Williams Hematology



Vitamin-Deficiency Anemias

Vitamin A Deficiency

Deficiencies of Members of the Vitamin B Group

Vitamin C (Ascorbic Acid) Deficiency

Vitamin E Deficiency
Trace Metal Deficiency

Copper Deficiency

Zinc Deficiency

Selenium Deficiency
Anemia of Starvation
Anemia of Protein Deficiency (Kwashiorkor)
Chapter References

Anemia may result from nutritional deficiencies of a variety of vitamins and trace minerals. Vitamin deficiencies that have been implicated as causes of anemia in humans, in addition to folic acid and vitamin B12, include vitamins A, C, and E, pyridoxine and riboflavin, members of the B group. In most instances the relationship between the hematologic abnormality and deficiency of a vitamin has been difficult to document in humans, since multiple defects are usually present in a clinical setting. Copper, as well as iron, is recognized as a mineral essential for optimal erythropoiesis; a number of different enzymes essential in the metabolism of iron are cuproenzymes. Complex nutritional disturbances such as those observed in starvation, protein-deficiency malnutrition, and alcoholism are also associated with anemia.

Acronyms and abbreviations that appear in this chapter include: MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular volume.

The anemias that result from deficiencies of vitamin B12, folic acid (Chap. 38), or iron (Chap. 39) are clearly defined; they are relatively common and they exist in pure states. In contrast, the characteristics of anemias that may occur when there are deficiencies of micronutrients, such as some of the other vitamins, are poorly defined. Many of these deficiencies are relatively rare in humans, and when they exist it is not as isolated deficiencies of one vitamin or one mineral but, rather, as a combination of deficiencies. In this context it is impossible to deduce which abnormalities are due to which deficiency. Studies in experimental animals, on the other hand, may not accurately reflect the role of a micronutrient in humans. Accordingly, our knowledge of the effect of many micronutrients on hematopoiesis is fragmentary and based on clinical observations and interpretations that may well be flawed.
Chronic deprivation of vitamin A results in anemia similar to that observed in iron deficiency.1,2,3 and 4 Mean corpuscular volume (MCV) and mean corpuscular hemoglobin concentration (MCHC) are reduced. Anisocytosis and poikilocytosis may be present, and serum iron levels are low. Unlike iron-deficiency anemia but similar to the anemia of chronic disease, the iron stores in the liver and marrow are increased, the serum transferrin concentration is usually normal or decreased, and the administration of medicinal iron does not correct the anemia. However, it has been suggested that vitamin A may facilitate iron absorption.5,6
Nutritional surveys conducted in developing countries have demonstrated a strong relationship between serum levels of vitamin A and blood hemoglobin concentration.7 Subjects with serum vitamin A concentrations in the range of 20 to 30 µg/dl had a mean hemoglobin concentration of 6 g/dl, compared with a mean hemoglobin level of 16 g/dl in subjects in whom the serum vitamin A concentration exceeded 60 µg/dl. Although vitamin A deficiency is recognized to occur in the United States, the relationship between it and anemia is not known.
Isolated nutritional deficiencies of members of the vitamin B group, with the exception of folic acid and vitamin B12, are apparently very uncommon in humans, and evidence linking isolated nutritional deficiencies of pyridoxine, riboflavin, pantothenic acid, and niacin to anemia in such patients is inconclusive. Deficiency states experimentally induced in animals are more commonly associated with hematologic abnormalities.
Vitamin B6 includes pyridoxal, pyridoxine, and pyridoxamine. These are converted to pyridoxal 5-phosphate, which acts as a coenzyme in the decarboxylation and transamination of amino acids and in the synthesis of d-aminolevulinic acid, the porphyrin precursor. Vitamin B6 deficiency induced in infants is associated with a hypochromic microcytic anemia.8 A malnourished patient with a hypochromic anemia who failed to respond to iron therapy but subsequently responded to the administration of vitamin B6 has also been described.9 Occasionally, patients receiving therapy with antituberculosis agents, such as isoniazid, which interfere with vitamin B6 metabolism, develop a microcytic anemia that can be corrected with large doses of pyridoxine.10,11 Some patients with sideroblastic anemias (see Chap. 64) respond to the administration of pyridoxine, but these patients are not deficient in this vitamin.
