the gums, leading to the mistaken diagnosis of "oral sepsis" with subsequent extraction of the teeth. Many patients date their symptoms to the time the teeth were pulled, little realizing the cause-andeffect relationship. The emphasis on the preservation of the body tissues, persisting since Addison's time, has made us lose sight of the fact that great changes in weight occur. We have found weight loss in almost every case during relapse and it was one of the presenting complaints in fully 60 per cent. Even more striking than the history of weight loss is the remarkable gain in weight after therapy is begun. This gain in the average case amounts to from 10 to 25 per cent of the body weight. 34 • 64 Symptoms Referable to the Nervous System
Symptoms referable to the nervous system occur in four out of five cases. Earliest and most common complaints are "tingling" and/or "numbness" of the finger tips, present bilaterally and usually symmetrically. The characteristic way in which patients describe this is by gently rubbing the thumb over the other fingers in rotation to indicate the site of involvement. The lower extremity is usually affected subsequently. At first the toes become numb, then there is a gradual extension upward with an increasing feeling of coldness. Still later the leg becomes unsteady and there are peculiar subjective sensations variously described as walking "on air," "on clouds," "on pillows," "on rubber," and so on. In later stages there may be an awareness of staggering and the feeling of "walking as if drunk." The coldness and numbness may in time involve all the extremities and the entire trunk, though the upper arms and thorax are usually spared. Walking, due to the loss of position sense
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and the spastIcIty of the lower extremities, by this time has become impossible. Responsible for the symptoms are the degeneration of the posterior columns of the spinal cord carrying primarily proprioceptive and joint position sensations. When degenerative changes in the posterior columns dominate, spasticity is not a remarkable feature; on the other hand, when the dominant degeneration is in the lateral columns, spasticity is foremost. Stiffness and/or numbness leading to difficulties in walking are among the outstanding symptoms, being present in a mild form in about half and in a severe form in about a quarter of the cases. Genito-urinary involvernent, manifesting itself particularly in bladder incontinence and decreased sexual desire in the male, is not uncommon. Rectal incontinence, frequently accompanying that of the bladder, together with trophic changes, predispose to complications which unfavorably affect prognosis. SIGNS
The common, though by no means constant, anthropological features found in patients with pernicious anemia have already been mentioned. There are a few other signs which are the rule . but here again exceptions are numerous. Pallor, especially of the mucous membranes, is most frequent and varies with the degree of anemia. Jaundice, varying from a faint trace, visible only in the sclerae (icterus index 8 or 10), to frank jaundice (icterus index 25 or 30) appears in inverse proportion to the anemia. It imparts a yellowish cast to the skin, so often and so incorrectly referred to as "lemon-yellow" pallor. Rarely jaundice may be even more marked, but this most frequently occurs in complicated cases, cases with gallbladder or liver disease. 7 The importance of the tongue as a diagnostic aid cannot be overemphasized, notwithstanding the fact that deviations from the typical mlooth tongue are many. The completely bald, shiny, glistening tongue with all its papillae completely atrophied occurs in no mote than 15 to 20 per cent of the cases-and when it does occur, unless complicated by dietary deficiencies, it is not "beefy red" but rather a pale, bloodless, orange-red ("veallike"). The absence of a "coat" from the tongue has been the least variable and the most important sign. A coated tongue is sometimes seen but these exceptions are so infrequent as to lead to little confusion, and help but to emphasize the fact that pernicious anemia is indeed a disease of exceptions.
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Changes in the heart are those secondary to the anemia, and as such vary with its severity. Dilatation is the rule and is best observed in the roentgenographic silhouette, which shows progressive shrinkage with improvement in the blood. Soft hemic 'mUr'mUrs appear when the hemoglobin falls below 50 per cent. They are usually systolic in time and are confined to the apical and pulmonary areas at first, but with the progression of the anemia may be heard over the entire precordium and in diastole as well. The presence of murmurs may lead to a mistaken diagnosis of heart disease, as we have had occasion to point out elsewhere. 53 A lowering of the blood pressure, usually not marked, is the rule, and is more pronounced in the systolic reading than in the diastolic. The electrocardiographic changes are nonspecific and manifest themselves most commonly as low voltage, low or inverted T's, and lowered S-T segments. Demonstrable enlargement of the liver is present in a fourth of the cases and it is not unusual to palpate the lower border 6 to 8 cm. below the costal margin. The liver edge in these cases is firm, sharply demarcated, and nontender. Splenomegaly of sufficient magnitude to make the spleen palpable is only found in from 10 to 20 per cent of the cases. This may be quite marked at times, the lower border reaching 8 or even 10 cm. below the costal margin. Shrinkage of both the liver and spleen follow induced remission. The persistence of splenomegaly in a treated case indicates a complication, 9 but it is not unusual to find some residual liver enlargement. Some edema of tbe legs is seen in almost every case with a hemoglobin level below 50 per cent (7.5 to 8 gm.). It becomes marked in only 10 to 15 per cent of cases, and may be very extensive at times, manifesting itself on rare occasions as generalized anasarca. When this occurs, the prognosis becomes extremely grave. Neurological signs most commonly encountered are the loss of vibration sensation in the lower extremities, cbanges in deep reflexes, the appearance of pathological reflexes, loss of position sense, and the appearance of a positive Romberg sign.~8 The earliest change is a quantitative diminution in vibration sensation at the level of the ankle. Gradually this spreads upwards and may reach the thoracic level with complete loss of vibration sense below. The deep reflexes (knee and ankle jerks) will be either hyperactive or hypoactive depending on whether the
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posterior or lateral columns dominate. More extensive involvement of the posterior columns will lead to hypoactive deep reflexes while more severe lateral column damage will lead to hyperactivity. The former occurs twice as frequently as the latter. The appearance of pathological reflexes also depends on disproportionate lateral column degeneration. Gait difficulties are essentially of two kinds: those depending on the loss of position sensation and hypotonicity and manifesting themselves as inability to walk in the dark, and as having a positive Romberg sign, and those due to spasticity and manifesting themselves in the typical scissors gait. Far more common than pure examples of either are combinations with one or the other type dominating. Occasionally involvement of the cranial nerves is encountered, the loss of the sense of taste and smell being the most common. Visual difficulties occur at times but are more usually due to hemorrhages in the fundi than to optic nerve changes. 37 A dulling of the sensoria secondary to the anemia of the brain is extremely common, and its significance lies in the fact that the anoxic changes may at times be irreversible. Psychotic manifestation~O may even lead to the mistaken diagnosis of psychiatric disease. Because these patients usually have in addition the complicating urinary and fecal incontinence, the trophic skin changes, and decubitus ulcers, their prognosis is as a rule very poor. LABORATORY FINDINGS
Most pertinent of laboratory findings in permclOUS anemia are those in the blood. The degree of anemia is extremely variable. In cases showing neurological changes primarily the anemia may be so insignificant as to cause diagnostic difficulties;49. 62 or the count may go to incredibly lbw levels, the writer having seen the red cell count as low as 340,000. Characteristically the blood shows an anemia, leukopenia, granulopenia and thrombocytopenia. The changes in the red cells may be considered pathognomonic and are characterized by macrocytosis, the large cells being ovoid in shape and, because of increased thickness, seem more highly colored than normal, with the resultant appearance of "hyperchro'llzia." Macrocytosis is the earliest change and may be found even with rer' ~ell levels at four million. As the ane-
