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A 71-year-old woman was treated with radiotherapy for carcinoma of the cervix. Nine year later she was found at laparotomy to have a thickened narrow ileum. At the time she had an iron-deficiency anaemia and when this was treated the blood picture changed to that of a severe megaloblastic anaemia. This was due to cobalamin deficiency resulting from malabsorption of cobalamin by the damaged ileum.

Only two (2.5%) of 80 outpatients with histologically proven ulcerative colitis had folate deficiency associated with anaemia or macrocytosis. Mean folate absorption, measured using micrograms/kg body weight of a tritium-labelled physiological folate derivative, 5-methyltetrahydroteroylglutamic acid, in six newly diagnosed patients was 76.7% (normal greater than 95%) but fell to 69.4% after three months' treatment with sulphasalazine. Mean difference in individual patients was 7.5% +/- 5.2% (SD) (p less than 0.02). Mean folate absorption in four patients with megaloblastic anaemia or macrocytosis which developed during treatment with sulphasalazine was 66.3%. This rose to 82.4% after the drug was stopped. Mean difference in individual patients was 16.6 +/- 6.6% (SD) (p less than 0.001). All patients who developed anaemia or macrocytosis with sulphasalazine had additional reasons for folate deficiency. These included coeliac disease, severe nutritional deficiencies, and haemolysis. It was concluded that sulphasalazine impairs folate absorption but this only becomes significant if other reasons for folate deficiency are also present.

A middle-aged woman developed a postgastric bypass megaloblastic anemia which responded to treatment. She eventually had the bypass reversed 6 1/2 yr after it had been performed. Gastric parietal cell function has remained abnormal almost 3 yr after reversal of the bypass, as demonstrated by abnormal Schilling tests and high serum gastrin levels. Parietal cell antibodies in high titer, but no intrinsic factor antibodies, were demonstrated in her blood. These observations are interpreted as indicating the development of irreversible chronic atrophic gastritis probably related to reflux of bile into the bypassed stomach.

The existence of tropical sprue in Africa is controversial. In this paper we present 31 cases seen in Rhodesia over a 15 month period. They have the clinical features, small intestinal morphology, malabsorption pattern, and treatment response of tropical sprue. Other causes of malabsorption, and primary malnutrition, have been excluded. The severity of the clinical state and intestinal malabsorption distinguish these patients from those we have described with tropical enteropathy. The previous work on tropical sprue in Africa is reviewed and it is apparent that, when it has been adequately looked for, it has been found. It is clear that the question of tropical sprue in Africa must be re-examined and that it existence may have hitherto been concealed by the assumption that primary malnutrition is responsible for the high prevalence of deficiency states.

Hyperpigmentation of the hands and feet developed in a 65-year-old Korean woman who had undergone a total gastrectomy and esophagojejunostomy due to early gastric cancer 7 years previously. A diagnosis of megaloblastic anemia due to vitamin B12 deficiency was made. In the areas of pigmentation, there were abnormally large nuclei in the keratinocytes. All of these findings were reversible upon the administration of vitamin B12. Ultrastructurally, there were many intracytoplasmic desmosomes, numerous aggregated bundles of tonofilaments, and highly condensed keratohyalin granules. The pathophysiologic mechanism of vitamin B12 deficiency associated with pigmentary disturbances and change of nuclear size is discussed.

After presentation of morphological and clinical characteristics concerning megaloblastic anemias, the differential diagnostic possibilities of these anemia, ase discussed. Finally a short survey concerning the therapeutic procedure is presented.

Megaloblastic anaemia in infancy is uncommon in western countries. We describe a case of an exclusively breast-fed monozygous twin with severe vitamin B12 deficiency with haematologic and neurologic abnormalities. Treatment with vitamin B12 resulted in a rapid haematological and clinical improvement.

An epileptic patient on chronic anticonvulsant drug therapy is described, in whom anaemia and neurological abnormalities including progressive dementia, bilateral pyramidal tract signs, incontinence and ataxia developed. Vitamin B12 serum levels and absorption were normal, but serum folic acid levels were low. Both the neurological disturbances and anaemia resolved following oral folic acid administration. This sequence of events in our patient suggests a cause and effect relationship between the folate deficiency and the coexistent, transient neurological syndrome.