Riboflavin deficiency results in a decrease in red cell glutathione reductase activity, since this enzyme requires flavin adenine dinucleotide for activation. The glutathione reductase deficiency induced by riboflavin deficiency is not associated with a hemolytic anemia or increased susceptibility to oxidant-induced injury.12 Human volunteers maintained on a semisynthetic riboflavin-deficient diet and fed the riboflavin antagonist galactoflavin develop pure red cell aplasia.13 Vacuolated erythroid precursors are evident prior to the development of aplasia. This anemia is reversed specifically by the administration of riboflavin.
Pantothenic acid deficiency, when artificially induced in humans, is not associated with anemia.14
Pellagra (niacin deficiency) is associated with anemia, which responds to treatment with niacin.15 However, it is not clear whether the anemia is a direct or an indirect effect of niacin deficiency.
Although approximately 80 percent of patients with scurvy16 are anemic, attempts to induce anemia in human volunteers by severe restriction of dietary ascorbic acid have been unsuccessful.17 It seems that the anemia observed in subjects with scurvy is not due directly to a deficiency of ascorbic acid but, rather, due to bleeding or a deficiency of folic acid.16 Human subjects with scurvy and megaloblastoid anemia fail to respond hematologically to vitamin C as long as they are kept on a folic acid–deficient diet. When folic acid is given to these subjects in a dose of 50 µg/day, a prompt hematologic response is observed.18
Ascorbic acid is required for the maintenance of folic acid reductase in its reduced, or active, form. Impaired folic acid reductase activity results in an inability to form tetrahydrofolic acid, the metabolically active form of folic acid. Patients with scurvy and megaloblastoid anemia excrete 10-formylfolic acid as the major urinary folate metabolite. Following ascorbic acid therapy, 5-methyltetrahydrofolic acid becomes the major urinary folate metabolite. This observation has led to the suggestion19 that ascorbic acid serves to prevent the irreversible oxidation of methyltetrahydrofolic acid to formylfolic acid. Failure to synthesize tetrahydrofolic acid or protect it from oxidation ultimately results in the appearance of a megaloblastic anemia. Under these circumstances, ascorbic acid therapy will produce a hematologic response only if enough folic acid is present to interact with the ascorbic acid.20 Dietary iron deficiency in children often occurs in association with dietary ascorbic acid deficiency. Scurvy itself may cause iron deficiency as a consequence of external bleeding. Iron balance may be further compromised by the ascorbic acid deficiency because this vitamin serves to facilitate intestinal iron absorption. Patients with scurvy, particularly children, may require both iron and vitamin C to correct a hypochromic microcytic anemia.21
In patients with iron overload from repeated blood transfusions, the level of vitamin C in leukocytes is often decreased because of rapid conversion of ascorbate to oxalate.22 Deferoxamine (desferrioxamine)-induced iron excretion is diminished when stores of vitamin C are reduced, but excretion returns to expected values with vitamin C supplementation.23,24 It has been suggested, however, that large doses of ascorbic acid may be harmful in patients with iron overload and should be given only after an infusion of desferal has been initiated (Chap. 43). The presence of scurvy in patients with iron overload may protect them from tissue damage.25 Both in scorbutic guinea pigs and in Bantu subjects with nutritional vitamin C deficiency and dietary hemosiderosis, iron accumulates in the monocyte-macrophage system rather than in the parenchymal cells of the liver.26,27
Vitamin E, a-tocopherol, is a fat-soluble vitamin that appears to serve as an antioxidant in humans and not as an essential cofactor in any recognized reactions. Nutritional deficiency of vitamin E in humans is extremely uncommon because of the widespread occurrence of a-tocopherol in food. The daily requirement for adults is in the range of 5 to 7 mg of d-a-tocopherol, but the requirement varies with the polyunsaturated fatty acid content of the diet and the content of peroxidizable lipids in tissues. Hematologic manifestations of vitamin E deficiency in humans are virtually limited to the neonatal period and to pathologic states associated with chronic fat malabsorption. Low-birth-weight infants are born with