The following tentative conclusions as to the relationship of pernicious anemia, nutritional macrocytic anemia and tropical sprue to one another and their pathogenesis are drawn from a study of the literature and from unpublished work:

1. That these three clinical conditions are three distinct entities possessing a common characteristic in the presence of a panhemopoietic dystrophy characterized by a megaloblastic erythropoiesis and corresponding changes in the myeloid cells and platelets.

2. That this panhemopoietic dystrophy possibly results from the breakdown of an intracellular enzyme system but that the deficiencies causing the breakdown differ; in pernicious anemia the liver principle is apparently at fault, in endemic nutritional macrocytic anemia another unidentified factor is missing, in sprue either or both may be at fault.

3. Folic acid is active therapeutically in all three diseases, but in all it generally fails to restore completely normal blood levels.

4. Pernicious anemia is probably due to a genetic defect which produces an atrophy of the gastric mucosa. As a consequence of this interference with gastric function there is a failure in the formation or absorption of the liver factor and possibly of another neurotrophic factor, which failure results in the development of a macrocytic megaloblastic anemia and the characteristic changes in the nervous system. Indefinite replacement therapy is necessary as the changes in the gastric mucosa are irreversible. The cause of the increased hemolysis is unknown.

5. Endemic nutritional macrocytic anemia is an unconditioned food deficiency, the deficiency being in a factor other than the liver principle, possibly a co-enzyme present in or associated with good biologic protein and the vitamin B2 complex. There are no characteristic pathologic changes except those of the hemopoietic organs which are not specific to the disease. A hemolytic type of the disease occurs in areas of high malarial incidence. After successful treatment the disease does not relapse if the diet is satisfactory. Pregnant women are particularly liable to develop the disease.

6. Tropical sprue is due to a functional disorder of the intestine, possibly primarily a failure in phosphorylation of fatty acids, glycerol and glucose. Diarrhea with characteristic stools and a macrocytic anemia are characteristic findings. The macrocytic anemia may be due to a failure in absorption of one or more essential hemopoietic factors or to a lack of Castle’s intrinsic factor. The cause of the functional breakdown is unknown. Treatment is with a high protein diet and liver extracts. Relapses are common.

My thanks are due to my colleagues for carrying on my work while I wrote this paper.

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