Vol. XXXIX.

Before attempt is made to suggest treatment for an ailment, it would appear quite essential first, that the nature of the affection under consideration be understood, and second, that any mode of treatment advanced be directed toward the remedy of known malfunctions and the local or systemic damage consequent upon such. Types of therapy departing from these basic principles are largely empiric and usually ephemeral.

Since Combes' original though imperfect, description of so-called pernicious or severe anemia in 1822 down to the present time, the nature of the disease has been obscure. Nevertheless, numerous systems of treatment have been advanced and have obtained a vogue. The chief virtue of many of these therapeutic regimes has been that the majority of them were harmless to the patient-in many instances the disease progressed in a sort of self-limited fashion to a fatal termination.

The unsatisfactory status of the treatment of so-called "pernicious" anemia may be ascribed chiefly to the facts that there has been great confusion in the medical mind as to what group of cases is to be made up of "pernicious" anemias and what type of case is to be excluded from the classification. Very likely the term "pernicious"

From the Division of Diseases of the Digestive System. Augustana Hospital.

Address in Medicine, Missouri Valley Medical Society, Des Moines, Ia., Sept. 16, 1919.

No. 2

taken in the sense of "fatal" is largely responsible for some of the existing confusion.

The adoption of this nomenclature has resulted in the more or less general conception that any anemia presenting the feature of chronicity, intermittance and of obscure origin should be classed as "pernicious." Moreover, if in a given case morphologic study of the blood picture revealed the megaloblastic features emphasized by Ehrlich, it was presumed that the disease should be included in the "pernicious" group. A second and perhaps more important cause for confusion arose as a consequence of the carelessly grouped but widely circulated classification of the anemias by Biermer in 1871. Although in 1855, following a masterly study of a peculiar anemia, Addison had clearly defined an unusual syndrome, Biermer, either through lack of knowledge of Addison's contribution, or as a result of his failing to appreciate the essential features of Addison's anemia, suggested the term "progressive pernicious anemia" to cover various forms of anemia both idiopathic and symptomatic in virtue of their having common clinical features. Although Biermer's classification was strenuously disputed by Eichhorst and Immermann, it secured wide-spread recognition and, in fact, furnished the bases for Ehrlich's later morphologic classi

fication of the severe anemias.

Before attempting to emphasize any mode of treatment of Addisonian anemia, it is quite necessary that the conception of the ailment as described by Addison should be appreciated. It is frequently stated that any severe anemia, provided it is not acutely fatal, may result in the clinical and morphologic variations from the normal described by Addison; that is, that Addisonian anemia and Biermer's progressive pernicious anemia are interchangeable terms which describe an identical disease and that moreover, this disease is not a true clinical entity but represents a state in the process of blood poverty from many obscure causes.

To anyone who has seriously compared the anemias clinically and pathologically, it becomes quite evident that the problem of classification

is by no means simple. The terms "secondary anemia" (that is, due to known or visible causes) and "primary", "essential" or "pernicious" anemia, (that is, anemia due to obscure causes and usually resistant to treatment) are not complete or exact. There is no sharp line separating the "secondary" from the "essential" anemia groups. Under this nomenclature it is common clinical observation that not rarely one form merges into the other. To the persistent, acute and brilliant efforts of Wm. Hunter, we are indebted for calling attention to and emphasizing a most vital and basic principle underlying the clinical, pathologic and hematologic features exhibited by the anemia described by Addison. Hunter's observations, it would seem, definitely segregate Addisonian anemia from the great group of severest anemias previously named generally, primary, essential, idiopathic or pernicious. After twenty-five years of patient endeavor, and work not generally directly appreciated, Hunter's views are in the main definitely substantiated by modern clinical investigation and the anemia of Addison segregated as a special form of anemia with a specific, probably group, etiology. It would seem to be now possible to define Addisonian anemia as essentially a haemolytic anemia. It would seem that further, it is specific, chronic anemia whose constant or intermittent haemolytic features are closely associated with sepsis or the consequences of such. This septic agent is generally intermittently active, extends over comparatively long periods of time and is associated with organisms or agents of the haemolytic groups. Such organisms or toxins invade tissue, are widely disseminated in the body, but probably have a special affinity for lymphoid tissue and their toxins a special destructive action upon lymphoid tissue. Such organisms are described variously as "streptococcus longus" (Hunter), "streptococcus viridans", "lytic staphylococci" and baccilli simulating those of the colon group. It is quite essential that these facts emphasized by Wm. Hunter in his septic theory should be appreciated. It is likewise necessary that the evidence of hemolysis in Addisonian anemia by recent investigators be recognized. These observations are basic as aids to the segregation of the type of anemia under consideration.