low serum and tissue concentrations of vitamin E. When these infants are fed a diet unusually rich in polyunsaturated fatty acids and inadequate in vitamin E, a hemolytic anemia will develop by 4 to 6 weeks of age, particularly if iron is also present in the diet.28 The anemia is often associated with morphologic alterations of the erythrocytes,29 thrombocytosis, and edema of the dorsum of the feet and the pretibial area.30 Treatment with vitamin E produces a prompt increase in hemoglobin level, a decrease in the elevated reticulocyte count, a normalization of the red cell life span, and a disappearance of the thrombocytosis and edema. Modifications of infant formulas have all but eliminated vitamin E deficiency in preterm infants.31
Vitamin E deficiency is common in patients with cystic fibrosis if they are not receiving daily supplements of the water-soluble form of the vitamin. Red cell life span is shortened in such patients to an average 51Cr half-life of 19 days. After vitamin E therapy, the red cell half-life increases to 27.5 days.32 Severe anemia may be present.33
Pharmacologic doses of vitamin E have been employed with apparent success in the absence of vitamin deficiency to compensate for genetic defects that limit the erythrocytes’ defense against oxidant injury. Chronic administration of 400 to 800 units of vitamin E per day lengthened the red cell life span in some34,35 and 36 but not all37 studies of patients with hereditary hemolytic anemias associated with glutathione synthetase deficiency or glucose-6-phosphate dehydrogenase deficiency.
The administration of 450 units of vitamin E per day for 6 to 36 weeks to patients with sickle cell anemia has been found to produce a significant reduction in the number of irreversibly sickled erythrocytes.38 Adult patients with sickle cell anemia have been reported to have significantly lower serum tocopherol values than do normal control subjects,39 and in children with sickle cell anemia, those with vitamin E deficiency were found to have significantly more irreversibly sickled cells than did children without vitamin E deficiency.40
Copper is present in a number of metalloproteins. Among the cuproenzymes are cytochrome c oxidase, dopamine [beta]-hydroxylase, urate oxidase, tyrosine and lysyl oxidase, ascorbic acid oxidase, and superoxide dismutase (erythrocuprein). More than 90 percent of the copper in the blood is carried bound to ceruloplasmin, an a2-globulin with ferro-oxidase activity. Copper appears to be required for the absorption and utilization of iron. Copper, in the form of hephaestin,41 converts and maintains iron in the Fe3+ state for its transport by transferrin.
Copper deficiency has been described in malnourished children42 and in both infants and adults43,44 and 45 receiving parenteral alimentation. It is characterized by a microcytic anemia that is unresponsive to iron therapy, hypoferremia, neutropenia, and usually the presence of vacuolated erythroid precursors in the marrow.44,45 In infants and young children with copper deficiency, radiologic abnormalities are generally present. These abnormalities include osteoporosis, flaring of the anterior ribs with spontaneous rib fractures, cupping and flaring of long-bone metaphyses with spur formation and submetaphyseal fractures, and epiphyseal separation. These changes have frequently been misinterpreted as signs of scurvy. Copper deficiency with a resultant microcytic anemia can be produced by chronic ingestion of massive quantities of zinc. Dietary zinc in large doses leads to copper deficiency by impairing copper absorption.46,47,48,49 and 50
The diagnosis of copper deficiency can be established by the demonstration of a low serum ceruloplasmin or serum copper level, but the copper level is thought to be more reliable because ceruloplasmin behaves as an acute-phase protein.44 Adequate normal values for the first 2 to 3 months have not been well defined and are normally lower than those observed later in life. Despite these limitations, a serum copper level less than 40 µg/dl or a ceruloplasmin value less than 15 mg/dl after 1 or 2 months of age can be regarded as evidence of copper deficiency. In later infancy, childhood, and adulthood, serum copper values should normally exceed 70 µg/dl. Low serum copper values may be observed in hypoproteinemic states such as exudative enteropathies and nephrosis as well as in Wilson disease. In these circumstances a diagnosis of copper deficiency cannot be established by serum measurements alone but requires an analysis of liver copper content or clinical response after a therapeutic trial of copper supplementation.
