Caballero B. (ed.) Encyclopaedia of Food Science, Food Technology and Nutrition. Ten-Volume Set

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suppresses the incorporation of subsequently added

radiolabeled thymidine to DNA due to conversion of

the added deoxyuridine to thymidylate within the

cell. In cells from deficient patients, suppression by

deoxyuridine is less efficient due to blockage of this

conversion. Folate and cobalamin deficiencies can be

distinguished by this test through its correction with

the respective vitamins.

0026 Determination of serum holohaptocorrin (cobala-

min-carrying haptocorrin), the cobalamin storage

glycoprotein, can be used to assess cobalamin body

stores. Measurement of holotranscobalamin II, the

cobalamin transport protein to tissues, may also be

used, because it falls below the normal range before

serum cobalamin does. The increase of urinary and

serum methylmalonic acid concentrations indicates

cobalamin deficiency, because of the impairment

in the methylmalonyl-CoA mutase reaction, which

requires adenosylcobalamin as a cofactor.

0027 The Schilling test is used to detect cobalamin

malabsorption. This test is performed usually in two

stages: (1) an oral dose of radiolabeled cobalamin is

given and its percentage of excretion in urine during a

24-h collection is determined, after flushing it into

urine with a large parenteral dose of unlabeled coba-

lamin; (2) another test is performed 3–7 days later,

with an oral dosing of radiolabeled cobalamin and

intrinsic factor. There are several interpretations of

the Schilling test regarding the causes of malabsorp-

tion in cobalamin-deficient patients, depending on

the results in each of the two stages. For instance,

when the result is abnormal in the first stage, but

normal in the second, pernicious anemia, or any

other cause of absence, abnormal or insufficient

amount of intrinsic factor, is present. A normal Schil-

ling test in these patients may indicate dietary defi-

ciency or protein-bound cobalamin malabsorption.

Pernicious anemia can also be diagnosed by

the presence of parietal cell autoantibodies and of

antiintrinsic factor autoantibodies in serum.

0028 The biochemical tests described above can all be

useful to detect folate and cobalamin deficiencies at

earlier stages, the so-called subclinical or marginal

deficiencies, well before the manifestation of the clin-

ical and overt signs of deficiency. The recognition of

the atypical and subclinical deficiency states is an

important step towards preventing not only the pro-

gression of deficiency to the clinical manifestations,

but also to avoid the consequences that even marginal

deficiencies of both vitamins can cause.

0029 Folate subclinical deficiency has been associated

with increased risk for dysplasia and various cancers,

such as in the uterine cervix, bronchus, and colon,

due to uracil misincorporation into DNA, impaired

chromosome repair, and DNA strand breaks. Other

adverse associations are immunological changes;

birth defects, such as the NTD; and abnormalities of

the homocysteine metabolism, leading to hyperhomo-

cysteinemia. This last condition is an independent

risk factor for cerebral, coronary, and peripheral

vascular diseases, and occurs in both folate and

cobalamin subclinical deficiencies. (See Cobalamins:

Physiology; Folic Acid: Physiology.)

Prevalence

0030Recent and comprehensive worldwide epidemi-

ological data on megaloblastic anemia and on sub-

clinical folate and cobalamin deficiencies, especially

in tropical and developing countries, the ones most

likely to be affected by these problems, are scarcely

available. Most data concerning the prevalence and

distribution of these deficiencies were obtained more

than two decades ago.

0031Those earlier studies showed that nutritional folate

deficiency had a worldwide distribution, differing

greatly in severity, with the subclinical, nonanemic

forms being predominant, and was, in general, a

primary cause of megaloblastic anemia. It affected

mainly pregnant women in the third trimester of

pregnancy, since their increased folate requirements

may be difficult to achieve through the habitual diet,

especially in low socioeconomic groups. Megalo-

blastic anemia due to dietary folate deficiency was

reported to be highly prevalent in Asian countries

such as India, Burma, Singapore, and Malaysia, and

in African countries, affecting up to 25% of non-

supplemented pregnancies in certain parts of Asia,

Africa, and Latin America, and 2.5–5.0% in de-

veloped countries. These values were higher (up to

60% in developing countries) when bone marrow

aspirates were used for the diagnosis. Subclinical

folate deficiency was estimated to affect up to one-

third of the pregnant women on a global scale. The

widespread use of iron and folate supplements sub-

stantially reduced the prevalence of folate deficiencies

during pregnancy. Presently, the patterns of folate

deficiency may still be the same, but scattered data

indicate a possible decline in the incidence and

prevalence of megaloblastic anemia, with a relative

increase of subclinical deficiencies. In developing

countries subclinical deficiency is high in nonsupple-

mented pregnancies. Folate deficiency, especially

subclinical, is highly prevalent in the elderly.

