Anemia In Relapse Research Articles

Intrinsic factor studies: II. The effect of gastric juice on the urinary excretion of radioactivity after the oral administration of radioactive vitamin B 12

The simultaneous oral administration of normal human gastric juice and small quantities of vitamin B12 results in hematopoiesis in patients with pernicious anemia in relapse, while oral vitamin B12 alone in similar amounts is usually ineffective. 1 Berk L. Castle W.B. Welch A.D. Heinle R.W. Anker R. Epstein M. Observations on the etiologic relationship of achylia gastrica to pernicious anemia. X. activity of vitamin B12 as food (extrinsic) factor. N Engl J Med. 1948; 239: 911 Google Scholar , 2 Schilling R.F. Harris J.W. Castle W.B. Observations on the etiologic relationship of achylia gastrica to pernicious anemia. XIII. Hematopoietic activity of (vitamin B12). Blood. 1951; 6: 228 Google Scholar , 3 Ungley C.C. Absorption of vitamin B12 in pernicious anemia. BMJ. 1950; 2: 905 Google Scholar , 4 Hall B.E. Morgan E.H. Campbell D.C. Oral administration of vitamin B12 in pernicious anemia. I. Presence of intrinsic factor in Berkefeld-filtered pooled human gastric juice: Preliminary report, Proc Staff Meet. Mayo Clin. 1949; 24: 99 Google Scholar , 8 Hall Byron E. Studies on the nature of the intrinsic factor of castle. BMJ. 1950; 2: 585 Google Scholar The hematopoietic activity of intravenously administered vitamin B12 was not enhanced by the simultaneous intravenous administration of sterile Berkefeld filtered gastric juice in amounts known to be active as intrinsic factor when given orally. 5 Wallerstein R.O. Harris J.W. Schilling R.F. Castle W.B. Observations on the etiologic relationship of achylia gastrica to pernicious anemia. XV. Hematopoietic effects of simultaneous intravenous and of simultaneous or serial oral administration of intrinsic factor in vitamin B12. J Lab Clin Med. 1953; 41: 363 Google Scholar Vitamin B12 by parenteral injection regularly corrects the hematologic abnormalities and arrests the neurologic disorder in pernicious anemia. Heinle and associates 6 Heinle R.W. Welch A.D. Scharf V. Meacham G.C. Prusoff W.H. Studies of excretion (and absorption) of Co60-labeled vitamin B12 in pernicious anemia. Trans Assoc Am Phys. 1952; 65: 214 Google Scholar have reported that the fecal exeretion of radioactivity in four pernicious anemia patients receiving 0.5 μg of radioactive vitamin B12 (B12Co60) by mouth was definitely greater than in normal subjects. They reported that the simultaneous oral administration of an intrinsic factor preparation and B12Co60 in three pernicious anemia patients was followed by a definite reduction of fecal radioactivity. The simplest interpretation of the above information is that the function of intrinsic factor is to promote the absorption of vitamin B12 from the intestinal tract.

Serum "uracil+uridine" levels in pernicious anaemia.

The serum "uracil+uridine" level, expressed as uracil, has been measured in 21 cases of vitamin B12 deficiency, in which the serum folate was normal, and compared with the level in 97 normal subjects. The level in the vitamin B12 deficient group (11.9 mumol/1). was significantly lower than in the controls (15.7 mumol/1., P less than 0.005). Nine of the former were complicated by stystemic illness but the clinical and haematological features in the remaining 12 were consistent with the diagnosis of pernicious anaemia in relapse. The serum uracil level in this group was even lower (10.21 mumol/1., P less than 0.01). This finding is unexpected in view of the generally accepted indirect role of vitamine B12 in the methylation of deoxyuridine monophosphate to deoxythymidine monophosphate. Reasons are given for not accepting these results as reflecting the main biochemical lesion in vitamin B12 deficiency. Although they do not give direct support to an impairment in the methylation of deoxyuridine monophosphate, they do not exclude it as they test only one possible metabolic pathway and moreover they could represent the result of more than one action of vitamin B12 on uracil metabolism. They do show, however, that some aspect of uracil metabolism other than methylation is affected in vitamin B12 deficiency in man.

Serum valine and methionine levels in pernicious anaemia under treatment.