The anemia and neutropenia are quickly corrected by the administration of copper. Treatment of copper-deficient infants consist of giving about 2.5 mg of copper (»80 µg/kg/day) oral supplementation as a copper sulfate solution.51 Intravenous bolus injection of copper chloride has also been used.45
Zinc is required for a large number of zinc metalloenzymes, zinc-activated enzymes, and “zinc finger” transcription factors. Zinc deficiency occurs in a variety of pathologic states in humans, including hemolytic anemias such as thalassemia52 and sickle cell anemia.53 Zinc deficiency with or without an associated copper deficiency has been described in a patient on intensive desferrioxamine therapy54 and in patients with decreased renal reabsorption of trace minerals.55
Although human zinc deficiency may produce growth retardation, impaired wound healing, impaired taste perception, immunologic abnormalities, and acrodermatitis enteropathica, there is no evidence at present that isolated zinc deficiency produces anemia.
A deficiency of selenium occurs in patients who live in areas in which the selenium content of the soil is very low56 and has been observed in patients receiving total parenteral nutrition.57,58 Although this results in a striking decrease in the level of red cell glutathione peroxidase, there do not appear to be any adverse hematologic consequences.
Studies conducted during World War II among prisoners of war and conscientious objectors demonstrated that semistarvation for 24 weeks can result in a mild to moderate normocytic normochromic anemia.59 Marrow cellularity is usually reduced and is accompanied by a decrease in the erythroid/myeloid ratio. Measurements of red cell volume and plasma volume suggest that dilution is a major factor responsible for the reduction in hemoglobin concentration.
In persons subjected to complete starvation either for experimental purposes or to treat severe obesity, anemia was not observed during the first 2 to 9 weeks of fasting.60 Starvation for 9 to 17 weeks produced a fall in hemoglobin and marrow hypocellularity.61 Resumption of a normal diet was accompanied by a reticulocytosis and disappearance of anemia. It has been suggested that the anemia of starvation is a response to a hypometabolic state, with its attendant decrease in oxygen requirements.62
Even strict vegetarians do not seem to develop hematologic problems related to the absence of animal proteins,63 except for some vegans who have been reported to suffer from B12 deficiency.64
In infants and children with protein-calorie malnutrition, the hemoglobin concentration may fall to 8 g/dl of blood,65,66 but some children with kwashiorkor have normal hemoglobin levels, probably because of a decreased plasma volume. The anemia is normocytic and normochromic, but there is considerable variation in the size and shape of red cells on the blood film. The white blood cells and the platelets are usually normal. The marrow is most often normally cellular or slightly hypocellular, with a reduced erythroid/myeloid ratio. Erythroblastopenia, reticulocytopenia, and a marrow containing a few giant pronormoblasts may be found, particularly if these children have an infection. With treatment of the infection, erythroid precursors may appear in the marrow and the reticulocyte count may rise. When nutrition is improved by giving high-protein diets (powdered milk or essential amino acids), there is reticulocytosis, a slight fall in hematocrit due to hemodilution, and then a rise in hemoglobin level, hematocrit, and red blood cell count. Improvement is very slow, however, and during the third or fourth week, when these children are clinically improved and the serum proteins are approaching normal, another episode of erythroid marrow aplasia may develop. This relapse is not associated with infection, does not respond to antibiotics, and does not remit spontaneously. It does respond either to riboflavin or to prednisone, and unless they are treated with these agents, children who develop this complication may die suddenly. It has been suggested67 that the erythroblastic aplasia is a manifestation of riboflavin deficiency.
Although the plasma volume is reduced to a variable degree in children with kwashiorkor, the total circulating red cell volume decreases in proportion to the decrease in lean body mass as protein deprivation reduces metabolic demands. During repletion, an increase in plasma volume may occur before an increase in red cell volume, and the anemia may seem to become more severe despite reticulocytosis.