Characteristics of the Disease.-A brief review of the essential clinical features of the ailment would appear to be opportune. The disease may be (a) chronic, or (b) acute.

(a) Chronic Addisonian Anemia-This form of the disease is most frequently encountered. Clinically, it is not possible to improve upon the classic description of the ailment presented by Thos. Addison in 1855. It is as follows: "For a long period I have from time to time met with a very remarkable form of general anemia oc

curring without any discoverable cause whatever -cases in which there had been no previous loss of blood, no exhausting diarrhoea, no chlorosis, no purpura, no renal, splenic, miasmatic, glandular, strumous, or malignant disease. Accordingly, in speaking of this form in clinical lectures, I, perhaps with little propriety, applied to it the term "idiopathic," to distinguish it from cases in which there existed more or less evidence of some of the usual causes, or concomitants of, the anemic state."

The disease presented, in every instance, the same general character, pursued a similar course, and, with scarcely a single exception, was followed, after a variable period, by the same result.

It occurs in both sexes, generally, but not exclusively, beyond the middle period of life; and so far as I at present know, chiefly in persons of a somewhat large and bulky frame, and with a strongly marked tendency to the formation of fat.

It makes its approach in so slow and insidious a manner that the patient can hardly fix a date to his earliest feeling of that languor which is shortly to become extreme.

The countenance gets pale, the whites of the eyes become pearly, the general frame flabby rather than wasted; the pulse perhaps large, but remarkably soft and compressible, and occasionally with a slight jerk, especially under the slightest excitement. There is an increas

ing indisposition to exertion, with an uncomfortattempting it; the heart is readily made to palpiable feeling of faintness or breathlessness on tate; the whole surface of the body presents a blanched, smooth, and waxy appearance; the biness of the solids increases; the appetite fails; lips, gums, and tongue seem bloodless; the flabbiness of the solids increases; the appetite fails; lessness and palpitation being produced by the extreme languor and faintness supervene, breathmost trifling exertion or emotion; some slight oedema is probably perceived about the ankles. The debility becomes extreme; the patient can no longer rise from his bed; the mind occasion

ally wanders; he falls into a prostate and halftorpid state, and at length expires. Nevertheless, to the very last, and after a sickness of perhaps several months (or years) duration, the bulkiness of the general frame and the obesity often present a most striking contrast to the failure and exhaustion observable in every other respect.

With perhaps a single exception, the disease in my own experience, resisted all remedial efforts and sooner or later terminated fatally. On examining the bodies of such patients, after death, I have failed to discover any organic lesion that could properly or reasonably be assigned as an adequate cause of such serious consequences; nevertheless, from the disease

having uniformly occurred in fat people, I was naturally led to entertain a suspicion that some form of fatty degeneration might have a share at least in its production; and I may observe that, in the case last examined, the heart had undergone such a change, and that a portion of the semilunar ganglion and solar plexus, on being subjected to microscopic examination was pronounced by Mr. Quekett to have passed into a corresponding condition.

"Whether any or all of these morbid changes are essentially concerned-as I believe they are— in giving rise to this very remarkable disease, future observation will probably decide."

Clinically, to Addison's description may be added gastric achylia without stagnation, diminished pancreatic ferment secretion, frequent or intermittent exhausting diarrhoea, continuous or intermittent albuminuria, spinal cord changes usually of the spastic type, disturbances in sensation, particularly malfunction of the special senses and not rarely psychic upsets.

(b) Acute Type of Addisonian AnemiaThis occurs infrequently. In 101 cases personally observed, it was present but four times. The following history emphasizes some of the clinical aspects of the acute form of the affection.