Summary:The serum levels of the amino acids, valine and methionine have been determined by a quantitative microbiological method in 17 cases of pernicious anaemia both before and on successive days after treatment. The results have been compared with the serum levels of the two amino acids in 16 normal subjects under similar conditions.The serum valine level is normal in pernicious anaemia in relapse. It falls sharply during the first 48 hours following treatment, thereafter rising gradually to reach about two‐thirds the pretreatment level by the fifth day. This confirms the fall in valine level in whole blood and marrow previously reported in pernicious anaemia under treatment.The serum methionine level is subnormal in pernicious anaemia in relapse. It rises to normal in 48 hours after treatment.Both vitamin B12 and folic acid are effective in lowering the serum valine and elevating the serum methionine.The rise in serum methionine can be explained in terms of the known actions of vitamin B12 and folic acid. The fall in serum valine cannot at present be explained but several possibilities are discussed.

The chromosome anomalies of the megaloblastic anaemias.

Chromosome studies carried out on bone-marrow cells in a case of classical pernicious anaemia in relapse disclosed structural abnormalities in 38% of the metaphases analysed. They were promptly corrected after vitamin B12 administration. No quantitative anomalies were detected.

Co57 Vitamin B12 Clearance Studies in Pernicious Anaemia

Clearance rate of intravenously administered radioactive vitamin B12 in untreated pernicious anaemia patients is slow in 50 per cent of cases studied. Administration of labelled vitamin B12 bound to slow serum to ‘normal clearing’ pernicious anaemia subjects or to normal persons is followed by normal clearance rate. Radioactive vitamin B12 bound to normal serum is cleared at a normal rate in pernicious anaemia patients with slow clearance rate. Radioactive vitamin B12 bound to slow serum when mixed with normal serum in proportions of 1:1 or 1:0.5 is cleared at a normal rate in ‘slow clearing’ pernicious anaemia patients. These studies suggest the presence of a ‘serum factor’ in normal serum and some patients with pernicious anaemia in relapse which enhances clearance of vitamin B12 bound to ‘slow serum’.

Steroids and addisonian pernicious anemia.

ADMINISTRATION of steroids to patients with Addisonian pernicious anemia in relapse often produces a hematologic response.1 There is an improvement in vitamin B12 absorption2 3 4 and with it an increase in secretion of intrinsic factor5 and a decline in the amount of intrinsic-factor antibody in the blood.6 The absorption of vitamin B12 after total gastrectomy is not improved by steroid therapy.7 There is good evidence that gastric atrophy is the result of an autoimmune process. It is also possible that the final failure of vitamin B12 absorption in pernicious anemia follows the development of antibodies against intrinsic factor. . . .

Chromosomal Aberrations in Pernicious Anemia: Study of Three Cases before and after Therapy

Abstract Numerical and morphologic chromosomal aberrations were demonstrated in three cases of pernicious anemia in relapse. The morphological abnormalities including chromatid breaks, gaps and "giant" chromosomes were reduced in remission following vitamin B12 therapy. The numerical changes consisted of aneuploidy (45 and 44 chromosomes) with the most common finding encountered (6 to 100 per cent of the cells) being monosomy involving the G 21 chromosome. This was present, not only in the marrow cells, but also in other tissues, e.g., peripheral blood and possibly skin fibroblasts, thus suggesting a more generalized disorder. The numerical anomalies persisted in remission. It is postulated that the structural anomalies, namely chromatid breaks, gaps, acentric fragments and "giant" chromosomes are related to vitamin B12 deficiency and are correctable. The cause of the aneuploidy, since it was not correctable by treatment, is not clear. Since the patients were not studied before the disease had ensued, a congenital or acquired predisposition to megaloblastosis on the basis of G 21 monosomy cannot be excluded. The origin and significance of the extra chromatin material translocated onto the short arms of G 21 chromosomes in cases 1 and 3 remains unexplained.

STUDIES ON THE MINIMUM DAILY REQUIREMENT FOR VITAMIN B12. HEMATOPOIETIC RESPONSES TO 0.1 MICROGM. OF CYANOCOBALAMIN OR COENZYME B12, AND COMPARISON OF THEIR RELATIVE POTENCY.