0032Cobalamin deficiency due to inadequate intake has

been mostly reported in strict Hindus from the Indian

subcontinent. Recent studies show that cobalamin

deficiency is more prevalent in other countries than

formerly believed, but it is mostly due to malab-

sorption. In developed countries, malabsorption of

224 ANEMIA (ANAEMIA)/Megaloblastic Anemias

cobalamin affects mainly elderly populations. In

northern Europe, cobalamin malabsorption is mainly

due to pernicious anemia, affecting 1–2.5% of

the population over the age of 60. Its frequency in

caucasians is higher in women than in men (about

1.5:1), and increases with increasing age, being rare

before 30 years of age. There is recent indication

that cobalamin malabsorption due to pernicious

anemia, and not folate deficiency, may be the main

underlying factor of megaloblastic anemia in sub-

Saharan Africa, as shown in Zimbabwe, where 86%

of patients with megaloblastic anemia had cobalamin

deficiency mainly due to pernicious anemia. In rural

Mexico, a high prevalence of low levels of cobalamin

in plasma of preschool children and in plasma and

milk of lactating anemic women has been reported

and seems to be caused by malabsorption.

Prevention and Treatment

0033 The prevention and treatment, not only of clinical

manifestations of cobalamin and folate deficiencies,

but also of the subclinical deficiencies are important

to avoid their consequences. The association of sub-

clinical deficiencies of these vitamins with adverse

conditions, as mentioned in a previous section, pro-

vides support for the case of improving the nutritional

status of both vitamins in individuals in the earlier

stages of deficiency progression.

0034 The consumption of foods rich in folate and coba-

lamin is the best prophylaxis for deficiencies of nutri-

tional origin of both vitamins. However, in conditions

of increased requirements, such as pregnancy, the

adequate intake of food folate may be difficult to

attain. Therefore, due to the overall high incidence

of folate deficiency in pregnant women, folate supple-

ments (0.4 mg day

1

) are usually recommended in the

latter half of pregnancy during prenatal care. Since

folate supplementation in the periconceptional period

results in a decreased risk of NTD-affected pregnan-

cies, in developed countries such as the USA, Canada,

UK, and Australia it is recommended that all women

of child-bearing age consume 0.4 mg day

1

of folic

acid. For women with a prior confirmed or suspected

NTD-affected pregnancy, a supplement of 4 mg of

folic acid is recommended if they might possibly

become pregnant.

0035 Possible public health strategies for supplying

women with folate in the periconceptional period

are the use of supplements by all women of child-

bearing age, changes in food habits, and food fortifi-

cation with folate. This last alternative, however, has

raised concern since a higher folate intake through

fortified foods by the general population could be

detrimental to individuals with cobalamin deficiency.

Although the elderly should benefit from increased

folic acid intake added to foods, in those with

cobalamin deficiency high intakes of folic acid

could contribute to the development of neurologic

abnormalities.

0036In the case of strict vegetarians, supplements or

fortified foods providing cobalamin should be used.

Folate supplements may also be recommended for

people with sickle-cell anemia.

0037Megaloblastic anemia due to folate deficiency is

usually treated with oral syntethic folic acid (5 mg

day

1

) for 2 months, or more depending on the

etiology. In the case of malabsorption, parenteral

folinic acid (5–10 mg) administered daily may also

be used.

0038Treatment of megaloblastic anemia due to cobala-

min deficiency resulting from low intake may be

carried out with oral administration of cyanocobal-

amin or intramuscular injections of 1 mg day

1

for

1 week, followed by the use of oral supplements or

fortified foods containing 2 mg cyanocobalamin if the

diet cannot be improved. When megaloblastic anemia

is due to malabsorption, intramuscular injections of

1 mg hydroxocobalamin are given daily for 1 month,

followed by monthly or bimonthly injections for life

in the case of pernicious anemia. In the cases where

the causes of cobalamin deficiencies are abnormal

transport and utilization, daily doses of 1 or 5 mg

are administered indefinitely. For patients with

neurological manifestations due to cobalamin defi-

ciency, 1 mg of cyanocobalamin every 2 weeks for

6 months is recommended. In the case of cobalamin

deficiency, folic acid supplementation may correct

megaloblastic hematologic changes, but allows the

development of neurologic abnormalities, because

synthetic folic acid, unlike dietary folate, is reduced

directly to tetrahydrofolate and not through the

methionine synthase reaction.

0039In any case, treatment of the primary causes of

folate and/or cobalamin deficiencies should concomi-

tantly be pursued.

See also: Cobalamins: Physiology; Folic Acid:

Physiology; Pregnancy: Maternal Diet, Vitamins, and

Neural Tube Defects

Further Reading

Beck WS (1991) Diagnosis of megaloblastic anemia.