On January 12, 1916, there was brought to our clinic upon a stretcher a semi-conscious female aged 35. At the time of entry she exhibited low muttering delirium, lemon yellow, waxy, oily skin, pale, water logged mucus surfaces, Extreme weakness and dyspnoea. The general body nourishment was moderately well preserved. The hemoglobin was 18%, the red cell count 920,000, the leucocyte count 2,300. The stained blood smear showed a large celled anemia, marked poikilocytosis and polychromatophilia and numerous normoblasts with an occasional megaloblast. The lymphocytes were 56% of the total differential count. The coagulation time was more than eight minutes.

The previous history of this patient is interesting. Up to Oct. 1915-three months before coming under observation, the patient was and had been in perfect health. So excellent had her health been that she was considered somewhat as a prize beauty in her county. In early October, she was affected with a form of I sore throat with grippe-like sequelae, which lasted about ten days and left her much exhausted. The exhaustion continued, a lemon color pallor became noticeable, a swelling appeared below the edge of the left ribs, irregular temperature was recorded and five weeks following the initial illness a blood examination revealed the quantitative and morphologic picture associated with Addisonian anemia. The patient was removed to a hospital in one of the large cities of Iowa and a standard form of treatment instituted by a very competent in

ternist. The patient made practically no progress. Anorexia, diarrhoea, dyspnoea, palpitation of the heart and mental changes became established. The swelling below the rib edge was proven to be the spleen, it persisted and increased and became so painful that deep breathing, lying on the left side, or palpation caused exquisite distress. The blood picture showed no change except quantitatively the hemoglobin and red cell mass slowly and steadily diminished.

In this striking picture, I would emphasize particularly the acute onset of the ailment in a previously well individual, the disease being initiated by a sore throat; the rapidly developing anemia in every respect that of a pernicious or Addisonian anemia: the clinical appearance of the patient in the space of a few months became that which is commonly associated with Addisonian anemia of long standing; the rapid and persistent enlargement of the spleen so painful as to be described by the patient herself as feeling like a "large boil." Further examination showed this case to be non-syphilitic. A haemolytic coccus was isolated from the throat and a similar organism from the tissue of the gall bladder and the spleen.

Blood Findings in Addisonian Anemia-Emphasis is to be placed upon the statement that the blood morphology set down by early investigators as indicating essential or idiopathic anemia or Addisonian anemia may be closely mimmicked in numerous forms of anemia where the cause is known or evident and that upon blood morphology alone or even upon quantitative blood studies alone, absolute diagnosis of the disease is not possible. The blood studies are only to be taken when considered with respect to the clinical course of the disease and possibly with regard to evidences of haemolysis.

Usually there are shown a low erythrocyte count (15%-50% of normal), the average being 1,200,000 (Cabot) while Quinke's case of 140,000 holds the record for low counts. The hemoglobin is decreased, but in lesser degree than the red blood cell count, thus making the color index greater than one in the majority of cases.

The fragility of the erythrocytes is increased. The platelets are diminished, often absent. The normal is 500,000 (J. H. Pratt), while in pernicious anemia they usually are less than 100,000 per cu. mm. The stained smear shows nucleated red blood corpuscles and multitudes of large and small, misshapen and contorted red blood cells. Cells measuring from two to twenty microns in diameter, (microcytes and macrocytes), "Dumbbells," "doughnuts", "pears", "commas", "ovals", "pseudopods" and "rings" (poikilocytes) are common. Nucleated red blood corpuscles are frequently present at some stage of the ailment. They vary in size and are designated microblasts, normcblasts and megaloblasts, accordingly. Cells

containing Howell's nuclear particles are often seen. These various blast cells represent the reserve currency of the bone marrow and indicate that the demand for erythrocytes is so imperative that the marrow, being unable to produce matured cells, throws off their parent form-the erythroblasts. The degree of the marrow's embarrassment is probably indicated by the type of blast found in the circulating blood, the more primitive the nucleated cell, the greater the call for red corpuscles. In very severe cases, however, no nucleated cells may be seen. This probably indicates almost complete marrow exhaustion.

Besides nucleation, the circulating red blood corpuscles show polychromatophilia, reticulation, Ehrlich's "spotting", vacuolation and rarely basophilic degeneration.