Of 27 Asians with a megaloblastic bone marrow, 22 (81%) had nutritional deficiency of vitamin B12 (NMA), while five (19%) had true pernicious anaemia (PA). All the patients were Hindu vegetarians except for a single Muslim who had PA. Dietary intakes of calories, protein, iron, vitamin B12 and folate were below the recommended level in both groups. The PA group had lower levels of serum B12 and higher levels of serum folate than the NMA group. Despite low levels of red cell folate (RCF) in the NMA patients, the abnormality in deoxyuridine (dU) suppression was always corrected by vitamin B12. The dU suppressed value showed a significant inverse relationship to the RCF level. Nutritional deficiency of vitamin B12 is the most common cause of megaloblastic anaemia in Hindu vegetarians but the incidence of true PA is higher than previously thought and may approximate to that of the white population.

In a 11 month-old child, a deep anemia with reticulocytopenia and megaloblastosis on bone marrow aspiration revealed a thalassemia major. The low folate intake and the increased needs probably account for initial findings. Folic acid deficiency has already been described in patients with dyserythropoiesis or chronic hemolysis. Daily folic acid treatment is necessary in these patients.

Urinary methylmalonic acid (MMA) excretion in megaloblastic anemia due to vitamin B12 (B12) deficiency was studied using a colorimetric method. Average MMA excretion in 20 patients with untreated B12 deficiency was 164 mg/day, whereas it increased to 518 mg/day following oral administration of 10 g L-valine. Urinary MMA correlated significantly with platelet number, erythroblast percentage and deoxyuridine suppression test, while no correlation was found with hemoglobin, leukocyte number, reticulocyte, serum LDH, serum B12 and folate concentration. Patients with neurological disturbances excreted significantly larger amounts of MMA than those without neurological disorders. The results also indicated that MMA could be a useful adjunct for differentiation of megaloblastic anemia from myelodysplastic syndromes showing marked megaloblastic changes.

Three cases of congenital selective malabsorption of vitamin B12 (Imerslund-Grasbeck syndrome) are presented. Pathophysiological aspected and clinical symptoms of this disease are discussed together with other megaloblastic anaemias in childhood caused by vitamin B12 deficiency.

Four patients with ruptured abdominal aortic aneurysm developed thrombocytopenia and marked megaloblastic changes within 3-10 days of surgery. In 2 patients, direct evidence of folate deficiency within marrow cells was obtained by measuring deoxyuridine suppression in short-term bone marrow cultures. The results suggest that folate deficiency was limited to marrow tissue. Folate deficiency localized to the bone marrow offers an explanation for the extremely rapid onset of thrombocytopenia in these patients. The significance of these findings with regard to folate metabolism is discussed. The importance of recognizing this potentially fatal complication of critical illness is emphasized, because it should be readily prevented by folic acid therapy.

Serum C3 and C4 levels have been determined in patients with Addisonian pernicious anaemia (PA) and megaloblastic anaemia due to vitamin B12 deficiency from other causes, before and after treatment, in order to study the interaction between vitamin B12 deficiency and complement and the role of complement in the pathogenesis of the gastric lesion of PA. C3 levels are significantly reduced in vitamin B12 deficiency and return to normal on treatment; C3 levels correlate with the degree of anaemia but not with serum vitamin B12 levels at diagnosis. C4 levels are normal. These observations suggest that the observed C3 hypocomplementaemia is not a consequence of immune mechanisms, but may be due to altered synthesis of C3 complement component.

Five cases of severe megaloblastic anaemia in Gambians are described. Three of the patients were found to have pernicious anaemia. The difficulties in diagnosis and the various features of pernicious anaemia in Negroes are discussed. A brief review of the literature is included.

Blood-counts and folate assays were performed on samples from 102 adults at a residential institution for severe mental impairment. 96 of these patients were receiving anticonvulsant therapy and 6 were not. Only 1 subject had a macrocytic blood-picture, and 5 subjects had hypochromic anaemia. No features of incipient metaloblastic haemopoiesis were identified in the remaining samples. However, serum-folate measured by two assay methods was subnormal in 83% of the samples; red-cell folate was subnormal in 40%. It is concluded that the development of macrocytic anaemia in subjects on long-term anticonvulsants therapy is probably not related to the biochemical process which causes their low assayable folate but reflects inadequate nutrition.

