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604 Part VI: The Erythrocyte Chapter 41: Folate, Cobalamin, and Megaloblastic Anemias 605

spontaneously after a few days; disappearance can be hastened by folinic function. Reduced serum cobalamin levels are not a problem when
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acid or cobalamin. Fatalities resulting from N O-induced megaloblas- these drugs are used for short intervals. 387
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tosis have occurred in tetanus patients given N O for weeks. Long- Pemetrexed is an antifolate approved for use in mesothelioma. It
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term recreational use of N O has led to a neurologic disorder similar to also has been used for treatment of non–small cell lung cancer. Like
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combined system disease. 374 other antifolate agents, pemetrexed can result in a megaloblastic ane-
Acute megaloblastic anemia occurs in other clinical settings. A mia that is treated with cobalamin and folate. Coadministration of the
rapidly developing megaloblastic state with acute thrombocytopenia drug with cobalamin and folate also reduces toxicity. Trimethoprim is a
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has occurred in seriously ill patients, often in intensive care units. FH reductase inhibitor that is designed to act on microbial rather than
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Especially at risk are patients who are transfused extensively at sur- the mammalian enzyme. Still, in patients with borderline folate status,
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gery, those on dialysis or total parenteral nutrition, and those receiv- trimethoprim can precipitate a state of folate deficiency.
ing weak folate antagonists such as trimethoprim. Morphologic clues to
the diagnosis (e.g., hypersegmented neutrophils) often are absent from MEGALOBLASTIC ANEMIA IN CHILDHOOD
the blood film. Both red cell folate and serum cobalamin levels may be Megaloblastic anemia in childhood is usually the result of genetic dis-
normal, but the marrow is always megaloblastic. A rapid response to orders affecting either the cobalamin binding proteins or the enzymes
therapeutic doses of parenteral folate (5 mg/day) and cobalamin (1 mg) concerned with intracellular trafficking of cobalamin or its conversion
is the rule. to coenzymatically active forms. Several recent reviews have dealt com-
prehensively with this topic. 321,388,389
MEGALOBLASTIC ANEMIA CAUSED BY DRUGS Defects Involving Cobalamin-Binding Proteins
Table 41–5 lists the drugs that cause megaloblastic anemia. Aminopterin Several genetic mutations and polymorphisms exist that affect the key
and methotrexate are almost structurally identical to folic acid. After binding proteins for cobalamin. Their effects range from being clinically
they enter cells via the folate carrier and acquire a polyglutamate benign to causing severe cobalamin deficiency with megaloblastic ane-
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chain, they act as very powerful inhibitors of FH reductase. By mia and neurologic complications usually manifesting in infancy or early
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blocking the FH →FH reaction and perhaps inhibiting other enzymes childhood, occasionally in adolescence or early adulthood. In general,
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of folate metabolism, they effect the rapid withdrawal of folates from the mutations and deletions affecting the encoded proteins cause serious
the one-carbon fragment carrier pool, causing a fall in nucleotide (espe- health consequences whereas the polymorphic variants may be totally
cially thymidine) biosynthesis that leads to a major derangement in inconspicuous or result only in a modified likelihood of disease risk.
