The Effects of Combined Folic Acid and Liver Extract Therapy

Abstract 1. Folic acid, when administered alone, did not prevent the development or progression of subacute combined degeneration in 12 of 22 patients receiving this agent for from twelve to twenty-five months. 2. One patient with total gastrectomy and a macrocytic anemia developed subacute combined degeneration after five months of folic acid therapy. 3. Neurologic disease did not develop in 6 pernicious anemia patients treated with folic acid and liver extract for three and one-half to thirty-nine months. 4. In 10 pernicious anemia patients with good nutrition, neurologic relapses did not progress when liver extract or vitamin B12 therapy was instituted, even though folic acid therapy was continued. In 2 patients with abnormal nutrition and complicating organic abnormalities, nervous system disease progressed after institution of liver extract therapy. 5. Our observations are best explained by the theory that the hematologic and neurologic manifestations of pernicious anemia and other macrocytic anemias associated with gastro-intestinal tract pathology and inadequate nutrition are due to a deficiency of more than one substance. The administration of folic acid may improve the hematologic status but induce a deficiency of another substance or substances, e.g., vitamin B12, which are essential for the maintenance of a normal blood picture and the integrity of the central nervous system. This deficiency will eventually result in the development of a suboptimal blood picture or subacute combined degeneration of the spinal cord, or both. 6. The hematologic status of patients with pernicious anemia is not maintained in a more satisfactory state by supplementation of liver extract or vitamin B12 therapy with folic acid. 7. Folic acid therapy did not produce neurologic disease in patients with iron deficiency anemia who had free gastric hydrochloric acid in their gastric secretions and presumably sufficient intrinsic factor. It did not influence response to ferrous sulfate therapy. 8. Patients with sprue, nutritional macrocytic anemia and other macrocytic anemias associated with gastro-intestinal tract pathology who are treated with folic acid should also be given supplemental liver extract or vitamin B12 to insure against the development of nervous system disease.

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THE DEVELOPMENT AND PROGRESSION OF SUBACUTE COMBINED DEGENERATION OF THE SPINAL CORD IN PATIENTS WITH PERNICIOUS ANEMIA TREATED WITH SYNTHETIC PTEROYLGLUTAMIC (FOLIC) ACID

Blood ◽

10.1182/blood.v3.1.68.68 ◽

1948 ◽

Vol 3 (1) ◽

pp. 68-90 ◽

Cited By ~ 63

Author(s):

J. F. Ross ◽

H. BELDING ◽

B. L. PAEGEL

Keyword(s):

Spinal Cord ◽

Folic Acid ◽

Pernicious Anemia ◽

Liver Extract ◽

Blood Levels ◽

Rapid Progression ◽

Neurologic Disease ◽

Subacute Combined Degeneration ◽

Acid Therapy ◽

Oral Doses

Abstract 1. Twenty-one patients with pernicious anemia were maintained on synthetic folic acid (pteroylglutamic acid) therapy alone for periods ranging from eight to seventeen months. Satisfactory blood levels were maintained in all cases receiving daily oral doses of 1.25 to 15.0 mg. Severe hematologic relapse occurred within six months in a case treated with monthly injections of 30 mg. 2. Synthetic folic acid in oral doses of 15 mg. daily induced satisfactory hematopoietic responses in 3 patients with pernicious anemia in severe relapse, but only slight hematopoietic response in a fourth patient with mild pernicious anemia but severe subacute combined degeneration of the spinal cord. 3. Ten patients showed a significant improvement in blood values for a few months after substitution of folic acid for liver extract. With one exception these subsided after six or more months to pre-folic acid levels comparable with those previously maintained with liver extract alone. 4. These observations suggest that a combination of orally administered folic acid and parenterally injected liver extract may maintain a better hematologic status than either substance alone. 5. A previously untreated patient with severe subacute combined degeneration of the spinal cord failed to show improvement in neural disease during twentyeight days of folic acid therapy. 6. Eleven patients developed, or showed progression of, subacute combined degeneration of the spinal cord during folic acid treatment. Neurologic disease developed in most of these patients when the peripheral blood was normal. 7. One patient showed an extremely explosive onset and rapid progression of neural disease. The progression of the disease was rapid in 3 other cases. 8. The institution of liver extract therapy in adddition to folic acid in 5 patients who developed subacute combined degeneration during folic acid maintenance therapy failed to prevent progression of the disease in 4 cases, and only partially arrested the disease in the fifth, in which improvement occurred more rapidly when folic acid was discontinued. 9. Subacute combined degeneration occurred with greater frequency in patients on large daily doses of folic acid than it did in patients with small or intermittent doses. 10. The possibility is discussed that folic acid in large daily doses may actually precipitate or aggravate neurologic disease. 11. It is suggested that folic acid may interfere with the metabolism of 1(+) glutamic acid in the central nervous system and possibly disturb the formation or function of acetylcholine.