THE minimum daily adult requirement for vitamin B12 has not been established.1 Shortly after the isolation of crystalline vitamin B12 in 1948 by Rickes et al.,2 West and Reisner3 reported that the minimum effective parenterally administered dose for patients with pernicious anemia was 1 microgm. daily. Noting that these investigators had not obtained a reticulocyte response to 0.1 microgm. of cyanocobalamin daily in the only patient given this dose, Darby and his associates4 found that parenteral administration of cyanocobalamin, in doses of 0.25 to 1.0 microgm. daily, to patients with pernicious anemia in relapse resulted in reticulocyte responses . . .

Clinical Studies on Glucose Metabolism via the Pentose Phosphate Pathway in Human Erythrocytes

Abstract Glucose metabolism via the pintos phosphate pathway was studied by measuring accelerated O2 uptake of human erythrocytes in the presence of methylene blue. Erythrocyte 02 uptake was independent of age in 67 normal patients. Erythrocyte 02 uptake was increased in pernicious anemia in relapse and in 5 of 6 jaundiced patients but was normal in pernicious anemia in remission and in 20 cases of malignancies of various types. In the latter cases there was no correlation between erythrocyte 02 uptake and hemoglobin content or reticulocyte count.

Relative Folate Deficiency of Erythrocytes in Pernicious Anemia and its Correction with Cyanocobalamin

AbstractTHE DETERMINATION of folate activity in serum with Lactobacillus casei allows recognition of patients with folate deficiency.1-3It has been observed that much of the L. casei-active folate in human serum consists of N5-methyl tetrahydropteroyl monoglutamate,4 and that the concentration of folate activity in serum is increased in some patients with pernicious anemia in relapse.5 However, not all such patients have high serum folate activity.

HEMATOLOGIC EFFECT OF 5,6-DIMETHYL-BENZIMIDAZOLYL COBAMIDE COENZYME IN A PATIENT WITH PERNICIOUS ANEMIA.

A patient with pernicious anemia in relapse was treated with coenzyme B12. The red blood cell count increased significantly following the single administration of 5μg of coenzyme B12. The hematologic effect of coenzyme B12 was compared with the effect of CN-B12 according to the reported data and was found to be almost equivalent in each other on a molar basis. The discussions was extended to the clinical application of coenzyme B12 in future.

STUDIES ON THE ABSORPTION OF VITAMIN B12

For the purpose of investigating whether or not Co60-B12 absorption tests are successfully applicable to Japanese subjects, the intestinal absorption of orally administered Co60-B12 was studied for the first time on the Japanese patients suffering from hematologic disorders including Addisonian pernicious anemia as well as the normals. At the same time, in view of the fact that pernicious anemia is rare in Japan, an attempt was made to study the difference in B12 metabolism between the Japanese and the European or the American pernicious anemia patients. As the methods for measuring intestinal absorption of B12, fecal or urinary excretion tests and hepatic uptake method were used in this study. Prior to this study, some fundamental investigations were made on these methods. The results obtained are as follows:1. In Japanese normals, fecal excretion was 29.0±9.0% of the radioactivity of the oral Co60-B12 on the average, urinary excretion 17.4±6.8%, and hepatic uptake 8.74±2.93%, showing a good agreement with those in the foreign normals.2. The measurement of hepatic uptake presented the evidence that absorbed B12 was preferentially taken up by the liver in the Japanese as well. It was also found that 0.2 or 0.5μg of Co60-B12 should be given as a test dose in urinary excretion test, since percentage urinary radioactivity was significantly decreased when the oral dose was raised above 1.0μg.3. In hematologic disorders such as leukemia, aplastic anemia, iron deficiency anemia, hemolytic anemia, lupus erythematosus, or anemia due to the lodging of tape worm, there could be observed no significant defect in B12 absorption.4. However, in three cases of pernicious anemia in relapse or in remission, B12 absorption was exceedingly abolished without exception, unless hog intrinsic factor concentrate was added. This fact indicates that the pathogenesis of pernicious anemia of the Japanese patients was quite identical with the patients of other countries.5. In addition, a diagnostic availability of B12 absorption tests for the differentiation of pernicious anemia from other resembling megaloblastic anemias was also referred to.Thus, the author was led to the general conclusion that B12 absorption test was also well applicable to Japanese subjects and that the mechanism of pernicious anemia was identical with each other, irrespective of the patients' nationality, no matter how low the incidence of pernicious anemia may be.