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mia progresses the macrocytosis becomes more pronounced and at about a two and half million level anisocytosis and poikilocytosis appear. With progression of anemia these changes become more and more extreme. Rarely, when iron deficiency complicates the picture, the macrocytosis may be absent but the other changes are nevertheless present. The presence of a leukocytosis before therapy is usually indicative of complications. Accounting for the leukopenia is not only the depression in granulocytes but also in lymphocytes. There is a right shift of the neutrophils with mature forms dominating, and many of the cells showing multiple lobulations of their nuclei. 35 The white ,cell count averages between 5000 and 6000 but drops sometimes to 1000 or 2000. Platelets are diminished in almost all cases,44 but the diminution is rarely of such magnitude as to lead to clinical symptoms. The second most informative laboratory test is the analysis of the gastric contents which, with extremely rare exceptions,22.48 shows an achlorhydria and achylia. The exceptions to this rule are so few as to make one discredit the diagnosis of pernicious anemia without very substantial additional proof. The icterus index is elevated41 from 10 to 20 and on rare occasions may even rise over 30 in uncomplicated cases. Urobilinogen in the urine is also increased. 20 The determination of the reticulocyte count for practical purposes is unimportant, but is of aid in determining the potency of liver extract, and may be of value when liver is employed in a therapeutic test. In untreated cases the reticulocytes vary between 0 and 5 per cent, and start to rise about two days after the beginning of therapy. The reticulocytes reach a peak, whose magnitude is inversely proportional to the'level of the original count,32 in five to seven days, on intramuscular liver therapy (40 per cent starting at one million; 20 per cent at two million; 10 per cent at three million). Red cell increase begins simultaneously with reticulocyte response and also rises at a rate inversely proportional to the original erythrocyte level,46 The simplest way of calculating the expected daily rise is to divide the difference between the original and ideal red cell levels by 60 since regardless of the original blood level the normal count will be reached in about eight weeks. The finding sine qua non is the 'fnegaloblastosis of the bonc marrow. 17 This must be present in every case in which the his-
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tory, physical finding, neurological changes without anemia, or the presence of free hydrochloric acid makes the diagnosis questionable. CONCOMITANT DISEASES
Although individuals who have pernicious anemia may develop the same complicating diseases as others in similar age groups, there are certain illnesses that apparently occur with increased, while others with decreased, frequency. Peptic ulcer is said not to occur,36 and explanation for this may be found in the achlorhydria and the emotional makeup. Tuberculosis is also said to be rare,55 though roentgenographic evidence of primary infection is seen frequently. We have seen active tuberculosis in patients with pernicious anemia, though, considering the increased susceptibility, the incidence should be greater. Prominent among other complicating conditions are artbritis, diabetes mellitus56 and asthma. Thyrotoxicosis, in our experience, has shown an unexpectedly high incidence, considering the fact that it is supposed to occur in an entirely different age group and in individuals of different constitutional predispositions. 4 • 47 Thyrotoxicosis may precede or develop during. the course of pernicious anemia. When the anemia develops after thyroidectomy in these cases it is not the macrocytic anemia occasionally encountered in the course of myxedema, but fulfiIls the strict diagnostic criteria of pernicious anemia, is accompanied by an elevated basal metabolism, and responds specifically to the administration of liver extract without additional thyroid. Gallbladder disease also shows a significantly increased20 incidence, 7 which may be secondary to the increased pigment metabolism. The termination of pernicious anemia in carcinoma of the stomach has been emphasized in the literature, metaplasia of the atrophic gastric mucosa with polyp formation and carcinomatous degenerati'on being postulated as the cause. 28 • 65 Considering the commonness of carcinoma of the stomach and the overlapping of the age groups in which both conditions are found, one may well question the validity of the emphasis placed on the relationship of the two diseases. In a large series of cases followed over a long period of time, I have been unimpressed by the frequency of stomach carcinoma. .
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DIAGNOSIS
The diagnosis of pernicious anemia is very easy when there are changes in the blood, the nervous system and the gastro-intestinal tract. Diagnostic difficulties are most likely to be encountered when a single symptom is disproportionately prominent and the others are either absent or insignificant. Thus a patient having only anemia might be suspected of cardiovascular disease because of the symptoms-a suspicion confirmed by the hemic murmurs, the occasional splenomegaly, and the fever. 53 Patients complaining of anorexia, nausea, vomiting and epigastric pains may be assumed to have gastro-intestinal disease especially when weight loss and change in bowel habits are added to the symptoms. Primary neurological disease is often diagnosed when the anemia is mild or absent, a circumstance by , no means uncommon since there is usually a reciprocal relation between the severity of the anemia and the nervous system involvement,60, 62, 67 At first glance the appearance of the patient may suggest nephritis or myxedema, but these diseases can be easily differentiated clinically. Hematologically, sprue,I° fish-tapeworm infestation and carcinoma of the stomach are said to lead to confusion most frequently, but in our experience aleukemic leukemia~ myelophthisic anemia, and aplastic anemia have caused the greatest diagnostic difficulties. The rules to follow in attempting to diagnose pernicious anemla are: 1. Suspect pernicious anemia in every case where no obvious cause for the anemia exists; where vague abdominal discomfort is associated with anemia, or where paresthesias of the extremities coexist with anemia or gastro-intestinal symptoms. At this stage pernicious anemia is suspected. 2. Examine the patient, looking in particular for the anthropological features described above, the gray hair, light eyes, pallor, scleral icterus, atrophy of the tongue papillae, the presence or absence of lymphadenopathy, hepatomegaly and splenomegaly. Neurologically, changes in the deep reflexes, a positive Romberg sign and loss of vibration sensation are looked for. Should confirmatory information be supplied by the examination, a tentative diagnosis of pernicious anemia may be made. 3. If the blood presents anemia with a high color index, leukopenia, thrombocytopenia and granulopenia, if the red cells
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are large and oval, and are well filled with hemoglobin, and in addition show alteration in size and shape (not at high red cell level!), and if in addition multilobed polymorphonuclear leukocytes are seen, the probable diagnosis of pernicious anemia may be made, and liver therapy begun lest the patient be jeopardized by waiting. 4. While awaiting therapeutic response (five to eight days) the following confirmatory tests should be performed. (a) Icterus index or Van den Bergh determination (b ) Urinary urobilinogen determinations
(These must be performed within twenty-four to fortyeight hours since their values drop markedly thereafter) (t) Analysis of the gastric contents following histamine stimulation (twenty to thirty minutes after the administration of 0.1 mg. of histamine hydrochloride per 10 kg. body weight subcutaneously) (d) Stool examination for occult blood and parasites or their ova
If the bilirubin of the blood and urobilinogen of the urine are increased, no free acid is found in the gastric secretions, and neither blood nor parasites are present in the stool, a positive diagnosis of pernicious anemia may be made. Occasionally one may wish to hasten making a positive diagnosis or may wish to confirm it with examination of the marrow whose changes are pathognomonic. 17 But even in cases thus diagnosed, the above described tests should be performed to rule out a pernicious anemia secondary to gastric neoplasm, fish tapeworm, or other causes. TREATMENT
Liver extract is specific for the treatment of pernicious anemia. Only general rules can be formulated as to the mode of its administration, since individualization of the patient43 is as important, or is even more important, than in other diseases where specific th~rapeutic agents are known. One unit* of liver extract per day on the average is required for maintenance, but extreme variations are encountered . .Cases may roughly be divided into two groups, depending on the presence or absence of neurological signs and symptoms. • A unit is defined as the amount of liver which, when given in a uniform daily dose in a case of pernicious anemia in relapse, will elicit a satisfactory red cell and reticulocyte response. .