Annual Reviews of Medicine 42: 311–322.

Carmel R (1999) Ethnic and racial factors in cobalamin

metabolism. Seminars in Hematology 36: 88–100.

Chanarin I (1990) The Megaloblastic Anaemias, 3rd edn.

Oxford: Blackwell Scientific Publications.

ANEMIA (ANAEMIA)/Megaloblastic Anemias 225

Lindebaum J and Allen RH (1995) Clinical spectrum and

diagnosis of folate deficiency. In: Bailey L (ed.) Folate

in Health and Disease, pp. 43–74. New York: Marcel

Dekker.

Scott JM (1999) Folate and vitamin B

. Proceedings of the

Nutrition Society 58: 441–448.

Snow CF (1999) Laboratory diagnosis of vitamin B

and

folate deficiency. Archives of Internal Medicine 159:

1289–1298.

Trugo NMF (1999) Nutritional macrocytic (megaloblastic)

anemia. In: Strickland TG (ed.) Hunter’s Tropical

Medicine and Emerging Infectious Diseases, 8th edn.

Philadelphia: W.B. Saunders.

Wickramasinghe SN (1999) The wide spectrum and

unresolved issues of megaloblastic anemia. Seminars

in Hematology 36: 3–18.

Wintrobe MN, Lukens JN and Lee CR (1993) The

approach to the patient with anemia. In: Lee GR, Bithel

TC, Foerster J, Athens JW and Lukens JN (eds) Wint-

robe’s Clinical Hematology, 9th edn, vol. 1, pp. 715–

790. Philadelphia: Lea & Febiger.

Zittoun J and Zittoun R (1999) Modern clinical strategies

in cobalamin and folate deficiency. Seminars in

Hematology 36: 35–46.

Other Nutritional Causes

F G Huffman, Florida International University, Miami,

FL, USA

S Nath and Z C Shah, Florida International University,

University Park, Miami, FL, USA

Background

0001 Anemia is a condition where there is a reduction in

the hemoglobin content, size, and/or number of

erythrocytes. Nutritional anemias may result from

various vitamin and mineral, as well as some macro-

nutrient deficiencies, but the most common are mega-

loblastic anemia, resulting from folic acid or vitamin

deficiency, and microcytic, hypochromic anemia,

resulting from iron (Fe) deficiency. The fat-soluble

vitamins A and E, and water-soluble vitamins B

(riboflavin), B

(pyridoxine), and C (ascorbic acid)

have also been implicated as causes of anemia in

humans. In addition, deficiencies of the micro-

minerals copper (Cu) and zinc (Zn), essential to

erythropoiesis, can cause anemia. Protein–energy

malnutrition (PEM), a multifaceted nutritional con-

dition, is also associated with anemia, but this is often

not classified as a true nutritional anemia, since the

role of PEM is physiologic rather than pathologic.

Essential fatty acid deficiency may also play a role in

the development of anemia. These nutritional associ-

ations with anemia are summarized in Table 1.

0002The two criteria for defining a nutritional anemia

are that: (1) deficiency or lack of a specific nutrient

must cause the anemia, and (2) replacement of that

specific nutrient must correct the anemia. Anemias

resulting from the aforementioned deficiencies of

vitamins and minerals may not directly conform to

these two criteria, because isolated deficiencies are

rare, and an anemia may not be directly related to a

single nutrient deficiency, but most often is compli-

cated by other nutrient deficiencies.

Fat-soluble Vitamins

Vitamin A

0003Vitamin A deficiency, or hypovitaminosis A, is a

prevalent nutritional problem in both developing

and developed countries, especially among children.

The biological interactions between vitamin A defi-

ciency, iron metabolism, hematopoiesis, and the

development of anemia are clearly established. How-

ever, polycythemia, as well as altered water balance

leading to dehydration may mask anemia resulting

from vitamin A deficiency.

0004Morphological changes, such as poikilocytosis

and anisocytosis in erythrocytes in peripheral

blood, may result from vitamin A deficiency. Sub-

jects with vitamin A deficiency often develop micro-

cytic, hypochromic anemia with elevated storage of

Fe in the liver and other reticuloendothelial systems.

