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UCH controversy has arisen

over the proper classification of and the causative factors in aplastic anemia. There has been some hesitancy on the part of certain writers, and probably rightfully, to consider it an entity in itself. Its similarity to pernicious anemia, its alleged occurrence following repeated severe hemorrhages, and the lack of experimental evidence have probably warranted such a stand.

There are patients with aplastic anemia whose blood pictures do not run true to form. The presence of normoblasts in considerable numbers, anisocytosis, and poikilocytosis, point to blood regeneration and simulate. the findings in pernicious anemia. A lemon yellow tint to the skin arouses suspicion of hemolysis. The stage of the disease at which the examination is made effects the blood picture.

Reports of cases with remissions and apparent cures, cases in which a pathologic examination was not made, have added to the uncertainty of the whole problem.

REPORT OF CASE

Case 31867. Mr. L. M., aged seventeen years, was first seen at the Jackson Clinic in July, 1922. He stated that ten months previously, following a sore throat, he had developed a swelling of the left side of the neck. The swelling gradually diminished in size but never entirely disappeared. A

month before this attack the lump began to increase in size and cause slight pain.

The boy was well nourished and had a normal color. His tonsils were of moderate size with cheesy plugs on both sides. In the left side of his neck there were several enlarged cervical glands, the largest being about 2 cm. in diameter.

was

On deep inspiration his spleen extended to a point about 2 cm. below the costal margin. The general examination otherwise negative. The blood count at that time showed hemoglobin 78 per cent, erythrocytes 5,650,000, leucocytes

13,200; differential, lymphocytes 25 per cent,

neutrophils 70 per cent, transitionals 4 per cent, and eosinophils 1 per cent.

A gland was removed for diagnosis. Examination showed a replacement of the

gland structure proper with fibrous tissue

and lymphoid cell infiltration together with a large number of eosinophilic cells. Dorothy Reed cells were also present.

A diagnosis was made of Hodgkin's disease. August 4 and September 2 the patient was given x-ray treatments over the affected glands.

The patient was not seen again until February 18, 1923. Two months before his return to the Clinic he became quite weak and noticed that he was becoming pale. The weakness rapidly became so severe that it necessitated his staying in bed. The appetite remained fairly good. The striking points of the examination at this time were the marked emaciation and pallor; his color was a typical ashen grey, and the mucous membranes were very pale. The cervical glands had entirely disappeared. Over the entire pericardium was heard a loud blowing systolic murmur transmitted to the axilla and back. The spleen was not palpable. The temperature was 104°, the pulse rate 130, and respirations 26.

Examination of the blood showed hemoglobin 15 per cent, erythrocytes 720,000, leucocytes 2400, neutrophils 68 per cent, lymphocytes 78 per cent, and large mononuclears 4 per cent.

February 27, the patient was given 200 cc. of blood by the citrate method, and March 2 he was given 450 cc. March 5, the hemoglobin was 20 per cent and the erythrocytes numbered 1,064,000. In spite of the transfusion there was no improvement. His temperature varied from 99° to 104°. Diagnosis was made of aplastic anemia. He became semi-comatose and delirious and died on March 7.

Permission was received to remove a piece of the tibia for pathologic examination, a general autopsy being refused.

Pathological report. Prof. C. H. Bunting of the University of Wisconsin Medical School submitted the following pathological report.

"Section of the marrow shows it to be essentially a fatty marrow with irregularly distributed, relatively large, islands of blood-cell-producing elements. There was found a wide-spread atrophy of the fat cells which were in many places reduced to less than one-fourth of their normal diameter. These cells were widely separated from each other by areas apparently of coagulative necrosis in which was a rather dense, a rather dense, fibrinous network, coagulated serum, hyaline necrotic cells, and pyknotic nuclear fragments, with here and there small areas of hemorrhage.

"In the persisting islands of blood-forming cells one found chiefly cells of the red blood-cell-producing series and of these the greatest number were cells with large vesicular nuclei. Normoblasts were relatively few. Comparatively few groups of neutrophilic myelocytes were found and mature neutrophilic leukocytes were almost entirely lacking. Scattered groups of eosinophilic myelocytes and mature leukocytes were seen. One eosinophilic myelocyte was found in mitosis. Megalokaryocytes were represented by a very few widely separated, naked, pyknotic nuclei. Reticuloendothelial cells appeared increased in the section and some of them showed phagocyted red blood cells. The circulation of the marrow appeared intact, except in the areas of

necrosis where the endothelial cells were apparently involved.

"While the necrotic areas were the most striking lesion as described before, there were changes which suggest that the toxic effect was the result of the virus of Hodgkin's disease. About the arteries and arterioles there were lymphoid accumulations (really a lymphoid sheath), consisting of small lymphocytes, atypical lymphoid cells, and endothelial giant cells all set in the lymph gland. There was also in some areas a rather marked proliferation of reticulo-endothelial cells and some fibroblastic proliferation about the vessels. The picture then was one consistent with the action of the Hodgkin's virus upon the bone marrow."

In this case two usual findings of aplastic anemia were absent. There was no decrease of neutrophils with a relative lymphocytosis and subcutaneous hemorrhages, and hemorrhages from mucous surfaces were not present at any time. The other signs and symptoms were characteristic of those found in anemias described as aplastic.

The following factors show that clinically and pathologically aplastic anemia distinctly differs from pernicious anemia.

1. Aplastic anemia is essentially a disease of early adult life, the majority of cases occurring before the age of thirty-five years. Pernicious anemia, on the other hand, is more commonly seen in persons above that age.