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Patients without neurological complications should get an average of 15 units of liver extract intramuscularly three times a week for the first two weeks, twice a week for the next two weeks, and weekly for the next month. By the end of this time (eight weeks) the blood has reached a normal level. From here on doses of 15 to 30 units of liver extract can be given anywhere from once a week to once every four to six weeks depending on individual requirement. The best plan is to "wean" the patient by cutting the frequency of injections by a week every two to three months. There is little merit in examining the blood at intervals less than two to three months, since th( patient's sense of well being, the paucity of complaints, the color, and the appearance of the tongue are sufficiently good indices of adequate therapy. Once the maintenance dose is established there need be little deviation from it unless complications (infections, bleeding, pregnancy, and so forth) occur. The need for liver increases considerably when complications are present and allowance must be made for this by increasing either the dose Or the frequency of administration, or both. The site of injection depends on preference. We have found the upper portion of the deltoid muscle the site of choice; here amounts up to 3 cc. are tolerated without discomfort. Treatment in cases complicated by neurological symptoms is much more intensive. In general, 20 to 30 units are given daily for the first two weeks, three times a week for four to six weeks, then twice weekly for another four to six weeks, and finally weekly until all neurological symptoms shall have disappeared, or until no further improvement is thought possible. Such intensive treatment should be continued for at least two years before one may assume that no further improvement is possible. Improvement in neurological symptoms is manifested by a return of normal sensation to the uppermost regions involved, with a gradual progression of this process downward. Objectively the improvement can best be followed in patients showing changes in vibration sensation, in whom the return of the sensation to lower and lower levels can be traced. It has been my impression that the cruder liver extracts (i.e., less potent extracts-not to be confused with diluted extracts) are more efficacious in the cases showing neurological changes. We do not deem it necessary to combine vitamins with liver to achieve optimal results. Once maximal improvement in the neurological
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symptoms is reached, the same process of "weaning" may be followed as described above, but it is seldom possible to reduce the liver to amounts comparable to those sufficient for purely hematological types without a recurrence of symptoms. The administration of hydrochloric acid routinely is unnecessary. We employ it only when gastro-intestinal complaints persist, or appear in spite of adequate liver therapy. Fifteen to 30 drops (Diluted Acid Hydrochloridi, D.S.P.) in half glass of water is either sipped with or is taken after meals. It is interesting that this almost insignificqnt amount (when compared to the normal gastric secretion) should result in the almost constant and striking relief that follows its admin~stration. The administration of iron, in addition to the liver extract, becomes necessary only when a concomitant iron deficiency develops. When this occurs it is first noted three to four weeks after the beginning of liver therapy and manifests itself as a gradually increasing hemoglobin lag and the development of a progressively lower color index. The red cell count levels off at about 4 million, with the hemoglobin at 60 per cent (10 gm.), and remains there until iron is given. With this both the red cells and the hemoglobin rise to normal levels. Complicating or' coexisting diseases are treated just as if the pernicious anemia were nonexistent, remembering only that additional amounts of liver may be necessary. A disconcerting complication, which occurs at some time in almost 10 per cent of patients treated for long periods, is the appearance of allergic reactions. These vary in severity from mild itching to shock and collapse. Changing the brand of liver will often suffice to eliminate reactions. If this fails, desensitization may be tried by the administration of increasingly larger doses beginning with extremely small amounts (such as %0 of a unit). Should this fail, two alternatives remain: theadministration of oral illstead of parenteral liver in the form of the liquid or dry extract, or the administration of stomach extract. Ordinarily certain practical objections exist which make the writer advise against the use of oral extracts. These may be summarized as follows: (1) eventual neglect of therapy due to lack of supervision, (2) greater cost, (3) greater difficulty in maintaining the blood at optimal level and (4) the development or progression of neurological signs and symptoms in spite of therapy.
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o.
SCHWARn
Therapeutically, few diseases in the field of internal med· icine are as satisfying to both the patient and his physician The dramatic and spectacular improvement following the ad· ministration of liver is practically unequalled, and with the ex· ception of the occasional inconvenience of liver injections, th( patient continues with a normal life expectancy. BIBLIOGRAPHY
1. Addison, T.: On the Constitutional and Local Effects of Disease of the Suprarenal Capsules. London, Highley, 8:43, 1855. 2. AIsted, G.: Lancet, 1:76, 1937. 3. Alsted, G.: Am. J. Med. Sci., 197:741, 1939. 4. Andrus, E. C. and Wintrobe, M. M~: Bull. Johns Hopkins Hosp., $9:291 1936. S. Askey, J. M.: Ann. Int. Med., 14:593, 194{). 6. Barclay: Med. Times (n.s.), 2:480, 1851. 7. Bethell, F. H. and Harrington, B. D.! Am. J. Digest. Dis. & Nutrition, 1. 256, 1934. 8, Biermer, A.: Korrespondenzblatt F. Schweiz Aerzte, 2:15, 1872. 9. Bigg, E.: Ann. Int. Med., 14:277, 1940. 10. Castellani, C. A.: Rev. Gastroenterol., ;:226, 1938. 11. Castle, W.: Am. J. Med. Sci., 178:748, 1929. . 12. Castle, W. B., Townsend, W. C. and Heath, C. W.: Am. J. ~ed. ScL 180:305, 1930.