The later finding suggests that the role of vitamin A

in erythropoiesis of mobilizing or releasing Fe form

the liver and adequate Fe in diet are not sufficient to

correct or prevent anemia. Vitamin A deficiency may

also decrease transferrin with subsequent reduction

in Fe transport. Experimental studies have demon-

strated this in subjects with vitamin A deficiency

who respond well to vitamin A supplementation,

but are refractory to Fe administered to correct

anemia. Results from randomized clinical trials

document that vitamin A supplementation alone or

in combination with Fe supplementation improves

anemia. Vitamin A supplementation alone yields a

significant increase in serum retinal and Fe, blood

hemoglobin (Hb), hematocrit (Hct), and erythrocyte,

and transferrin saturation without affecting the total

iron-binding capacity and serum ferritin. However,

in contrast to Fe-deficiency anemia, serum ferritin

levels remain normal, and vitamin A supplementa-

tion does not alter the absorption of Fe in the

intestines. This implies that vitamin A does not

inhibit the absorption of Fe, and that a high liver

226 ANEMIA (ANAEMIA)/Other Nutritional Causes

concentration of Fe is not the result of hemolysis

secondary to the increased erythrocyte fragility asso-

ciated with vitamin A deficiency. Rather, experts in

this field of research speculate that vitamin A may

improve the metabolic utilization of Fe.

0005 Several mechanisms of vitamin A action have been

proposed in erythropoiesis, including mobilization

of Fe from the tissue stores (reticuloendothelial

system) through increased receptor synthesis; an in-

fluence on the proliferation or differentiation of red

blood cells; and facilitation of Fe absorption by

forming a complex with nonheme Fe. It has also

been noted that vitamin A deficiency increases one’s

susceptibility to infection, leading to diminished ery-

thropoiesis.

0006 Vitamin A deficiency may also impair the utiliza-

tion of other nutrients crucial for erythropoiesis. The

relationship between vitamin A and Zn has been

documented in view of the role of vitamin A in the

synthesis of Zn-dependent retinal-binding protein

(RBP), and absorption and transport of Zn. In some

instances, the association between RBP and hemo-

globin synthesis is explained in children and pregnant

women.

Vitamin E

0007 Vitamin E, primarily a-tocopherol, acts as a free-

radical scavenger and natural antioxidant to protect

cell membranes against free-radical reactions or lipid

peroxidation. Normal healthy individuals who con-

sume a nutritionally adequate diet rarely develop

vitamin E deficiency, and no overt deficiency symp-

toms have been described. Table 2 describes some

circumstances that may result in a low vitamin E

level in humans.

0008 In animals, vitamin E deficiency-associated anemia

was induced experimentally, with Dinning and Day in

1957 first describing vitamin E deficiency anemia in

rhesus monkeys. The monkeys developed a very low

reticulocyte count that was reversed by vitamin E

supplementation, with subsequent correction of the

anemia. Subsequent prolonged vitamin E deficiency

studies in similar animals revealed normochromic

and normocytic (occasional macrocytic) anemia in

peripheral blood, but bone marrow examination

showed hyperplasia of erythroid cells and the pres-

ence of nuclear chromatin abnormalities with multi-

nucleated forms. A high rate of red blood cell

hemolysis has also been reported. It was presumed

that all these changes were the result of an abnormal

erythropoiesis, but ineffective erythropoiesis was

eliminated as the primary cause of anemia, since the

stability of reduced glutathione, osmotic fragility, and

serum iron were normal.

tbl0001 Table 1 Selective nutrients and characteristic features of anemias resulting from deficiencies

Nutrient deficiency Peripheralblood Bone marrow

Vitamin A Microcytic Not known

Vitamin E ‘Distorted and fragmented’ RBCs, anisocytosis,

poikilocytosis, polychromatophilia,

spherocytosis, Heinz bodies

Erythroid hyperplasia

Vitamin B

Normocytic, normochromic, sideroblastic Erythrocytic hopoplasia, increased myeloid

erythroid ratio, pronormoblast

Vitamin B

Hypochromic, microcytic, sideroblastic Erythroid hyperplasia, basophilic normoblast

Vitamin C Normocytic normochromic Not known

Copper Normocytic, microcytic or macrocytic Cytoplasmic vacuoles in myeloid and erythroid

precursors, ringed sideroblast

Zinc Microcytic, normochromic or macrocytic Ringed sideroblast, cytoplasmic vacuolization in

both myeloid and erythroid precursors

Protein Normochromic, normocytic, variations in size

and shape

Normo- or hypocellular, reduced erythroid/myeloid

ratio

Essential fatty acid Aplastic Not known

tbl0002Table 2 Causes of vitamin E deficiency

Congenital i. Cystic fibrosis

ii. Inherited hemolytic anemia

iii. Biliary cirrhosis

iv. Abetalipoproteinemia

Acquired i. Liver disease

ii. Gallbladder disease

iii. Pancreatitis

iv. Sprue

v. Inflammatory bowel disease

vi. Extensive small bowel

resection

vii. Malabsorption

viii. Steatorrhea

Premature infants Poor absorption and metabolism

of nutrients resulting from

underdeveloped systems

Infants and children with

protein–energy

malnutrition

Poor intake, transport,

metabolism, and storage of

nutrients.