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FOLIC ACID IN THE TREATMENT OF PERNICIOUS ANEMIA

Blood ◽

10.1182/blood.v2.1.50.50 ◽

1947 ◽

Vol 2 (1) ◽

pp. 50-62 ◽

Cited By ~ 22

Author(s):

LEO M. MEYER

Keyword(s):

Folic Acid ◽

Pernicious Anemia ◽

Liver Extract ◽

Macrocytic Anemia ◽

Signs And Symptoms ◽

Well Being ◽

Blood Picture ◽

Acid Therapy ◽

Small Doses ◽

Symptoms And Signs

Abstract 1. Folic acid in daily doses of 15 to 50 mg., orally, or 20 mg. intramuscularly, usually produced a submaximal reticulocytosis in patients with pernicious anemia. 2. In 3 patients the hemoglobin and red cells rose to a level of about 12.0 Gm. and 4.3 million respectively without further rise after 3 months of therapy. 3. Folic acid in the above doses failed to prevent the development or progression of neurological symptoms indicative of subacute combined sclerosis. 4. In 5 patients folic acid in doses of 5 or 10 mg. orally daily combined with ½ unit of liver extract injected intramuscularly daily produced a reticulocytosis greater than that anticipated from adequate liver extract therapy alone. 5. With combined liver extract and folic acid therapy there was evidence of improvement in the symptoms and signs of subacute combined sclerosis in 3 patients. 6. Folic acid, combined with ½ unit of liver extract, was found to produce a complete hematological remission. 7. Folic acid, alone or in combination with small doses of liver extract, produced an improvement in appetite and general well-being in patients with pernicious anemia. 8. The possible enhancing effect of liver extract when combined with folic acid cannot be due to the folic acid content of the former since 1 unit of liver extract contains only 0.38 micrograms of folic acid.31 9. Folic acid administered to a patient with macrocytic anemia due to faulty postoperative intestinal digestion and absorption, produced a complete remission in the blood picture and a marked improvement in signs and symptoms.

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Microspectrophotometric Determination of Desoxyribosenucleic Acid in Megaloblasts of Pernicious Anemia

Blood ◽

10.1182/blood.v6.4.344.344 ◽

1951 ◽

Vol 6 (4) ◽

pp. 344-349 ◽

Cited By ~ 10

Author(s):

EDWARD H. REISNER ◽

ROY KORSON

Keyword(s):

Bone Marrow ◽

Folic Acid ◽

Vitamin B12 ◽

Pernicious Anemia ◽

Blood Cells ◽

Nuclear Dna ◽

Liver Extract ◽

Megaloblastic Anemia ◽

Gradual Loss

Abstract 1. In 9 patients with various types of megaloblastic anemia responding to treatment with vitamin B12, folic acid or liver extract, no significant deviations from the normal amounts of total or polymerized DNA were observed in the nuclei of red blood cells in marrow smears. 2. During the maturation of megaloblasts in the bone marrow there is a gradual loss of nuclear DNA. 3. This pattern is quantitatively and qualitatively similar for normal marrow and for that of pernicious anemia in relapse and after treatment.

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LIVER EXTRACT REFRACTORY MEGALOBLASTIC ANEMIA

Blood ◽

10.1182/blood.v4.10.1117.1117 ◽

1949 ◽

Vol 4 (10) ◽

pp. 1117-1123 ◽

Cited By ~ 1

Author(s):

JOHN F. MUELLER ◽

V. R. HAWKINS ◽

RICHARD W. VILTER

Keyword(s):

Folic Acid ◽

Vitamin B12 ◽

Liver Extract ◽

Megaloblastic Anemia ◽

Macrocytic Anemia ◽

Mass Action ◽

Deficiency Anemia ◽

Normal Limits ◽

Unknown Factor ◽

Relationship Of

Abstract 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.

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STUDIES ON THE RELATIONSHIPS OF VITAMIN B12, FOLIC ACID, THYMINE, URACIL, AND METHYL GROUP DONORS IN PERSONS WITH PERNICIOUS ANEMIA AND RELATED MEGALOBLASTIC ANEMIAS

Blood ◽

10.1182/blood.v5.8.695.695 ◽

1950 ◽

Vol 5 (8) ◽

pp. 695-717 ◽

Cited By ~ 75

Author(s):

RICHARD W. VILTER ◽

DANIEL HORRIGAN ◽

JOHN F. MUELLER ◽

THOMAS JARROLD ◽

CARL F. VILTER ◽

...