13. Channing, W.: Northeast Quart. J. Med. & Surg., 1:157, 1842. 14. Cohn, E. J., Minot, G. R., Alles, G. A. and Salter, W. T.: J. BioI. Chem., 77:325, 1928.. 15. Cohnheim, J.: Virchow's Archiv. f. path. Anat., 68:291, 1876. 16. Combe, J. 5.: Tr. Med.-Chir. Soc., Edinburgh, May, 1822. 17. Dameshek, W. and Valentine, E. H.: Arch. Path., 23:159, 1937. 18. Draper, G.: The Human Constitution. Philadelphia, W. B. Saunders Company, 1924. 19. Elliotson, J.: Practice of Medicine, 2nd ed. Butler, London, 1846. 20. Farquharson, R. F., Borsook, and GQulding, A. M.: Arch. Int. Med., 48:1156, 1931. 21. Fenwick, 5.: On the Atrophy of the Stomach and on the Nervous Affections of the Digestive Organs. London, J. & A. Churchill, 1880. 22. Finney, J. 0.: Ann. Int. Med., 12:1521, 1939. 23. Friedlander, R. D.: Am. J. Med. Sci., 187:634, 1934. 24. Gates, L. R.: Thesis, Dr. P. H., U. of Michigan, 1932, 25. Goldhamer, S. M.: Am. J. Med. ScL, 19$:17, 1938. 26. Goldhamer, S. M., Isaacs, R. and Sturgis, C. c.: J. Clil). Investigation, 14:708, 1935. 27. Groen, J. and Snapper, I.: Am. J. Med. Sci., 193:633, 1937. 28. Haring, W.: Sonderdruck Aus Klinische Wochenschrift, 4$:1586, 1938. 29. Helmer, O. M. and Fouts, P. J.: Am. J. Med. ScL, 194:399, 1937. 30. Herman, M., Most, H. and Jolliffe, N.: Arch. Neurol. & Psychiat., 38: 348, 1937. . 31. Hunter, W.: Pernicious Anemia, Its Pathology, Septic Origin, Symptoms, Diagnosis and Treatment. Strand, Griffin & Co., 1901. 32. Isaacs, R. and Friedman, A.: Am. J. Med. Sci., 196.:718, 1938.
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33. Jones, C. M., Benedict, E. B. and Hampton, A. 0.: Am. J. Med. Sci., 34. 35. 36. 37. 38. 39. 40.
190:596, 1935.
Jones, E.: Am. J. Med. Sci., 195:150, 1938. Jones, O. P.: Arch. Int. Med., 60:1002, 1937. Kahn, J. R.: Am. J. Med. Sci., 194:463, 1937. Karnpmeier, R. H. and Jones, E.: Am. J. Med. Sci., 195:633, 1938. Magnus, H. A. and Ungley, C. C.: Lancet 2:420, 1938. Meulengracht, E.: Am. J. Med. Sci., 197:201, 1939. Meyer, K. A., Schwartz, S. O. and Weissman, L. H.: Arch. Surg., 42:
18, 1941. ' 41. Mills, J. and Mawson, C. A.: Lancet, 2:1455, 1938. 42. Minot, G. R. and Murphy, W. P.: J.A.M.A., 87:470, 1926. 43. Moench, L. M.: Ann. Int. Med., 10:1115, 1937. 44. Paddock, F. K. :a.nd Smith, K. E.: Am. J. Med. Sci., 198:372, 1939. 45. Quinke, H.: Volkman's Klinische Vortage, p. 22, 1876. 46. Riddle, M. C.: Am. J. Med. Sci., 200:145, 1940. 47. Robinson, S. c.: Illinois M. J., 71:1, 1938. 48. Rozendaal, H. M. and Washburn, R. N.: Ann. Int. Med., 11:1834, 1938. 49. Sanford, C. H.: Ann. Int. Med., 9:189, 1935. 50. Schemm, F. R.: Am. J. Med. Sci., 199:167, 1940. 51. Schiff, L., Rich, M. L. and Simon, S. D.: Am. J. Med. Sci., 196:313, 1938. 52. Schindler, R. and Serby, A. M.: Arch. Int. Med., 63:334, 1939. 53. Schwanz, S. O. and Legere, H.: Am. J. Med. Sci., 206:1, 1943.
54. Schwartz, S. O. and Gore, M.: Arch. Int. Med., In press. 55. Sharp, D. V.: Minnesota Med., 21:258, 1938. 56. Smithburn, K. c., Fisher, \V. S. and Zerfas, L. G.: J. Indiana M. A., 23:
57. 58. 59. 60.
528, 1930.
Stamos, Strauss, Strauss, Strauss,
H. F.: Am.' J. Med. Sci., 200:586, 1940. I.: Bull. New York Acad. Med., 3:561, 1927. M. B. and Castle, W. B.: New England J. Med., 207:55, 1932. M. B., Solomon, P. and Fox, H. J.: New England J. Med., 222:
373, 1940.
Sturgis, C. C. and Isaacs, R.: J.A.M.A., 93:747, 1929. Suh, T. H. and Merritt, H. H.: Am. J. Med. Sci., 196:57, 1938. Vatcher, S.: Lancet, 2:192, 1939. Vaughan, J. M.: Arch. Int. Med., 47(5) :689, 1931. Velde, G.: Ztschr. f. Klinische Medizin, 134:653, 1938. Whipple, G. H., Robscheit-Robbins, F. S. and Hooper, C. W.: Am. Physiol., 53:151, 167, 236, 1920. 67. Woltrnan, H. W. and Heck, F. J.: Arch. Int. Med., 60:272, 1937. 61. 62. 63. 64. 65. 66.
J.
PERNICIOUS anemia is a disease usually insidious in onset and protracted in course, manifesting itself as an involvement of the hemopoietic, gastro-intestinal and nervous systems with differing degrees of inte'nsity. Involvement of the hemopoietic systsem results in a megaloblastic bone marrow and varying degrees of anemia, leukopenia, granulopenia and thrombocytopenia. Prime manifestation of gastro-intestinal involvement is the atrophy of the gastric mucosa with an accompanying achlorhydria and achylia; while degenerative changes of the posterior and lateral columns of the spinal cord characterize the nervous system changes. The administration of liver induces a remission in the manifestations of the disease.· HISTORY
Thomas Addison is credited with the original description of pernicious anemia, though his concept of the interrelationship with suprarenal gland disease was incorrect, and several writers recorded the disease before him. His masterly description published in 1855 1 has well earned him the eponym, albeit in strict justice credit for priority should go elsewhere. Combe16 in 1822 is said to have been the first to report an authentic case, while others were published by Andral (1823), Hall (1837), Piorry (1841), Pearce (1845),31 Elliotson (1846)/9 and Barclay (1851).6 Channing as early as 1842/3 recognized a severe pernicious anemia-like picture in the puerperium and discussed the use of blood transfusions in its treatment. Biermer, 8 unaware of Addison's work, reported fifteen cases in 1871 and is often credited by German writers with priority, even though another German, Lebert, had published two cases previously. • From the Hematological Laboratory, Cook County Hospital. Aided by a grant from the Wilson Laboratories.