There is a marked leukopenia, usually about 3,500, although counts as low as 330 and as high as 13,000 have been reported. Higher leucocyte counts are rare. They probably are associated with active infection or the free absorption of toxic agents which temporarily stimulate the defensive mechanism in the blood making centers. Evidence suggestive of this is adduced from the prompt leucocytosis following blood transfusion with or without associated splenectomy.

The leucocytes are of smaller size than normal, myelocytes more numerous and often basolphilic granules are seen in the cytoplasm. The differential counts usually show an increase in the small lymphocytes and a decrease in the polymorphonuclear percentages-in fact, the normal percentages are often reversed, so that lymphocytes outnumber polymorphonuclears three to one. Such reversal of the normal differential leucocyte ration might be interpreted as indicating diminution of the blood's defensive mechanism.

Changes in the Blood Plasma-Coagulation time is prolonged, but not so greatly as in hemophilia and icterus. Our cases ranged from 3 to 10 minutes. The appearance of the blood is watery, milky or greasy, and sometimes it is nearly impossible to smear it evenly on a slide. Ehrlich describes the flow from a puncture wound as "streaked". The volume of erythocytes, as determined by the hematocrit of Oliver, is lessened out of proportion to the serum, which is often pinkish in color from the free hemoglobin. The specific gravity of the serum, freed from corpuscles, is nearer normal.

Nayen and LeNoble say that the fibrin is decreased and that the clot in pernicious anemia. does not retract even after 72 hours. Other observers do not agree with this statement. We have noticed that the clot is soft and insecure, and is easily dislodged.

Blandenhorn has recently demonstrated an

increase in the bile pigment in the blood in cases of Addisonian anemia. There would also seem to be variations in the cholesterin and iodine factors. It has not been constantly shown that the lytic bodies are increased. In certain cases it has been shown by Eppinger and by King that the blood serum contains an increase in the unsaturated fatty acids in the blood some of which have been shown to be highly lytic.

Pathologic Alterations-General-The most striking feature of the disease is the general fatty degeneration of the systemic nonstriated and heart musculature and of the liver, kidneys and bone marrow. All the body tissues are hydraemic except the spleen which is commonly firm and congested. Multiple small hemorrhages into the meninges, brain, spinal cord and retina are not uncommon. Such lesions are, however, not especially specific of Addisonian anemia. The researches of Hunter and others would, however, indicate that in Addisonian anemia there are specific changes which have been commonly overlooked by many observers.

Hunter lays particular emphasis upon the lesions in the mouth. It is a common observation that in many forms of severe anemia, infected gums, tonsils and nasal accessory sinuses are coincident. Not infrequently, the infecting organisms are haemolytic cocci or bacteria. Decayed, broken teeth are very generally noted. Hunter emphasizes the importance of these long persisting infections with respect a peculiar glossitis which he claims is quite characteristic for Addisonian anemia. for Addisonian anemia. We, ourselves, have noticed the tongue changes as being practically constant in haemolytic anemias of Addisonian type, in fact, we have never seen a true case of Addisonian anemia in which the tongue did not show varying degrees of atrophy of the mucous membrane and hyperplasia of the muscles of the tongue. Hunter claims that there is no other anemia in which the glossitis is so constant and persistent. He claims that the glossitis fluctuates in severity as does the disease and that the presence of the glossitis accounts for the alterations in the special senses, particularly of taste so characteristic of the disease. Hunter has shown that while in many severe anemias, superficial inflammatory changes of the tongue are quite common, in Addisonian anemia there is an actual invasion of the lymph spaces and muscle bundles of the tongue with lytic streptococci. Hunter claims that the tongue furnished the most important portal of entrance for these bacteria or their toxins into the general circulation. Tissue cultures from the tongue would apparently show these organisms in pure culture. Pathologic changes similar to those observed in the tongue have been observed in the stomach wall and that of the large intestine. In the early course of the disease, the gastro-intestinal lesions are of

the ulcerative type, later inflammatory action results in scar tissue with atrophy of the mucosa and muscularis. Haemolytic bacteria can often be isolated from the walls of both stomach and intestine, upon tissue culture after the technic of Rosenow.

