ALBERT

Description: 1. The hematologic syndrome called refractory anemia with hyperplastic bone marrow, aregenerative anemia, chronic bone marrow failure, pseudo-aplastic anemia, and many other terms, has been separated into five types on the basis of clinical and hematologic studies on 23 patients carried out over a period of 16 years. These groupings are probably highly artificial but are made to facilitate presentation and description. As more is learned of the chemistry of the bone marrow cells in patients with refractory anemia, a more satisfactory classification will be possible. 2. Type 1 is characterized by bizarre chromatin in the normoblasts, mast cell hyperplasia, hemosiderosis or hemochromatosis and a tendency for spontaneous remissions to occur. 3. Type 2 is at first typified by complete or almost complete erythroid aplasia. Hyperplasia of erythroid cells with maturation arrest and bizarre chromatin pattern may occur later, and finally spontaneous remission may appear with considerable frequency. Mast cell hyperplasia, thymoma and hemosiderosis have been noted. 4. Type 3, associated with exogenous toxins and the preleukemia state, is characterized by pancytopenia and a bizarre chromatin pattern in the normoblasts. Some of these patients may he classified as "DiGuglielmo syndrome." 5. Type 4 also is typified by pancytopenia and hyperplasia of bone marrow but with cells of normal appearance. These patients responded partially or completely when splenectomy was performed, and probably represent a variant of the "hypersplenism" syndrome. 6. Type 5 is refractory megaloblastic anemia with typical cytologic changes evident in all cell types similar to those found in pernicious anemia. 7. Hypotheses are proposed to explain these various types of anemia on the basis of abnormalities in the metabolism of nucleic acids, particularly DNA. Deficiencies of metabolites, inhibition of metabolic reactions by exogenous or endogenous toxins, or by immune mechanism in which DNA serves as haptene, are possible explanations.

Description: 1 . The patient described in this report had macrocytic anemia, megaloblastic maturation arrest in the bone marrow, glossitis, hyper-reflexia and diminished vibration perception in the feet. None of these abnormalities was improved by liver extract or vitamin B12 but all responded rapidly to folic acid except the neurologic signs. 2. This patient appears to have had a megaloblastic anemia which has been described in European clinics under the names "achrestic anemia" and "refractory megaloblastic anemia." It appears to be similar to "Wills" factor deficiency anemia" and some cases of pernicious anemia of pregnancy. 3. This patient did not appear to have a primary deficiency of folic acid since the excretion of this substance in the urine was within normal limits. A deficiency of an unknown factor probably equivalent to "the Wills’ factor" is suggested. 4. It seems likely that folic acid induced a remission in this case by a "mass action" effect. The possible relationship of folic acid, vitamin B12, the unknown factor and liver extract to nucleo-protein synthesis is discussed.

Description: 1. Patients with pernicious anemia who are maintained on folic acid, 30 mg. three times a week, for two to three years may have a hematologic relapse which will remit satisfactorily if refined liver extract is given, or partially if the dose of folic acid is increased to 50 mg. daily, or if thymine is given. 2. The hematologic remission succeeding the increased dosage of folic acid is followed within several months by a second relapse. At this time the response of these patients to liver extract or vitamin B12 is retarded. Recovery occurs after two to four months. 3. These experiments suggest that folic acid exerts its effect by "mass action" in pernicious anemia and that it is essential to the formation of thymine and other pyrimidines and purines or facilitates the utilization of these substances. 4. Posterolateral column disease or peripheral neuritis occurred in every person with pernicious anemia who received increasing doses of folic acid to maintain an hematologic remission. This observation suggests that folic acid, by pushing a chemical reaction through to completion in the face of a serious deficiency of vitamin B12, depleted the supply of this factor even more and led to the development of combined system disease. 5. Uracil produced a hematologic response in 2 of 3 persons with pernicious anemia in relapse when given in doses of 15-30 grams daily. The data suggest that uracil may be a precursor of thymine. 6. A patient with pernicious anemia of pregnancy failed to respond to uracil, 30 grams daily, but did respond partially when choline, 3 grams, and methionine, 6 grams were given. Thymine induced a complete response. The partial response to methionine and choline and the better response to thymine suggest that choline and methionine supplied methyl groups for the formation of thymine, but that activating substances for the methylating process were missing. 7. Reference is made to a patient previously reported from this laboratory who had liver extract and vitamin B12-refractory megaloblastic anemia but who responded to folic acid and on a second relapse to thymine. Studies on the output of folic acid in the urine of this patient did not support the possibility of folic acid deficiency, and the suggestion was made that another substance, possibly the "Wills’ factor," was deficient, and that this factor together with folic acid activated the formation of thymine. These two factors correspond to the activators of the transmethylation reaction mentioned in the preceding paragraph. 8. These studies on human beings and similar ones in bacterial metabolism suggest that folic acid, liver extract and vitamin B12 are essential to the formation of nucleic acid and nucleoprotein through a chemical chain reaction. The suggestion is made that the megaloblast common to pernicious anemia and related macrocytic anemias is a primitive erythroblast with an abnormality in the metabolism of nucleoprotein. The so-called maturation arrest in all marrow elements occurs because of this abnormality which may be induced by a deficiency of vitamin B12, folic acid, the "Wills’ factor," and probably other chemical activators of this reaction.