214
PERNICIOUS ANEMIA
215
By 1860 when Wilks pointed out the absence of an increase in the white blood cells, much interest was manifested in both the clinical and pathological aspects of the disease. Greatest progress, in retrospect, was made between 1874 and 1888. In 18? 4 Immennan called attention to the fever which accom~ panied the disease (an association also noted by Biermer) and attributed it to the anemia. In 1875 Pepper and a year later Cohnheim1.5 described accurately for the first time the changes in the marrow and suggested that these were responsible for the anemia. During the same year Quinke45 depicted the rich iron deposits in the liver, pancreas, kidneys and other organs and pointed out the difference in the size of the red blood cells, calling attention to their variations in shape, which he named poikilocytosis. The next year Bromwell was reporting favorable results in some cases following the administration of arsenic, and three years later Fenwick21 not only recorded that the gastric mucosa was. atrophic. but clairvoyantly expressed the view that the symptoms of the disease were the results of this rather than the secondary deficiency of the blood. Between 1880 and 1883 came Ehrlich's discovery of nucleated red cells in the circulating blood, Eichhorst's finding of the microcytes, and Laache's observation on the disproportionately high hemoglobin-red cell ratio and emphasis of the large, deeply colored red cell which he thought characteristic. Soon afterwards Lichtheim (1887) recognized the pathological, and resultant clinical, nervous system changes. Momentum was given the theory of parasitic etiology by the findings of Ankylostoma duodcnale by Baumler (1881) and Sahli (1883) and Dibothriocephalus latus by Rehber (1884) and Runcberg (1888) in cases of apparent pernicious anemia. But Hunter, basing his thesis on the increased stores of iron, the hyperplasia of the bone marrow, and evidences of blood destruction, postulated a toxic, hemolytic causation. There is little bf significance, excepting the increasingly widespread use of blood transfusions and the brief era of splenectomy, separating these early years from the "modern" era. Basing his observations on the efficacy of liver in relieving dogs made anemic by bleeding, Whipple66 suggested that there might be a scarcity of red cell stroma building material in pernicious anemia. Minot, prompted by this work and the knowledge that liver was of benefit in sprue, together with Murphy42 began
216
. STEVEN O. SCHWA1UZ
feeding large amounts of liver to patients and by 1926 had become satisfied with both the objective and subjective response to this therapy. Soon Cohn and Minot14 were able to show that oral extracts of liver were as efficacious as the whole organ, and not long afterwards Ginssle prepared the first practical parenteral extract. The next milestone is represented by Castle's experimentsl l, 12 showing that pernicious anemia is the result of a lack of the socalled "intrinsic factor," which is normally produced by the stomach and interacts with certain foods containing the "extrinsic factor" to produce the "anti-pernicious anemia principle." Sturgis and Isaacs61 (I 929) showed that stomach tissue had properties similar to liver, and since then these properties have been demonstrated in kidney, brain, placenta and other organs. Much has been written and many of the finer clinical and hematological details clarified in the intervening years, but with the exception of the concentration of the liver extract and attempts at the establishment of its chemical identity, with the view of synthesis, no further progress has been made. ETIOLOGY
Pernicious anemia results from the failure of the gastric mucosa to elaborate the "intrinsic factor" of Castle, which is normally produced in the pyloric portion of the stomach in man. B9 When the "intrinsic factor" is absent or markedly diminished/6, 29 no "anti-pernicious anemia principle" is formed by interaction with the "extrinsic factor."59 The "anti-pernicious anemia principle" is stored in the liver51 and thence supplies the functional needs of the bone marrow, the integument and its appendages, and the central nervous system. Occasionally destruction of the "intrinsic factor" producing portion of the stomach by disease,25 chemicals, 2 or surgery40 will give rise to pernicious anemia. Infrequently, diets abnormally low in "extrinsic factor" may have the same results.B,27 Pregnancy, Ankylostoma duodenale, Dibothriocephalus latus and many other infestations and conditions have been incriminated as etiologic agents, but considerable doubt exists whether these are truly etiologic agents or merely precipitating factors in latent cases.
217
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INCIDENCE
Although pernicious anemia occurs most frequently in Caucasians from the temperate regions,23. 24 exceptions are so numerous that one cannot rely on nationality as a diagnostic aid. It is said to be unusual in ·the Negro, but we have recently shown54 that its incidence has been much underestimated. The same is probably true for its rarity in Orientals, I myself having observed the disease in three Chinese. Seventy-five per cent of the cases occur between the forty-fifth and seventy-fifth years, but the age range is extreme. The occurrence in young children is debatable, though an occasional case is reported. Our youngest proved case was in a girl of seventeen. 53 We have noted a progressive increase in the rate per 100,000 beginning with 0.5 in the decade between ages ten and nineteen and reaching 553 in the decade between ages seventy and seventy-nine. There is a falling off of the rate above this but this falling off is probably more apparent than real (Tabulation). TABULATION INCIDENCE OF PERNICIODS ANEMIA ACCORDING TO AGE
Age Group Rate 10-19 .................. ,. . . . . . . . . . . . . .. . . . . . . .. . . 20-29 ........................................... 30-39 ........................................... 40-49 ........................................... 50-59 ........................................... 60-69 ........................................... 70-79 ........................................... 80-89 ...........................................
per 100,000 OS 405 21.0 66.0 157.0 310.0 553.0 191.0
In our experience males and females have been about equally affected (495 males and 505 females). Heredity is not of great significance, yet there is a distinct familial incidence, about 18 per cent of the patients24 having relatives with the'disease. Five proven cases in one generation, 50 occurrence in twins and in successive generations5 • 57 have all been reported, and I am aware of a family where three successive generations of daughters are affected. The finding of hypoclrromic anemia and achlorhydria in the families of patients with pernicious anemia is too frequent to be dismissed as pure coincidence. Draper18 has described the pernicious anemia "type" as a
218
STEVEN O. SCHWARTZ
person having medium to tall build, broad face, large mandibular angle, short nose, long thin ears, wide, deep and short chest, wide subcostal angle, highly placed umbilicus, long abdomen, relatively wide pelvis and long lower extremities, eunochoidal habitus, and feminine quality of the secondary sex characteristics in the male. To this description we may add the broad spadelike hand and the usually massive bony structure, as well as the light eyes and light hair, which turns gray at an early age. 24 SYMPTOMS
The symptoms of pernicious anemia usually appear so slowly that the patient cannot date the onset of the illness or its first manifestation with any exactitude. For the most part the symptoms may be divided into four groups: (1) general complaints, (2) those referable to the cardiovascular system, (3) those to the gastro-intestinal tract, and (4) to the nervous system. This arbitrary division, though highly artificial since close interrelation and interdependence exists among the expressions of the disease, is justified by convenience for descriptive purposes. General Complaints
Most frequent complaints are weakness and a sense of being unwell-one or both of these being present in almost every case. The degree of weakness is variable and may be so mild as to manifest itself only as slight lassitude or may be severe enough to cause total disability. When extreme, the slightest exertion becomes impossible-the profound "languor" of which Addison spoke almost a hundred years ago. With the weakness go also the symptoms due to the anoxia of the central nervous system such as faintness, dizziness, inability to concentrate, loss of memory, ringing in the ears, spots before the eyes, occasional blurring of vision and a sense of coldness. As a rule the development of the general symptoms parallels the fall in the hemoglobin level. Cardiovascular Symptoms
The symptoms referable to the cardiovascular system follow even more closely the level of the blood. Few cardiovascular manifestations are noted while the hemoglobin is above 50 per cent (8 gm.), and in the slowly developing cases the paucity of complaints even with the hemoglobin level at 20 per cent (3 to
PERNICIOUS ANEMIA
219
4 gm.) or less is astonishing. It is to be remembered in this connection that it is the hemoglobin and not the red. cell level that is of importance here since the individual cells contain more than their normal complement of hemoglobin and this determines the oxygen carrying capacity of the blood. Dy spnea, appearing at first only after exertion and later with increasing ease, occurs in the majority of patients by the time they present themselves for examination. Edema is the second most important symptom and depends for its development on cardiac dilatation and subsequent relative failure, on tissue anoxia, on lowered blood proteins, and the anemia itself. It is usually confined to the legs but may be more extensive. Palpitation is almost as frequent a complaint as dyspnea, and is at first also noted particularly after exertion, though occasionally there is a constant awareness of the heart "pounding" even when lying down. With severe anemia, especially in the presence of changes in the coronary vessels, such as arteriosclerosis, where the blood supply of the heart muscle is already impaired, angina pectoris may be a complication. 63 With the amelioration of the anemia the pain disappears in most instances. Gastro-intestinal Symptoms
Most prominent among the gastro-intestinal symptoms is the loss of appetite. This may vary from a mild distaste for certain foods to anorexia so marked that little besides milk and cereals are eaten. To aggravate matters, the most essential food substances are the first ones eliminated. Dairy products, cereals and starches constitute the diet in the average case. Aversion to meat is so common as to bear special mention, the usual reason given being the "inability to digest it" and the "loss of taste for it." Frequently much patience and persuasion are required to reeducate the patient to eat a balanced diet, and meat in particular, even after the therapeutically induced remission. Epigastric distress-usually described as "pains in the stomach" -and nausea and vomiting are the symptoms next in importance. D!arrhea is one of the "text-book" symptoms, but in our experience occurs in no more than a tenth of the cases, while alternating diarrhea and constipation is seen only in about 5 per cent. We have, on the contrary, found constipation to be the rule, occurring in well over half the cases.