A 40-year-old man who was resected ascending colon and terminal ileum (10 cm) in Aug. 1978, with the diagnosis of Crohn's disease, was admitted to our hospital with general fatigue, paresthesia and tremor in May. 1984. A peripheral blood examination on admission revealed Hb 10.1 g/dl, RBC 234 X 10(4)/mm3, MCV 131.4 fl, MCH 43.2 pg. A bone marrow specimen showed marked erythroid hyperplasia (W/E 1.44) with megaloblastic change. While serum folate level was normal, serum vitamin B12 value was low and Schilling test showed vitamin B12 malabsorption. Roentgenologic and endoscopic examinations revealed diffuse cobblestone appearances in small intestine (from anastomosis part to duodenal bulb). These examinations suggested vitamin B12 malabsorption with diffuse Crohn's disease caused megaloblastic anemia. The patient had been treated with vitamin B12 1,000 micrograms/day injection and, in Sep. 1984, he recovered from megaloblastic anemia (Hb 13.4 g/dl, RBC 440 X 10(4)/mm3, MCV 90.7 fl, MCH 30.4 pg).

We studied a six-month-old infant with severe megaloblastic anemia, coma and hyperpigmentation of the extremities. He was found to have methylmalonic aciduria (79 mumol per milligram of creatinine) and homocystinuria (0.85 mumol per milligram of creatinine). Additional biochemical abnormalities included cystathioninuria, glycinuria, methylcitric aciduria, 3-hydroxypropionic aciduria and formic aciduria. The concentration of vitamin B12 in the serum was 20 pg per milliliter. This severe nutritional deficiency was a consequence of inadequate intake, for the infant was exclusively breast-fed by a strictly vegetarian mother who manifested methylmalonic aciduria. Our observations emphasize the importance of educating strict vegetarians about the deficiency of vitamin B12 in their diets and the importance of vitamin B12 supplementation.

A 34-year-old Black woman had severe megaloblastic anemia in childhood. Initially, and over the years, she responded well to massive doses of parenteral cobalamin (Cbl) or oral folic acid. Metabolic reactions involving Cbl and folate enzymes were normal during both relapse and remission except for the absence of thymidylate synthetase in relapse. Amino acid analyses of urine and plasma showed no significant abnormalities. Neither cystathionine, homocystine, formiminoglutamic acid, nor methylmalonic acid was detected in the urine. The serum Cbl level was repeatedly elevated even when the patient was receiving only folic acid therapy. The elevation of the vitamin in the serum was found to be a result of markedly increased levels of transcobalamin II (TC II), as identified by several physicochemical techniques. The patient's TC II-Cbl shared immunologic properties with normal TC II but did not facilitate or impede the uptake of Cbl or Cbl bound to normal TC II, respectively, by human cells.

The serum folate level of 100 aged persons (after 70) was decreased (less than 4 ng/ml) in 41% of the cases (manifest deficiency of folic acid). In the group of aged persons having normal folate values, in 41% of the cases the clearance method proved a latent folic acid deficiency, being the 15 minute value after 15 gamma/kg folic acid i.v., less than 25 ng/ml.

Ninety-five patients who had megaloblastic anaemia, and who lived in a subtropical climate, were studied to elucidate the importance of puerperium, malabsorption, gastric dystrophy, diet and infection in the aetiology of the disease. All 5 factors were found to be common, and to occur in a variety of combinations, producing a wide spectrum of illness variously resembling nutritional megaloblastic anaemia, sprue, pernicious anaemia and many stages in between. It is concluded that megaloblastic anaemia in this population is a multifactorial disease, and a tentative scheme, relating the aetiological factors, is drawn up. Neither serum vitamin B(12) levels, nor folate estimation in serum or red cells emerged as very reliable guides to the underlying biochemical deficiency.

When temperature-sensitive (ts) mutant lines of mouse L-cells, ts AIS9 and ts CI, are shifted from 34C to 38.5C, a rapid inhibition of DNA synthesis and mitosis occurs. During this phase, cell and nuclear growth continues and results in a substantial increase in cell and nuclear volume. Such cellular modifications are also associated with a marked dispersal of the condensed chromatin masses of interphase nuclei, so that after 48-72 h of incubation at 38.5C, nuclear profiles of both ts cell lines bear a striking resemblance to the nuclear features characteristic of megaloblastic anaemia. Despite these marked alterations in nuclear chromatin organization, morphometric analysis indicates that the volume of condensed chromatin does not decrease. Current biochemical, cytological and morphometric data on the two ts lines of mutant mouse L-cells during expression of the mutation, suggest that they might provide a useful model to further elucidate cytological features of megaloblastic anaemia.