2. The course of the disease is rapid with a fatal termination within a period of one or two months. Remissions have been reported, but are extremely rare and are the exception rather than the rule. The course of the disease is uninfluenced, except in a very mild degree, by any therapeutic measure. Death from pernicious anemia almost never occurs during the

first crisis, this disease being characterized by one or more remissions.

3. In the anemia of aplastic anemia there is a pronounced reduction in the percentage of leucocytes and erythrocytes with a color index usually below 1. A normal or high index would suggest that there were areas of hyperplastic marrow yet untouched by the disease.

4. The erythrocytes in aplastic anemia are perfectly normal. Poikilocytosis and anisocytosis, polychromatophilia and stippling are not found, and erythroblasts are rare. In an anemia with an aplastic marrow, immature erythrocytes are usually not present, as the marrow has lost its power of regeneration. Cases of aplastic anemia are reported which show the presence of normoblasts, polychromatophilia, and cells varying in size and shape. It is inconceivable that any toxic agent should render inactive the blood-forming marrow of all bones simultaneously. In cases in which there are immature cells, the marrow of certain bones may show slight hyperplasia in places. If there is still some hyperplasia of the marrow when death occurs, early in the course of the disease it should be much more extensive and more marked, and evidence of blood regeneration might be found. In pernicious anemia the bone marrow is called upon to work beyond its capabilities and immature cells are thrown into the blood stream. These cells present variations in size and shape; polychromatophils are found in large numbers, and erythroblasts are usually present.

5. Leukopenia in pernicious anemia may be as low as that found in aplastic anemia, but is usually somewhat

higher. The reduction in the number of leucocytes in aplastic anemia is extreme, the count usually being about 2000 to a cubic millimeter of blood.

6. Aplastic anemia invariably runs a febrile course. The fever is more continuous and of a higher degree than that noted in any other type of anemia.

7. In aplastic anemia the normal red marrow is replaced by an aplastic fatty marrow; in pernicious anemia even the normal fatty marrow becomes hyperplastic.

8. Glossitis, or sore mouth, so frequently found in pernicious anemia is wanting in the aplastic type.

9. In aplastic anemia there is no evidence of the excessive hemolysis which characterizes pernicious anemia. The skin does not have that lemon hue, an indication of increased hemolysis, nor is hemosiderin found in the internal organs.

10. Symptoms of changes in the central nervous system are absent throughout the course of aplastic anemia. Paresthesias are frequently one of the chief complaints of persons suffering with pernicious anemia.

CONCLUSIONS

Aplastic anemia viewed from all aspects is seemingly due to some severe toxin acting primarily upon the bone marrow. This is conceded by most writers.

In the majority of instances the origin of this toxic agent is unknown. Whether this be true or whether the agent is the virus of Hodgkin's disease or of some other disease the results produced are similar and characteristic.

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NE of the most interesting pathological findings

as

sociated with certain cases of diabetes is the lipoidosis of reticuloendothelial cells in various parts of the body, particularly in the spleen, liver, lymph nodes and bone-marrow and in the connective tissue of the skin (xanthoma or xanthelasma). In diabetes with lipemia the spleen may present a condition closely resembling that of Gaucher's disease. It may be much enlarged, the lymphoid tissue scanty, Malphigian corpuscles few or entirely absent and the pulp consisting almost entirely of hyperplastic reticulo-endothelial cells showing a marked vacuolation. The vacuoles are formed by a substance staining faintly with Soudan III and Nile-blue sulphate, but giving a positive Ciaccio reaction and staining like myelin with the Weigert method. It is probable that this substance is a phosphorated lipoid closely related to lecithin. The vacuolated cells are reticulo-endothelial; and the same vacuolation may be seen in the Kupffer cells of the liver, and the reticulo-endothelial cells cells throughout the body, especially in the lymph-nodes, hemolymph nodes, adrenals, and bone-marrow. In fatty diabetes it may exist in any degree of intensity, and the most

severe cases may be mistaken histologically for Gaucher's disease. The histologic picture, as far as the reticulo-endothelial system is concerned, may be identical with that of Gaucher's disease, and the chemical reactions are also identical. In both Gaucher's disease and fatty diabetes there is a hyperplasia and a lecithinic infiltration of the cells of the reticuloendothelial system; and in both conditions there is an associated hypercholesterinemia. Recent researches make it probable that cells of the Gaucher type are formed constantly in the reticulo-endothelial system, and their number is in proportion to the concentration of the lipoids of the blood. They are increased in the majority of cases of diabetes. Experimental cholesterinemia in animals is associated with a similar lipoidosis of the reticulo-endothelial system. In xanthelasma and xanthoma a similar cholesterol-ester lipoidosis, associated with hemosiderosis, is found in the reticuloendothelial cells of the dermis. There occurs a tumor-like proliferation and lipoidosis of the fusiform cells lying in the interstices of the connective tissue, with an associated hemosiderosis. The lipoid cells appear identical with those found in the spleen, liver, bone-marrow, etc.; and the condition is also associated with cholesterinemia. Xanthoma cells occur usually in individuals showing either diabetes or hepatic disease.

The condition may be found, however, in patients who give no evidence of either of these affections, but in whom there is a cholesterinemia. It can be concluded that Gaucher's disease, the lipoidosis of fatty diabetes and of xanthoma and xanthelasma represent a pathological condition of the reticulo-endothelial system associated with cholesterinemia. There conditions differ only in localization and degree. A new fact of

especial interest is the observation that xanthoma diabeticorum may rapidly resolve under insulin treatment. In what way the insulin acts upon the cholesterol metabolism cannot be stated at the present time. It will be of great interest to see what results may follow the administration of insulin in Gaucher's disease and in cases of xanthoma not associated with diabetes.