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STEVEN O. SCHWARTZ
The intensity of gastro-intestinal complaints roughly parallels the tongue changes, since in general the more extensive the atrophy of the tongue the more marked the atrophy of the upper gastro-intestinal mucosa. 33 • 38. 52 The tongue symptoms in turn follow the atrophic changes seen in the papillae. Varying degrees of tongue changes occur in almost all cases but tongue symptoms will be volunteered by only about a fourth of the patients. They are variously described as "burning," "smarting," the sensation of "acid" on the tongue, or as intolerance to sour, salty, hot and occasionally rough foods. Sometimes these sensations extend to the oral mucous membranes and the gums, leading to the mistaken diagnosis of "oral sepsis" with subsequent extraction of the teeth. Many patients date their symptoms to the time the teeth were pulled, little realizing the cause-andeffect relationship. The emphasis on the preservation of the body tissues, persisting since Addison's time, has made us lose sight of the fact that great changes in weight occur. We have found weight loss in almost every case during relapse and it was one of the presenting complaints in fully 60 per cent. Even more striking than the history of weight loss is the remarkable gain in weight after therapy is begun. This gain in the average case amounts to from 10 to 25 per cent of the body weight. 34 • 64 Symptoms Referable to the Nervous System
Symptoms referable to the nervous system occur in four out of five cases. Earliest and most common complaints are "tingling" and/or "numbness" of the finger tips, present bilaterally and usually symmetrically. The characteristic way in which patients describe this is by gently rubbing the thumb over the other fingers in rotation to indicate the site of involvement. The lower extremity is usually affected subsequently. At first the toes become numb, then there is a gradual extension upward with an increasing feeling of coldness. Still later the leg becomes unsteady and there are peculiar subjective sensations variously described as walking "on air," "on clouds," "on pillows," "on rubber," and so on. In later stages there may be an awareness of staggering and the feeling of "walking as if drunk." The coldness and numbness may in time involve all the extremities and the entire trunk, though the upper arms and thorax are usually spared. Walking, due to the loss of position sense
PERNICIOUS ANEMIA
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and the spastIcIty of the lower extremities, by this time has become impossible. Responsible for the symptoms are the degeneration of the posterior columns of the spinal cord carrying primarily proprioceptive and joint position sensations. When degenerative changes in the posterior columns dominate, spasticity is not a remarkable feature; on the other hand, when the dominant degeneration is in the lateral columns, spasticity is foremost. Stiffness and/or numbness leading to difficulties in walking are among the outstanding symptoms, being present in a mild form in about half and in a severe form in about a quarter of the cases. Genito-urinary involvernent, manifesting itself particularly in bladder incontinence and decreased sexual desire in the male, is not uncommon. Rectal incontinence, frequently accompanying that of the bladder, together with trophic changes, predispose to complications which unfavorably affect prognosis. SIGNS
The common, though by no means constant, anthropological features found in patients with pernicious anemia have already been mentioned. There are a few other signs which are the rule . but here again exceptions are numerous. Pallor, especially of the mucous membranes, is most frequent and varies with the degree of anemia. Jaundice, varying from a faint trace, visible only in the sclerae (icterus index 8 or 10), to frank jaundice (icterus index 25 or 30) appears in inverse proportion to the anemia. It imparts a yellowish cast to the skin, so often and so incorrectly referred to as "lemon-yellow" pallor. Rarely jaundice may be even more marked, but this most frequently occurs in complicated cases, cases with gallbladder or liver disease. 7 The importance of the tongue as a diagnostic aid cannot be overemphasized, notwithstanding the fact that deviations from the typical mlooth tongue are many. The completely bald, shiny, glistening tongue with all its papillae completely atrophied occurs in no mote than 15 to 20 per cent of the cases-and when it does occur, unless complicated by dietary deficiencies, it is not "beefy red" but rather a pale, bloodless, orange-red ("veallike"). The absence of a "coat" from the tongue has been the least variable and the most important sign. A coated tongue is sometimes seen but these exceptions are so infrequent as to lead to little confusion, and help but to emphasize the fact that pernicious anemia is indeed a disease of exceptions.