ANEMIA (ANAEMIA)/Other Nutritional Causes 227

0009 The relationship between vitamin E deficiency

and anemia in humans is less conclusive, since no

clinically and hematologically well-defined anemia

has been reported in humans. It has been theorized

that vitamin E deficiency may cause hemolytic

anemia in humans by affecting the hematopoietic

system. It is widely accepted that erythrocytes are

susceptible to membrane damage in premature

infants with vitamin E deficiency because of high

lipid peroxidation. Increased erythrocyte fragility,

when exposed to hydrogen peroxide (H

), is con-

sidered to be an index of tissue vitamin E deficiency,

as the consistent inverse relationship between serum

tocopherol concentration and degree of H

hem-

olysis has been established. For example, it has been

shown that a serum tocopherol level < 0.2 mg dl

1

correlated with a mean H

fragility of about

90%. In 1952, increased hemolysis of red blood

cells in vitamin E-deficient premature infants was

observed when the cells were exposed to H

. How-

ever, in-vivo experiments have not documented any

significant damage to red blood cells.

0010 In 1967, Oski and Barness first described vitamin E

deficiency anemia in a group of premature infants 6–10

weeks of age. Peripheral blood smears showed

‘distorted and fragmented’ erythrocyte morphology

characterized by anisocytosis, poikilocytosis, polychro-

matophilia, fragmented red cells, and a few mild spher-

ocytosis and Heinz bodies. Examination of the bone

marrow of these premature infants revealed erythroid

hyperplasia. A low serum concentration of vitamin E

(< 0.5 mg dl

1

), low hemoglobin level (7.6 + 1gdl

1

and increased sensitivity of the erythrocytes to hemoly-

sis when exposed to dilute H

solution have

also been reported. All these hematological abnormal-

ities were corrected by vitamin E supplementation.

Other researchers have also reported vitamin E defi-

ciency anemia among premature infants (body weight

< 1500 g) with moderately high reticulocyte counts that

responded to vitamin E therapy, suggesting an anemia

that is hemolytic in nature.

0011 It has been reported that plasma levels of vitamin E

are similar in both premature and mature infants, and

a linear relationship has been described between body

tocopherol content and body weight during gestation.

Some studies have found shortened red blood cell

survival in vitamin E deficient premature infants and

adults, suggesting the presence of hemolytic anemia.

Several other studies have observed that, although

premature infants and adults with vitamin E-deficient

diets did not develop anemia, they experienced

decreased plasma tocopherol levels and increased

erythrocyte susceptibility to H

0012 Convincing results from studies involving patients

with sickle-cell anemia (SCA) also support the

association between vitamin E deficiency and anemia.

One of the clinical manifestations of SCA is chronic

hemolytic anemia. Among sickle-cell patients who

usually experience impaired vitamin E absorption,

increased susceptibility of sickle erythrocytes to per-

oxidation has been demonstrated, partly due to

abnormal membrane phospholipid organization and

low serum and erythrocyte vitamin E deficiencies. It

has been documented that preincubation of sickle

erythrocytes with vitamin E may significantly reduce

susceptibility to oxidation.

0013It is also plausible that vitamin E plays a role

in erythropoiesis. The potential role of vitamin E

in erythropoiesis has been highlighted in studies

conducted in Uganda, Jordan, and Thailand on

protein–energy-malnourished subjects who developed

anemia and responded to vitamin E supplementa-

tion. In contrast, subjects in India and West Africa

with similar deficiencies did not respond to vitamin E

supplementation. Chronic vitamin E deficiency is

found among patients with cystic fibrosis, biliary

atresia, biliary cirrhosis, sprue, pancreatitis, extensive

small bowel resection, inflammatory bowel disease,

and other malabsorption syndromes without any

evidence of related anemia or ineffective erythro-

poiesis.

0014In summary, based on currently available informa-

tion, there are several plausible mechanisms for

hemolytic anemia resulting from vitamin E deficiency,

such as increased oxidation of erythrocyte cell mem-

branes with increased erythrocyte susceptibility to

fragility. There is also the promotion of free radical

generation by iron and hemoglobin in vitamin E defi-

ciency, with free radicals acting as potent catalysts for

erythrocyte lipid peroxidation.

Water-soluble Vitamins

Vitamin B

0015The two biologically active coenzyme forms of vita-

min B

(riboflavin) are flavin mononucleotide and

flavin adenine dinucleotide. The latter is required

for red blood cell glutathione reductase activity, and

so a deficiency of riboflavin may lead to anemia.