A Case of Juvenile Pernicious Anemia: Study of the Effects of Folic Acid and Vitamin B12

Abstract Observations on a 4-year-old boy with Addisonian pernicious anemia have been presented. Noteworthy clinical features included the onset of glossitis at the age of 4 months, followed by anemia severe enough to require hospitalization at the age of 1 year. Relapse occurred in the absence of specific therapy with vitamin B12 and was completely unaffected by the administration of folic acid. Studies with radioactive vitamin B12 demonstrated that almost all of the compound administered by mouth was unabsorbed and was recovered in the stools. When the vitamin was given simultaneously with a concentrate of intrinsic factor, however, approximately 70 per cent was absorbed. Furthermore, the child’s gastric juice, when mixed with radioactive vitamin B12 and fed to an adult with pernicious anemia in relapse, failed to enhance the latter’s absorption of the vitamin. The failure of our patient to absorb the vitamin alone, but his ability to do so when it was administered with intrinsic factor concentrate, was also confirmed by the "Schilling test," in which a proportion of the absorbed radioactive vitamin was "flushed" into the urine by parenteral injection of one milligram of conventional vitamin B12. Of special interest was the occurrence in the urine of an unidentified derivative of tetrahydrofolic acid, derived from orally administered pteroylglutamic acid. The presence of this compound in the urine was demonstrated chromatographically when the patient was critically ill with his disease prior to treatment with vitamin B12. Subsequent to therapy with vitamin B12, while the administration of folic acid was continued, the abnormal metabolite of folic acid could not be found in the urine. Similarly, the administration of folic acid did not lead to the appearance of this metabolite in the urine at a time when, after more than two years without specific therapy, a hematological relapse occurred that was much less severe than that previously observed. The implications of these observations, with respect to the metabolic interrelationships of folic acid and vitamin B12, are discussed. Of further interest were the findings of strongly acid gastric juice containing much mucus and free hydrochloric acid. A fairly normal gastric mucosa was demonstrated by biopsy. The meaning of these unusual findings is discussed and an hypothesis to account for them is offered. The probable sequence of events in these patients from childhood to the development of anemia, usually in later life, is set forth.

The Maturation Rate of Reticulocytes

Abstract An in vitro culture technic for the study of reticulocyte maturation was described. The method gave reproducible results and proved to be of value in the comparative study of reticulocyte maturation in blood disorders. By this method it was shown that variations in the reticulocyte maturation in vitro paralleled similar variations present in vivo. The maturation of reticulocytes from patients with different types of anemia was investigated. In some anemias the in vitro maturation of reticulocytes was prolonged, not only because younger reticulocytes were present in the blood, but also because the rate at which the reticulum substance disappeared was delayed. This was particularly evident in the anemia of chronic uremia, in Cooley’s anemia and in pernicious anemia in relapse. In only occasional cases of hereditary spherocytosis and of autoimmune hemolytic anemia was the rate of reticulocyte maturation found to be moderately delayed. In patients with iron deficiency anemia or bleeding anemia it was always normal. From the above findings the following conclusions were derived: 1. The reticulocyte number in the circulating blood is the resultant of three variables: (a) the rate of output of new reticulocytes from the bone marrow; (b) the stage of maturation at which reticulocytes are delivered into the peripheral circulation; (c) the rate of disappearance of the reticulum substance. 2. The number of reticulocytes in the circulating blood cannot be indiscriminately used as a precise index of red cell production in erythrokinetics. 3. There is good reason to believe that a defect in the rate at which the reticulocytes mature in the circulating blood is an index of a similar defect in the process of erythroblastic differentiation in the bone marrow.

The Kinetics of Intravenously Injected Radioactive Vitamin B12: Studies on Normal Subjects and Patients with Chronic Myelocytic Leukemia and Pernicious Anemia

Abstract 1. Studies of the fate of intravenously injected radioactive vitamin B12 have been performed in patients with normal, low and high serum concentrations of vitamin B12. 2. Abnormal plasma disappearance curves were noted in chronic myelocytic leukemia, pernicious anemia in relapse and in remission, total gastrectomy and malabsorption syndrome. 3. In chronic myelocytic leukemia, the slow clearance of plasma radioactivity may be explained by the increased binding capacity of the plasma proteins for vitamin B12. 4. Plasma clearance of radioactivity is slower than normal in pernicious anemia, even in remission. The failure of the disappearance curve to return to normal in pernicious anemia in complete remission suggests the existence of a plasma "B12-transferase," whose function is to transfer circulating B12 to the tissues. The disappearance curves suggest that the amount of such "B12-transferase" is diminished in pernicious anemia, total gastrectomy and certain Cases of malabsorption syndrome. 5. A relationship between a hypothetical "B12-transferase" and intrinsic factor is discussed.