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STEVEN O. SCHWARTZ
Changes in the heart are those secondary to the anemia, and as such vary with its severity. Dilatation is the rule and is best observed in the roentgenographic silhouette, which shows progressive shrinkage with improvement in the blood. Soft hemic 'mUr'mUrs appear when the hemoglobin falls below 50 per cent. They are usually systolic in time and are confined to the apical and pulmonary areas at first, but with the progression of the anemia may be heard over the entire precordium and in diastole as well. The presence of murmurs may lead to a mistaken diagnosis of heart disease, as we have had occasion to point out elsewhere. 53 A lowering of the blood pressure, usually not marked, is the rule, and is more pronounced in the systolic reading than in the diastolic. The electrocardiographic changes are nonspecific and manifest themselves most commonly as low voltage, low or inverted T's, and lowered S-T segments. Demonstrable enlargement of the liver is present in a fourth of the cases and it is not unusual to palpate the lower border 6 to 8 cm. below the costal margin. The liver edge in these cases is firm, sharply demarcated, and nontender. Splenomegaly of sufficient magnitude to make the spleen palpable is only found in from 10 to 20 per cent of the cases. This may be quite marked at times, the lower border reaching 8 or even 10 cm. below the costal margin. Shrinkage of both the liver and spleen follow induced remission. The persistence of splenomegaly in a treated case indicates a complication, 9 but it is not unusual to find some residual liver enlargement. Some edema of tbe legs is seen in almost every case with a hemoglobin level below 50 per cent (7.5 to 8 gm.). It becomes marked in only 10 to 15 per cent of cases, and may be very extensive at times, manifesting itself on rare occasions as generalized anasarca. When this occurs, the prognosis becomes extremely grave. Neurological signs most commonly encountered are the loss of vibration sensation in the lower extremities, cbanges in deep reflexes, the appearance of pathological reflexes, loss of position sense, and the appearance of a positive Romberg sign.~8 The earliest change is a quantitative diminution in vibration sensation at the level of the ankle. Gradually this spreads upwards and may reach the thoracic level with complete loss of vibration sense below. The deep reflexes (knee and ankle jerks) will be either hyperactive or hypoactive depending on whether the
PERNICIOUS ANEMIA
223
posterior or lateral columns dominate. More extensive involvement of the posterior columns will lead to hypoactive deep reflexes while more severe lateral column damage will lead to hyperactivity. The former occurs twice as frequently as the latter. The appearance of pathological reflexes also depends on disproportionate lateral column degeneration. Gait difficulties are essentially of two kinds: those depending on the loss of position sensation and hypotonicity and manifesting themselves as inability to walk in the dark, and as having a positive Romberg sign, and those due to spasticity and manifesting themselves in the typical scissors gait. Far more common than pure examples of either are combinations with one or the other type dominating. Occasionally involvement of the cranial nerves is encountered, the loss of the sense of taste and smell being the most common. Visual difficulties occur at times but are more usually due to hemorrhages in the fundi than to optic nerve changes. 37 A dulling of the sensoria secondary to the anemia of the brain is extremely common, and its significance lies in the fact that the anoxic changes may at times be irreversible. Psychotic manifestation~O may even lead to the mistaken diagnosis of psychiatric disease. Because these patients usually have in addition the complicating urinary and fecal incontinence, the trophic skin changes, and decubitus ulcers, their prognosis is as a rule very poor. LABORATORY FINDINGS
Most pertinent of laboratory findings in permclOUS anemia are those in the blood. The degree of anemia is extremely variable. In cases showing neurological changes primarily the anemia may be so insignificant as to cause diagnostic difficulties;49. 62 or the count may go to incredibly lbw levels, the writer having seen the red cell count as low as 340,000. Characteristically the blood shows an anemia, leukopenia, granulopenia and thrombocytopenia. The changes in the red cells may be considered pathognomonic and are characterized by macrocytosis, the large cells being ovoid in shape and, because of increased thickness, seem more highly colored than normal, with the resultant appearance of "hyperchro'llzia." Macrocytosis is the earliest change and may be found even with rer' ~ell levels at four million. As the ane-
224
STEVEN O. SCHVVARTZ
mia progresses the macrocytosis becomes more pronounced and at about a two and half million level anisocytosis and poikilocytosis appear. With progression of anemia these changes become more and more extreme. Rarely, when iron deficiency complicates the picture, the macrocytosis may be absent but the other changes are nevertheless present. The presence of a leukocytosis before therapy is usually indicative of complications. Accounting for the leukopenia is not only the depression in granulocytes but also in lymphocytes. There is a right shift of the neutrophils with mature forms dominating, and many of the cells showing multiple lobulations of their nuclei. 35 The white ,cell count averages between 5000 and 6000 but drops sometimes to 1000 or 2000. Platelets are diminished in almost all cases,44 but the diminution is rarely of such magnitude as to lead to clinical symptoms. The second most informative laboratory test is the analysis of the gastric contents which, with extremely rare exceptions,22.48 shows an achlorhydria and achylia. The exceptions to this rule are so few as to make one discredit the diagnosis of pernicious anemia without very substantial additional proof. The icterus index is elevated41 from 10 to 20 and on rare occasions may even rise over 30 in uncomplicated cases. Urobilinogen in the urine is also increased. 20 The determination of the reticulocyte count for practical purposes is unimportant, but is of aid in determining the potency of liver extract, and may be of value when liver is employed in a therapeutic test. In untreated cases the reticulocytes vary between 0 and 5 per cent, and start to rise about two days after the beginning of therapy. The reticulocytes reach a peak, whose magnitude is inversely proportional to the'level of the original count,32 in five to seven days, on intramuscular liver therapy (40 per cent starting at one million; 20 per cent at two million; 10 per cent at three million). Red cell increase begins simultaneously with reticulocyte response and also rises at a rate inversely proportional to the original erythrocyte level,46 The simplest way of calculating the expected daily rise is to divide the difference between the original and ideal red cell levels by 60 since regardless of the original blood level the normal count will be reached in about eight weeks. The finding sine qua non is the 'fnegaloblastosis of the bonc marrow. 17 This must be present in every case in which the his-
PERNICIOUS ANEMIA
225
tory, physical finding, neurological changes without anemia, or the presence of free hydrochloric acid makes the diagnosis questionable. CONCOMITANT DISEASES
Although individuals who have pernicious anemia may develop the same complicating diseases as others in similar age groups, there are certain illnesses that apparently occur with increased, while others with decreased, frequency. Peptic ulcer is said not to occur,36 and explanation for this may be found in the achlorhydria and the emotional makeup. Tuberculosis is also said to be rare,55 though roentgenographic evidence of primary infection is seen frequently. We have seen active tuberculosis in patients with pernicious anemia, though, considering the increased susceptibility, the incidence should be greater. Prominent among other complicating conditions are artbritis, diabetes mellitus56 and asthma. Thyrotoxicosis, in our experience, has shown an unexpectedly high incidence, considering the fact that it is supposed to occur in an entirely different age group and in individuals of different constitutional predispositions. 4 • 47 Thyrotoxicosis may precede or develop during. the course of pernicious anemia. When the anemia develops after thyroidectomy in these cases it is not the macrocytic anemia occasionally encountered in the course of myxedema, but fulfiIls the strict diagnostic criteria of pernicious anemia, is accompanied by an elevated basal metabolism, and responds specifically to the administration of liver extract without additional thyroid. Gallbladder disease also shows a significantly increased20 incidence, 7 which may be secondary to the increased pigment metabolism. The termination of pernicious anemia in carcinoma of the stomach has been emphasized in the literature, metaplasia of the atrophic gastric mucosa with polyp formation and carcinomatous degenerati'on being postulated as the cause. 28 • 65 Considering the commonness of carcinoma of the stomach and the overlapping of the age groups in which both conditions are found, one may well question the validity of the emphasis placed on the relationship of the two diseases. In a large series of cases followed over a long period of time, I have been unimpressed by the frequency of stomach carcinoma. .