Anemia secondary to riboflavin deficiency was ini-

tially observed among animals as hypoplastic anemia

with fatty infiltration of the bone marrow and nor-

mocytic hypochromic anemia in riboflavin-deficient

dogs and calves, respectively. In humans, anemia

resulting from riboflavin deficiency has only been

reported among patients receiving medications such

as galactoflavin, ouabain, theophylline, penicillin,

probenecid, and chlorpromazine, which decrease the

absorption or metabolism of riboflavin. This anemia

228 ANEMIA (ANAEMIA)/Other Nutritional Causes

is characterized in peripheral blood smears by red

blood cell morphology described as normocytic and

normochromic. However, in the bone marrow, there

is marked erythrocytic hypoplasia with increased

myeloid erythroid ratio, pronormoblasts with cyto-

plasmic and nuclear vacuoles, and a marked decrease

in normoblasts. Reticulocytopenia is also noted.

Riboflavin supplementation results in a prompt de-

crease in the myeloid erythroid ratio and the disap-

pearance of anemia.

0016 New research has identified two paths by

which flavoproteins may be linked to sideroblastic

anemia. Flavin monooxygenase is an intracellular

ferrireductase involved in the reduction of iron (ferric

to ferrous) so that it can be incorporated into heme by

ferrochetalase. Decreased flavin monooxygenase can

result in accumulation of ferric iron in the mitochon-

dria of erythroid cells, the production of ringed side-

roblasts, and impaired hemoglobin synthesis. This

may lead to sideroblastic anemia and erythropoietic

hemochromatosis. Another flavoprotein, pyridoxine

phosphate oxidase, is essential in the formation of

pyridoxal 5

-phosphate (PLP) from pyridoxine and

pyridoxamine phosphate. The riboflavin link to side-

roblastic anemia in this case is therefore indirectly

through its role in the activation of vitamin B

Vitamin B

0017 PLP, the most active coenzyme form of vitamin B

essential for numerous metabolic reactions, including

the initial regulatory step of heme biosynthesis

involving d-aminolevulinic acid, the precursor of

porphobilinogen (Figure 1).

0018 The typical features of anemia resulting from pyr-

idoxine deficiency have been described as hypo-

chromic, microcytic, and hyperferremic, with bone

marrow showing erythroid hyperplasia and matur-

ation arrest with predominantly basophilic normo-

blasts. Malnourished patients with hypochromic

anemia respond to vitamin B

supplementation but

are unresponsive to iron therapy. Complete recovery

from anemia with normal hemoglobin levels can be

achieved by adequate pyridoxine therapy, but not by

Fe or other vitamins or minerals.

0019 Some researchers have tried to illustrate that the

association between pyridoxine and the development

of sideroblastic anemia involves the defective conver-

sion of pyridoxine to PLP. However, there was no

evidence of low erythrocyte pyridoxine kinase

among patients with sideroblastic anemia or there

was no deficiency of vitamin B

. The relationship

between pyridoxine deficiency and sideroblastic

anemia therefore warrants further investigation.

0020Vitamin B

deficiency has also been reported

among patients with sickle cell anemia, who re-

sponded well to PLP supplementation. PLP binds

specifically to the amino terminus of the b chain of

deoxyhemoglobin, and high levels of PLP may be an

active inhibitor of erythrocyte ‘sickling’ in vitro.In

addition, PLP may increase the affinity of hemo-

globin-S to oxygen and, at high concentrations,

inhibits the gelation of deoxyhemoglobin-S and re-

duces the number of sickled erythrocytes. However,

in-vivo studies have not proven that vitamin B

sup-

plementation increases red blood cell counts or im-

proves hemoglobin status.

0021Although isolated vitamin B

deficiency is rare,

some populations such as users of some oral contra-

ceptives, amphetamines, isoniazid, chlorpromazine,

and reserpine, as well as alcoholics have developed

an anemia that can be easily corrected by therapeutic

doses of vitamin B

Vitamin C

0022Although anemia is commonly observed among

patients with the vitamin C deficiency disease scurvy,

the direct role of vitamin C or ascorbic acid in hemo-

poiesis is not well documented. Usual hematological

findings in this case are normocytic, normochromic

anemia with reticulocytosis, which can be corrected,

with an accompanying rise in hemoglobin concentra-

tion, by vitamin C supplementation.

0023Vitamin C deficiency may be involved indirectly in

the development of anemia through its relation to

folic acid and Fe metabolism. It is well established

that vitamin C increases the bioavailability of Fe in

foods and facilitates intestinal Fe absorption, particu-

larly nonheme Fe. Vitamin C also enhances the util-

ization of heme Fe and facilitates ferritin synthesis.

It has been documented that vitamin C augments

the translation of ferritin mRNA by maintaining the

Fe-responsive element-binding protein in its active

form. In addition, in-vitro experiments have shown

that vitamin C prevents degradation and enhances the

stability of ferritin. A proposed, but indirect, role of

vitamin C in erythropoiesis is that vitamin C facili-

tates the turnover of Fe in the body.