From the study of the anemia of protein deficiency in rats,68 it was deduced that oxygen consumption and therefore erythropoietin production are reduced. Other studies confirmed this observation but related the reduction to calorie deprivation, with its associated decrease in the blood levels of T3 and T4.62 As a result, erythropoiesis decreases and the reticulocyte count falls. The plasma iron turnover and red cell uptake of radioactive iron are markedly reduced, and the red cell volume gradually declines.68 Protein deficiency also produces a maturation block at the erythroblast level and a slight decrease in the erythropoietin-sensitive progenitor cell pool.69 If exogenous erythropoietin is provided, normal erythropoiesis is restored despite protein depletion,70 an observation that explains the successful use of starved rats in the bioassay for erythropoietin.
Chronic alcohol ingestion is often associated with anemia. The anemia may be due to nutritional deficiencies, chronic gastrointestinal bleeding, hepatic dysfunction, or direct toxic effects of alcohol on erythropoiesis. Quite commonly all these factors work in concert to produce the anemia. Pyridoxal phosphate and folate deficiencies are common71 in alcoholics. Alcohol affects not only the red cells, as described here, but also the platelets (see Chap. 119).72,73
Macrocytosis is common in chronic alcoholics74 and is often associated with a megaloblastic anemia. Among hospitalized malnourished alcoholics, it is the most common type of anemia, occurring alone or in combination with ringed sideroblasts in approximately 40 percent of all patients.75,76 In contrast, megaloblastic anemia is rarely observed in nonhospitalized chronic alcoholics or relatively well-nourished subjects admitted to the hospital for purposes of alcohol withdrawal.77 Anemia, when associated with megaloblastic marrow changes in alcoholics, is almost always due to folate deficiency. Iron deficiency is often associated with folate deficiency in alcoholics.77 In patients with both nutritional deficiencies, the blood film will be “dimorphic,” with macrocytes, hypersegmented neutrophils, and hypochromic microcytes. Although liver disease is frequently present in alcoholics with megaloblastic anemia, it is not responsible for the folate deficiency. Megaloblastic anemia occurs almost exclusively in alcoholics who have been eating poorly. It is seen more commonly in heavy drinkers of wine and whiskey, substances that contain little or no folate, than in drinkers of beer, a rich source of the vitamin. Although decreased dietary folate intake appears to be a necessary factor in the etiology of the megaloblastic anemia, ethanol itself interferes with folate metabolism (see Chap. 38).78,79
However, macrocytosis does not always indicate the presence of a megaloblastic anemia,74 reticulocytosis secondary to hemolysis or bleeding, or liver disease. A so-called macrocytosis of alcoholism80 is found in as many as 82 to 96 percent of alcoholics. In these patients the macrocytosis is usually mild, with a MCV in the range of 100 to 110 fl, and anemia is usually absent. In the blood film, the macrocytes are typically round rather than oval, and neutrophil hypersegmentation is not present. The macrocytosis persists until the patient abstains from alcohol. Even then, the MCV does not become completely normal for periods of 2 to 4 months.79
Alcohol ingestion for 5 to 7 days will produce vacuolization of early red cell precursors, and the formation of vacuoles can be observed in in vitro marrow cell cultures.76,81 These changes disappear promptly when alcohol ingestion is discontinued. Vacuolization of a similar appearance occurs in subjects who are fed a phenylalanine-deficient diet, patients treated with chloramphenicol or pyrazinamide, patients in hyperosmolar coma, and individuals deficient in copper or riboflavin.80
A relatively rare hematologic complication of alcoholism is Zieve syndrome,82 consisting of transient hemolytic anemia, jaundice, hyperlipidemia, and alcohol-induced liver disease.
This chapter is based upon that contributed to the fifth edition by the late Frank A. Oski, M.D.

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McCurdy PR, Rath CE: Vacuolated nucleated bone marrow cells in alcoholism. Semin Hematol 17:100, 1980.

Yeung KY, Klug PP, Lessin LS: Alcohol-induced vacuolization in bone marrow cells: Ultrastructure and mechanism of formation. Blood Cells 13:487, 1988.

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Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology


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