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STEVEN O. SCHWARTZ
DIAGNOSIS
The diagnosis of pernicious anemia is very easy when there are changes in the blood, the nervous system and the gastro-intestinal tract. Diagnostic difficulties are most likely to be encountered when a single symptom is disproportionately prominent and the others are either absent or insignificant. Thus a patient having only anemia might be suspected of cardiovascular disease because of the symptoms-a suspicion confirmed by the hemic murmurs, the occasional splenomegaly, and the fever. 53 Patients complaining of anorexia, nausea, vomiting and epigastric pains may be assumed to have gastro-intestinal disease especially when weight loss and change in bowel habits are added to the symptoms. Primary neurological disease is often diagnosed when the anemia is mild or absent, a circumstance by , no means uncommon since there is usually a reciprocal relation between the severity of the anemia and the nervous system involvement,60, 62, 67 At first glance the appearance of the patient may suggest nephritis or myxedema, but these diseases can be easily differentiated clinically. Hematologically, sprue,I° fish-tapeworm infestation and carcinoma of the stomach are said to lead to confusion most frequently, but in our experience aleukemic leukemia~ myelophthisic anemia, and aplastic anemia have caused the greatest diagnostic difficulties. The rules to follow in attempting to diagnose pernicious anemla are: 1. Suspect pernicious anemia in every case where no obvious cause for the anemia exists; where vague abdominal discomfort is associated with anemia, or where paresthesias of the extremities coexist with anemia or gastro-intestinal symptoms. At this stage pernicious anemia is suspected. 2. Examine the patient, looking in particular for the anthropological features described above, the gray hair, light eyes, pallor, scleral icterus, atrophy of the tongue papillae, the presence or absence of lymphadenopathy, hepatomegaly and splenomegaly. Neurologically, changes in the deep reflexes, a positive Romberg sign and loss of vibration sensation are looked for. Should confirmatory information be supplied by the examination, a tentative diagnosis of pernicious anemia may be made. 3. If the blood presents anemia with a high color index, leukopenia, thrombocytopenia and granulopenia, if the red cells
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are large and oval, and are well filled with hemoglobin, and in addition show alteration in size and shape (not at high red cell level!), and if in addition multilobed polymorphonuclear leukocytes are seen, the probable diagnosis of pernicious anemia may be made, and liver therapy begun lest the patient be jeopardized by waiting. 4. While awaiting therapeutic response (five to eight days) the following confirmatory tests should be performed. (a) Icterus index or Van den Bergh determination (b ) Urinary urobilinogen determinations
(These must be performed within twenty-four to fortyeight hours since their values drop markedly thereafter) (t) Analysis of the gastric contents following histamine stimulation (twenty to thirty minutes after the administration of 0.1 mg. of histamine hydrochloride per 10 kg. body weight subcutaneously) (d) Stool examination for occult blood and parasites or their ova
If the bilirubin of the blood and urobilinogen of the urine are increased, no free acid is found in the gastric secretions, and neither blood nor parasites are present in the stool, a positive diagnosis of pernicious anemia may be made. Occasionally one may wish to hasten making a positive diagnosis or may wish to confirm it with examination of the marrow whose changes are pathognomonic. 17 But even in cases thus diagnosed, the above described tests should be performed to rule out a pernicious anemia secondary to gastric neoplasm, fish tapeworm, or other causes. TREATMENT
Liver extract is specific for the treatment of pernicious anemia. Only general rules can be formulated as to the mode of its administration, since individualization of the patient43 is as important, or is even more important, than in other diseases where specific th~rapeutic agents are known. One unit* of liver extract per day on the average is required for maintenance, but extreme variations are encountered . .Cases may roughly be divided into two groups, depending on the presence or absence of neurological signs and symptoms. • A unit is defined as the amount of liver which, when given in a uniform daily dose in a case of pernicious anemia in relapse, will elicit a satisfactory red cell and reticulocyte response. .
228
STEVEN O. SCHWARTZ
Patients without neurological complications should get an average of 15 units of liver extract intramuscularly three times a week for the first two weeks, twice a week for the next two weeks, and weekly for the next month. By the end of this time (eight weeks) the blood has reached a normal level. From here on doses of 15 to 30 units of liver extract can be given anywhere from once a week to once every four to six weeks depending on individual requirement. The best plan is to "wean" the patient by cutting the frequency of injections by a week every two to three months. There is little merit in examining the blood at intervals less than two to three months, since th( patient's sense of well being, the paucity of complaints, the color, and the appearance of the tongue are sufficiently good indices of adequate therapy. Once the maintenance dose is established there need be little deviation from it unless complications (infections, bleeding, pregnancy, and so forth) occur. The need for liver increases considerably when complications are present and allowance must be made for this by increasing either the dose Or the frequency of administration, or both. The site of injection depends on preference. We have found the upper portion of the deltoid muscle the site of choice; here amounts up to 3 cc. are tolerated without discomfort. Treatment in cases complicated by neurological symptoms is much more intensive. In general, 20 to 30 units are given daily for the first two weeks, three times a week for four to six weeks, then twice weekly for another four to six weeks, and finally weekly until all neurological symptoms shall have disappeared, or until no further improvement is thought possible. Such intensive treatment should be continued for at least two years before one may assume that no further improvement is possible. Improvement in neurological symptoms is manifested by a return of normal sensation to the uppermost regions involved, with a gradual progression of this process downward. Objectively the improvement can best be followed in patients showing changes in vibration sensation, in whom the return of the sensation to lower and lower levels can be traced. It has been my impression that the cruder liver extracts (i.e., less potent extracts-not to be confused with diluted extracts) are more efficacious in the cases showing neurological changes. We do not deem it necessary to combine vitamins with liver to achieve optimal results. Once maximal improvement in the neurological
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symptoms is reached, the same process of "weaning" may be followed as described above, but it is seldom possible to reduce the liver to amounts comparable to those sufficient for purely hematological types without a recurrence of symptoms. The administration of hydrochloric acid routinely is unnecessary. We employ it only when gastro-intestinal complaints persist, or appear in spite of adequate liver therapy. Fifteen to 30 drops (Diluted Acid Hydrochloridi, D.S.P.) in half glass of water is either sipped with or is taken after meals. It is interesting that this almost insignificqnt amount (when compared to the normal gastric secretion) should result in the almost constant and striking relief that follows its admin~stration. The administration of iron, in addition to the liver extract, becomes necessary only when a concomitant iron deficiency develops. When this occurs it is first noted three to four weeks after the beginning of liver therapy and manifests itself as a gradually increasing hemoglobin lag and the development of a progressively lower color index. The red cell count levels off at about 4 million, with the hemoglobin at 60 per cent (10 gm.), and remains there until iron is given. With this both the red cells and the hemoglobin rise to normal levels. Complicating or' coexisting diseases are treated just as if the pernicious anemia were nonexistent, remembering only that additional amounts of liver may be necessary. A disconcerting complication, which occurs at some time in almost 10 per cent of patients treated for long periods, is the appearance of allergic reactions. These vary in severity from mild itching to shock and collapse. Changing the brand of liver will often suffice to eliminate reactions. If this fails, desensitization may be tried by the administration of increasingly larger doses beginning with extremely small amounts (such as %0 of a unit). Should this fail, two alternatives remain: theadministration of oral illstead of parenteral liver in the form of the liquid or dry extract, or the administration of stomach extract. Ordinarily certain practical objections exist which make the writer advise against the use of oral extracts. These may be summarized as follows: (1) eventual neglect of therapy due to lack of supervision, (2) greater cost, (3) greater difficulty in maintaining the blood at optimal level and (4) the development or progression of neurological signs and symptoms in spite of therapy.
230
STEVEN
o.
SCHWARn
Therapeutically, few diseases in the field of internal med· icine are as satisfying to both the patient and his physician The dramatic and spectacular improvement following the ad· ministration of liver is practically unequalled, and with the ex· ception of the occasional inconvenience of liver injections, th( patient continues with a normal life expectancy. BIBLIOGRAPHY
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