0024Vitamin C is also required for the maintenance of

folic acid reductase, which converts folic acid to its

active tetrahydrofolate form. Failure to synthesize

tetrahydrofolate leads to megaloblastic anemia.

Occasional megaloblastic cells have been observed

among scurvy patients.

Succinyl CoA

PLP

Glycine

α-Amino-β-ketoadipate δ-Aminolevulinate

fig0001 Figure 1 Role of pyridoxal phosphate in the biosynthesis of

d-aminolevulinate.

ANEMIA (ANAEMIA)/Other Nutritional Causes 229

Minerals Implicated in Anemias

Copper

0025 The essential trace element copper (Cu), is widely

distributed in commonly eaten foods, and deficiency

of this mineral is extremely rare in people who main-

tain adequate and recommended caloric intakes. The

indispensable role of Cu in humans was first docu-

mented during the 1960s among anemic children in

Peru, who were refractory to iron (Fe) but responsive

to Cu supplementation. Subsequent studies have

established that Cu is essential for red and white

blood cell maturation and Fe transport.

0026 Cu is a component of several metalloenzymes

called the cuproenzymes, with ceruloplasmin (Cp)

being the most studied. More than 90% of the

body’s Cu is found as Cp, and about 60% of the Cp

in red blood cells, is bound to superoxide dismutase.

Cu-deficiency anemia is thought to result from re-

duced Cp activity, resulting in impaired iron mobil-

ization. The other Cp-associated enzymes whose

impaired function may result in anemia include fer-

roxidase (which converts Fe

2þ

to Fe

3þ

), ferrochela-

tase and cytochrome aa

. Ferroxidase is vital in the

incorporation of Fe into circulating transferrin, so

that decreased Cp results in poor ferroxidase activity,

and Fe, being trapped in the reticuloendothelial

system, is unavailable for erythropoiesis. Decreased

ferrochelatase and cytochrome aa

activity are asso-

ciated with poor heme synthesis owing to decreased

reduction of Fe

2þ

in the mitochondria and poor in-

corporation of iron into protoporphyrin IX.

0027 Cu deficiency may be acquired easily as a result of

an imbalance between body requirements and dietary

Cu supply as well as a high zinc intake. In 1956,

Sturgeon and Brubaker first described Cu-deficiency

anemia in infants. Under normal conditions, liver

stores provide adequate amounts of Cu to comply

with the infant’s need during the first 5 months of

life. Acquired Cu deficiency in premature infants is

well documented because of a small liver size, low Cu

deposits in the liver, and increased need due to the

high growth rate. Healthy infants who are fed exclu-

sively cow’s milk are prone to Cu deficiency because

of the low Cu content and poor bioavailability of

Cu from cow’s milk. Individuals who receive total

parenteral nutrition may also develop Cu deficiency.

Table 3 presents several causes of acquired Cu defi-

ciency in humans.

0028 The most common clinical manifestations of ac-

quired Cu deficiency are anemia and pancytopenia

observed in both animals and humans. A wide range

of morphologic changes in peripheral blood smears

and bone marrow biopsies have been reported.

The red blood cells can be normo- or macrocytic,

dimorphic, and hypochromic. A low reticulocyte

count and bone marrow iron content, as well as

hypoferremia may exist. Morphological findings in

bone marrow cytology include megaloblastic changes

with two consistent findings – cytoplasmic vacuoles

in the myeloid and erythroid precursors, and the mat-

uration arrest of the myeloid precursors with the

appearance of ringed sideroblasts. However, patients

with Cu deficiency may not develop megaloblastic

changes or there may be the absence of sideroblasts

in bone marrow. These changes are easily reversed by

Cu supplementation, but refractory to Fe therapy.

0029Three mechanisms have been proposed for these

clinical/morphological manifestations, including re-

duced Cp activity leading to defective Fe mobiliza-

tion/transporation. First, even in the presence of

normal Fe stores, Fe transfer from macrophages and

hepatocytes to plasma is impaired, resulting in hypo-

ferremia. Second, Fe cannot be incorporated into

heme and accumulates in the cytoplasm, producing

sideroblasts. Third, there is shortened erythrocyte

survival as a result of membrane defects secondary

to decreased superoxide dismutase activity.

Zinc

0030The trace element zinc (Zn) functions in several bio-

chemical reactions by way of Zn metalloenzymes.