In our clinic, tissue cultures have been made of removed appendices and gall bladders. While grossly all these appendices and gall bladders show chronic inflammatory changes with or without evidences of ulceration, in some of the specimens, streptococcus viridans, lytic staphlococci and organisms of the colon group have been recovered.

Besides fatty change and frequent enlargement, the liver presents a rather characteristic picture with respect to the distribution of iron pigment. The deposits of iron pigment are increased from six to ten times the normal amount. This increased iron is characteristically deposited in the outer and middle zones of the lobules. This increase of iron pigment does not occur as result of iron medication nor does it occur in secondary anemias to such extent nor in such position. By Charnas and Schneider's methods for the estimation of blood derived pigments, duodenal catheterized fluid appears to characteristically reveal a great increase in the elimination of urobolin and urobolinogen by the liver. In only the lytic anemias is this great increase in blood derived pigments constantly found. This observation is of the greatest value in separating instances of true Addisonian anemia from anemia where the blood morphology indicates a severe anemia often carelessly called “Addisonian".

Examination of the kidneys in pernicious anemia shows increased iron deposits. In the urine are demonstrated increased urobiligen and hetro- and perhaps iso-hemolysins.

Bone Marrow-Smears of the bone marrow reveal in the early stages of pernicious anemia megaloblastic hyperplasia in the majority of instances. This is apt to be succeeded by aplasia which represents an overwork of fatigue. In certain cases of Addisonian anemia aplasia may be early manifested. Bone marrow cultures have not been made in sufficient number of cases of Addisonian anemia to enable one to definitely state whether or no there is actual bone marrow infection. It would appear that the bone marrow changes are secondary and compensatory. They represent reactions to the haemolytic agent. It would seem in Addisonian anemia the bone marrow is not primarily at fault. Injections with pure cultures of staphylococcus pyogenes aureus cause definite bone marrow reactions closely resembling the megaloblastic reactions produced in Addisonian anemia. Following the injection of non-bacterial haemolytic agents as has been described by Bunting similar changes are ob

served. It is quite likely that in Addisonian anemia, wide spread infection with haemolytic cocci retards blood formation. This infection may actually exist in the bone marrow and bone marrow changes found in this disease represent an hyperplasia due to the hematopoietic tissues having to simultaneously resist damage consequent upon infection and to manufacture new blood cells.

Spleen-Spleens removed at laparotomy from cases of Addisonian anemia in our clinic almost universally show increase in size, blood congestion, chronic peri-splenitis and often increase in weight. On sectioning, the tissue evidences chronic hyperplasia. The iron content is greatly decreased. In some instances of Addisonian anemia tissue cultures from the spleen pulp have returned haemolytic cocci and colon-like bacilli. Spleen extracts do not exhibit increased iso- or hetero-haemolysins.

It might be well to review certain functions performed by the spleen. Even though the exact use of the spleen is unknown, it would appear from its embryology to be an important organ concerned with digestion or assimilation of food. It will be recalled the blood supply of the spleen comes from the coeliac axis as does that of the stomach, liver and pancreas. The spleen is derived from the fore gut as are also these organs. Its venous afferents are direct tributaries to the portal circulation. The chief functions of the spleen would appear to be those connected with control of blood formation and with blood de

struction. In the human embryo erythocytes are produced by the spleen, but at birth this production ceases and the bone marrow becomes practically the sole source of the red blood cells. The spleen is, however, intimately concerned with the production of leucocytes. Kolliker and Ebener found more leucocytes in the splenic vein than in the splenic artery. The large mononuclears (splenocytes) formed in the spleen probably do not enter the blood stream but remain and serve as partial sources of haemolysis. There is reason to believe that even normally the spleen exercises a certain degree of inhibition upon the bone marrow, influencing the formation and the addition to the circulation of both red and white cells. Lethaus, Kuttner, Roetner and Lagg have noted polycythemia following the removal of the spleen traumatically ruptured. Schupfer, Levison and Muhsan and Mayo have similarly noted increased red cells following splenectomy in Banti's disease. The tremendous medullary reaction after splenectomy in pernicious anemia has been commonly noted. Sometimes the pain in the long bones following the operation is definitely associated with this increased medullary activity.

That the spleen bears a direct relation to iron metabolism has been abundantly proven by