DNA replication (Chaps. 10 and 22). 380 Cobalamin malabsorption occurs in four childhood conditions
Toxic effects include necrotic mouth lesions; ulcerations of the associated with a genetic component: (1) cobalamin malabsorption in
esophagus, small intestine, and colon, with abdominal pain, vomiting, the presence of normal intrinsic factor secretion, (2) congenital abnor-
and diarrhea; megaloblastic anemia; alopecia; and hyperpigmentation. mality of intrinsic factor, (3) TC deficiency, and (4) true PA of child-
The drug is excreted by the kidney, so effects and toxicity are prolonged hood. The management of cobalamin deficiency in childhood has been
and enhanced if renal function is impaired. Toxicity caused by these comprehensively reviewed. 389
folate antagonists is treated with folinic acid (N -formyl FH ). Folic acid Selective Malabsorption of Cobalamin, Autosomal Recessive
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itself is useless in this setting because the blocked reductase cannot con- Megaloblastic Anemia, Imerslund-Gräsbeck Disease Imerslund-
vert folate to the active tetrahydro form. Folinic acid is already in the Gräsbeck disease is an inherited failure of transport of the intrinsic
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tetrahydro form, so folinic acid is effective despite reductase blockade. factor–Cbl complex by the ileum, usually accompanied by proteinuria,
The usual dose of folinic acid is 3 to 6 mg/day IM. Larger doses are mostly of albumin. It may be the most common cause of cobalamin
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given in chemotherapy protocols that use folinic acid to rescue patients deficiency in infancy in some populations. Cobalamin deficiency usu-
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deliberately treated with otherwise fatal doses of methotrexate. Folinic ally is seen before age 2 years, but may appear earlier or later. Cobalamin
acid was used intrathecally in a patient in whom a large overdose of malabsorption is not corrected by addition of intrinsic factor. Endoge-
methotrexate was accidentally delivered into the subarachnoid space. 381 nous intrinsic factor and HCl secretion, TC and HC levels, and gastric and
Zidovudine (azidothymidine [AZT]) is used for HIV infections intestinal histology are all normal. Intrinsic factor antibodies are absent.
(AIDS; Chap. 81). Its principal toxic effect is severe megaloblastic Intrinsic factor–Cbl receptors are present in some but not all patients. The
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anemia. Anemia or neutropenia produced by zidovudine limits use of molecular defect responsible for this disease has been elucidated. For the
this drug. 383 ileal phase of cobalamin absorption, two genes code distinct proteins that
HIV infection itself suppresses hematopoiesis, leading to pancy- form part of the cobalamin–IF receptor (cobalamin-intrinsic factor recep-
topenia with myelodysplastic features (Chaps. 81 and 87). The blood tor) complex. The first, which codes for the protein CUBN, is affected by
film shows vacuolated monocytes. Megaloblastosis in HIV infection several mutations described in Finnish patients with MGA1. 95,392 The sec-
may result from folate or cobalamin deficiency or AZT or trimeth- ond, affecting the protein AMN results in a milder MGA1 phenotype and
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oprim toxicity. is found in Norwegian patients. 95,393 Again, several mutations in the gene
Hydroxyurea is used at high doses to treat chronic myelogenous coding for the AMN protein have been described. Patients are treated
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leukemia, polycythemia vera, and essential thrombocythemia, and at with IM cobalamin. The anemia is corrected, but proteinuria persists.
lower doses to treat psoriasis, rheumatoid arthritis, and sickle cell dis- Congenital Intrinsic Factor Deficiency Congenital intrinsic fac-
ease (Chap. 22). It inhibits conversion of ribonucleotides to deoxyribo- tor deficiency is an autosomal recessive disease in which parietal cells
nucleotides. Marked megaloblastic changes are routinely found in the fail to produce functionally normal intrinsic factor. Patients pres-
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marrow 1 to 2 days after initiating hydroxyurea therapy. These changes ent with irritability and megaloblastic anemia when cobalamin stores
are rapidly reversed after the drug is withdrawn. Megaloblastosis as a (<25 mcg at birth) are exhausted. The disease usually presents at age
result of N O is discussed in “Acute Megaloblastic Anemia” above. 6 to 24 months. HCl secretion and gastric histology are normal, pro-
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Long-term use of omeprazole and presumably other H /K -AT- teinuria is not present, and antiintrinsic factor antibodies are absent.
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Pase inhibitors is associated with reduced serum cobalamin levels, Abnormal cobalamin absorption is corrected by oral intrinsic factor.
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presumably because of the ability of these drugs to inhibit parietal cell Treatment consists of standard doses of IM cobalamin.
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