Although several pathological conditions have been

related to Zn deficiency in humans, at present, there

is no evidence that isolated Zn deficiency causes

anemia. In iron depletion, Zn protoporphyrin (ZPP)

is formed, and although it is able to bind to heme sites

tbl0003Table 3 Etiology of acquired copper deficiency in humans

Decreased storage in liver Premature infants

Decreased supply i. Total parenteral nutrition

ii. Infants fed cow’s milk only

Increased requirements High growth rate

i. Celiac disease

ii. Tropical and nontropical

sprue

iii. Cystic fibrosis

iv. Short bowel syndrome

v. Intestinal resection

Decreased absorption vi. Diarrhea

vii. Abnormal bile loss

viii. Intestinal fistula

ix. High zinc intakes

x. High iron intakes

xi. High vitamin C intakes

xii. Fructose and other refined

sugars

Interactions with drugs i. Penicillamin

ii. High alkali therapy

230 ANEMIA (ANAEMIA)/Other Nutritional Causes

on globin, the resulting molecule is nonfunctional.

However, there is evidence that the ZPP–globin com-

plex (Figure 2) accumulates in developing erythro-

cytes where it inhibits the action of heme oxygenase

(involved in heme catabolism), thereby conserving

heme.

0031 The involvement of Zn in anemia may be indirectly

through its role in Cu metabolism. Several studies

have documented that, in the absence of evidence of

hemolysis or other nutritional deficiencies, excessive

Zn intakes (> 660 mg) may induce Cu deficiency by

sequestering Cu in the enterocytes, thus limiting its

absorption and increasing fecal losses. Since Cu is

essential for mitochondrial Fe transport and heme

synthesis, Zn-induced Cu deficiency produces the

same anemia as isolated Cu deficiency.

Protein Deficiency and Protein–Energy

Malnutrition

0032 Protein is essential for optimal production of hemo-

globin and red blood cells. Animal studies have pro-

vided evidence of a causal relationship between

protein deficiency and the development of anemia.

Rats fed a protein-deficient diet show a marked re-

duction in erythropoiesis and subsequently develop

severe anemia, which can be reversed by restoring

protein to the diet. In humans, this condition is

associated with kwashiorkor. It is thought that pro-

tein deficiency causes reduced body mass and a de-

creased oxygen consumption or requirement, which

then leads to reduced erythropoeisis and a fall in red

cell mass. Protein deficiency also interferes with the

maturation of erythroblasts and decreases the ery-

thropoietin-sensitive pool. The resulting anemia

manifests as normocytic, macrocytic, megaloblastic,

hypoplastic, normochromic or hypochromic anemia,

accompanied by higher-than-normal reticulocyte

counts, and a normal to low mean corpuscular hemo-

globin concentration. Low serum total protein, albu-

min fraction, serum iron, and total iron-binding

capacity are also observed.

0033 Anemia, as a result of PEM, is poorly understood,

and the underlying mechanisms remain obscure. It is

thought that this anemia is an adaptation to a

lowered oxygen requirement in PEM. Assessing

anemia in PEM or kwashiorkor is extremely difficult

because of ethical concerns and multiple associations

such as infections and deficiencies of iron, folic acid,

vitamins B

, and E, and selenium. In PEM, there

is decreased red cell survival, whereas erythropoetin

levels are adequate or elevated, and bone marrow

iron supplies are normal. Selenium deficiency is

thought to significantly influence red cell survival

through its relationship with impaired glutathione

peroxidase activity. In addition, PEM-related anemia

presents with normocytic, normochromic RBCs, low

serum Fe, serum iron-binding capacity, serum total

protein, albumin, and Fe absorption, but increased g-

globulin. There is evidence that protein supplemen-

tation alone in PEM does not correct the related

anemia but may exacerbate it. Even when serum

vitamin E levels are normal, concurrent protein

and vitamin E supplementation appears to signifi-

cantly increase hemoglobin levels.

Essential Fatty Acid Deficiency

0034Anemia has also been associated with essential fatty

acid (EFA) deficiency. An EFA intake of < 2–4%

of total calories is reflected in red blood cells by

decreased linoleic acid levels with corresponding

increases in eicosatrienoic acid levels. This results in

altered triene/tetraene ratios (> 0.4 being considered

EFA deficiency). In the plasma fatty acid profile, lino-

leic acid is generally elongated to arachidonic acid,

but in a deficiency, linoleic (tetraene) is replaced by

oleic (triene) acid. The RBC fatty acid profile reflects

that of the plasma because RBC fatty acids are con-

tinually diacylated and reacylated with those in the

plasma. Aplastic anemia and thrombocytopenia are

the result of altered fatty acid profiles seen in EFA

deficiency.

See also: Antioxidants: Natural Antioxidants; Dietary

Reference Values; Dietary Requirements of Adults;

Fats: Requirements; Malnutrition: Malnutrition in

Developing Countries; Minerals – Dietary Importance;

Protein: Deficiency; Vitamins: Overview