Keyword(s):

Folic Acid ◽

Vitamin B12 ◽

Pernicious Anemia ◽

Liver Extract ◽

Megaloblastic Anemia ◽

Complete Response ◽

Mass Action ◽

Folic Acid Deficiency ◽

Human Beings ◽

Combined System

Abstract 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.

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JUVENILE PERNICIOUS ANEMIA

PEDIATRICS ◽

10.1542/peds.8.1.88 ◽

1951 ◽

Vol 8 (1) ◽

pp. 88-106

Author(s):

EDWARD H. REISNER ◽

JAMES A. WOLFF ◽

R. JAMES MCKAY ◽

EUGENIA F. DOYLE

Keyword(s):

Vitamin B12 ◽

Pernicious Anemia ◽

Gastric Juice ◽

Liver Extract ◽

Macrocytic Anemia ◽

Intrinsic Factor ◽

The Other ◽

Free Hydrochloric Acid ◽

Laboratory Findings ◽

Gastric Contents

Histories have been presented of two pairs of sibling children with recurrent macrocytic anemia with megaloblastic bone marrow responding specifically to liver extract and vitamin B12. The clinical features and laboratory findings were similar to those of adult pernicious anemia in every respect except for the inconstant presence of histamine refractory achlorhydria. All the patients responded to vitamin B12 given parenterally, but in three to whom it was given by mouth no response was obtained. Two of these subsequently responded to oral B12 when it was accompanied by normal gastric juice. The other two developed histamine refractory achlorhydria while in hematologic remission. This is interpreted as proof that the anemia was due to deficient intrinsic factor in the gastric juice. Three patients showed evidence of disease of the spinal cord, in two of whom the symptoms were severe. These symptoms were compatible with a diagnosis of dorsolateral sclerosis, and improved with antipernicious anemia therapy. In one of these patients, treated with folic acid, the neurologic lesions were aggravated severely. Pernicious anemia due to the absence of gastric juice intrinsic factor occurs in children. The presence of free hydrochloric acid in the gastric contents does not preclude the possibility of the disease.

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PERNICIOUS ANEMIA IN CHILDHOOD REPORT OF CASE IN SIX YEAR OLD GIRL RESPONDING TO REFINED LIVER EXTRACT, FOLIC ACID AND VITAMIN B12 IN SUCCESSIVE RELAPSES

Blood ◽

10.1182/blood.v4.12.1361.1361 ◽

1949 ◽

Vol 4 (12) ◽

pp. 1361-1366 ◽

Cited By ~ 6

Author(s):

R. WENDELL DAVIS ◽

RICHARD M. CHRISTIAN ◽

DONALD M. ERVIN ◽

LAWRENCE E. YOUNG

Keyword(s):

Folic Acid ◽

Hydrochloric Acid ◽

Vitamin B12 ◽

Pernicious Anemia ◽

Gastric Juice ◽

Liver Extract ◽

Megaloblastic Anemia ◽

Free Hydrochloric Acid ◽

Neurologic Complications ◽

Hematologic Response

Abstract A case of megaloblastic anemia without specific neurologic complications in a 6 year old girl is presented as an example of pernicious anemia in childhood despite the fact that a small amount of free hydrochloric acid was present in the gastric juice after injection of histamine. Prompt hematologic response was obtained following administration of refined liver extract, folic acid and vitamin B12 in successive relapses.

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A case report on Subacute Combined Degeneration of spinal cord in children – A rare neurological manifestation in Vitamin B12 deficiencies

International Journal of Bioassays ◽

10.21746/ijbio.2017.6.12.2 ◽

2017 ◽

Vol 6 (12) ◽

pp. 5562

Author(s):

Tiana Mary Alexander ◽

Vineeta Pande ◽

Sharad Agarkhedkar ◽

Dnyaneshwar Upase

Keyword(s):

Spinal Cord ◽

Case Report ◽

Vitamin B12 ◽

Pernicious Anemia ◽

Chronic Diarrhea ◽

Megaloblastic Anemia ◽

Vegetarian Diet ◽

Malabsorption Syndrome ◽

Subacute Combined Degeneration ◽

B12 Deficiency

Megaloblastic anemia is a common feature between 6 months – 2 years and rarely occurs after 5 years of age, especially in a child consuming non-vegetarian diet. B12 deficiency may occur after 5 years of age because of chronic diarrhea, malabsorption syndrome, or intestinal surgical causes. Pernicious anemia causes B12 deficiency, but nutritional B12 deficiency with subacute combined degeneration causing ataxia is rare.

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