Cyanocobalamin, Ascorbic Acid and Pteroylglutamates in Normal and Megaloblastic Bone Marrow

Abstract The B12 activity as estimated by Lactobacillus leichmannii, the folic-acid-like activity by Streptococcus faecalis (F.A.A.) and the ascorbic acid concentration have been determined in the blood and buffy coat of bone marrow of normal subjects, 10 patients with pernicious anemia in relapse, a group of patients with non-Addisonian megaloblastic anemia and some patients with iron deficiency. A correlation between the serum B12 and the plasma ascorbic acid and their respective levels in bone marrow was observed. The marrow and serum B12 levels in prenicious anemia were abnormally low, but they did not differ from a group of 5 patients with hypochromic normoblastic anemia who had both low serum and marrow levels. The concentration of F.A.A. in the marrow of patients with pernicious anemia was reduced, but it was felt that this was more likely a manifestation of the megaloblastic anemia rather than a causative factor. One of six patients with megaloblastic anemia of pregnancy had no detectable deficiency, while the other five had reduced B12, folic acid and ascorbic acid concentrations. The possible therapeutic implications are discussed. There was a significant reduction in the bone marrow concentration of ascorbic acid in all patients with megaloblastic anemia.

Failure of oral therapy in the maintenance of pernicious anemia.

Introduction Oral administration of cyanocobalamin (vitamin B 12 ) and intrinsic factor derived from hog stomach is known to be effective in producing remissions in patients with pernicious anemia in relapse. However, the efficacy of maintenance therapy with such preparations has been more difficult to evaluate. Short-term studies have indicated that satisfactory remission can be maintained on an oral preparation containing both cyanocobalamin and intrinsic factor. 1 Likewise, massive oral doses of cyanocobalamin without intrinsic factor may maintain patients with pernicious anemia in remission. 2-4 Since it has been observed that it may take several months to years for some patients with pernicious anemia to relapse, evaluation of a treatment program should be based upon a long-term study. The purpose of the present report is to compare the effectiveness of an oral preparation with that of parenteral cyanocobalamin in the management of pernicious anemia over a three-year period. During the observation

Vitamin B 12 requirement of adult man

1. 1. Patients with pernicious anemia in relapse have been studied as examples of vitamin B 12-depleted subjects. A critical study of the minimal dosage of parenterally administered vitamin B 12 required for initial response and the long-term maintenance of these patients has been made. From these data estimates of the dietary requirement of vitamin B 12 have been derived. 2. 2. The data on initial response and on maintenance consistently indicate a daily utilization of vitamin B 12 ranging from 0.5 to 2.0 μg., the more usual range being 0.5 to 1.0 μg. Considering the efficiency of absorption by normal persons of quantities of this order of vitamin B 12 we estimate that the minimal daily dietary needs for this vitamin may be met by approximately 0.6 to 2.8 μg., with a narrower range of 0.6 to 1.2 μg. sufficient for most persons. 3. 3. Long-term observations on patients receiving smaller than minimal dosage indicate that the demands of vitamin B 12 for hemopoiesis exceed those for other clinically recognized physiologic functions, and that macrocytosis is the most sensitive indicator of vitamin B 12 deficiency. In appraising vitamin B 12 nutriture careful estimates of erythrocyte size therefore are important.

Observations on vitamin B12 absorption in primary pernicious anemia during administration of adrenocortical steroids.

IT has been adequately demonstrated that the basic defect in pernicious anemia is failure of the mucosal cells in the fundal portion of the stomach to secrete intrinsic-factor substance. This factor is necessary for normal absorption of vitamin B12 from the small intestine. A few reports in the literature have shown suboptimal reticulocyte responses in patients with pernicious anemia in relapse receiving ACTH and cortisone.1 2 3 4 We have recently studied the effect of adrenocortical-steroid administration on the absorption of radioactive vitamin B12 in classic primary pernicious anemia utilizing the Schilling test, which measures the absorption of orally administered radioactive . . .

Hematologic Responses in Pernicious Anemia to Orotic Acid

Hematologic Responses in Pernicious Anemia to Orotic Acid