eMedicine Specialties > Pediatrics: General Medicine > Hematology

Anemia, Megaloblastic

Author: James L Harper, MD, Associate Professor, Department of Pediatrics, Division of Hematology/Oncology and Bone Marrow Transplantation, Associate Chairman for Education, Department of Pediatrics, University of Nebraska Medical Center; Assistant Clinical Professor, Department of Pediatrics, Creighton University; Director, Continuing Medical Education, Children's Memorial Hospital; Pediatric Director, Nebraska Regional Hemophilia Treatment Center
Contributor Information and Disclosures

Updated: Aug 20, 2007

Introduction

Background

Megaloblastic anemia is an uncommon problem in childhood that is most frequently associated with vitamin deficiency or gastrointestinal disease. The megaloblastic effect is characterized by an aregenerative macrocytic anemia with nuclear dysmaturity, where the nucleus appears immature relative to the cytoplasm because of impaired DNA synthesis.

DNA synthesis is impaired because of inadequate amounts of metabolically active folate derivatives necessary for DNA base synthesis. Megaloblastic changes affect all 3 hematopoietic cell lines. Thrombocytopenia, leukopenia, and anemia are all observed to varying extents.

The 2 most common causes of megaloblastic anemia are vitamin B-12 deficiency (cobalamin) and folinic acid deficiency. Although their clinical settings differ considerably, no hematologic finding can distinguish between the 2 conditions. Other less common causes include the use of metabolic inhibitors such as methotrexate and 6-mercaptopurine and certain rare inborn errors such as Lesch-Nyhan syndrome and hereditary orotic aciduria.

Vitamin B-12 is commonly ingested with meat or fish. It binds to salivary haptocorrins, which are digested in the stomach, allowing the cobalamin to bind to intrinsic factor (IF). IF is produced by the parietal cells of the stomach. The IF-cobalamin complex makes its way to the terminal ileum, where it binds to receptors on the enterocyte. It is transported across the cell and enters the circulation bound to a transport molecule, TC II. The cobalamin-TC II complex is absorbed into cells by endocytosis. In the cell, cobalamin acts as a coenzyme in 2 reactions: the synthesis of methionine from homocysteine and the conversion of methylmalonyl CoA to succinyl CoA.

Vitamin B-12 deficiency can be caused by decreased ingestion (eg, poor dietary intake), impaired absorption (eg, failure to release B-12 from protein, intrinsic factor [IF] deficiency, chronic pancreatic disease, competitive parasites, intrinsic intestinal disease), or impaired utilization (eg, congenital enzyme deficiencies, lack of transcobalamin II, administration of nitrous oxide).

Inadequate B-12 dietary intake is extremely rare in children. Pernicious anemia, the most common cause of B-12 deficiency in adults, is rare in childhood. Deficiency of vitamin B-12 activity is usually due to intestinal malabsorption or a congenital deficiency of one of the vitamin B-12 carrier proteins. In recent years, vitamin B-12 deficiency has been described in patients with human immunodeficiency virus (HIV) infection, with or without acquired immunodeficiency syndrome (AIDS).

In addition to the hematologic manifestations of vitamin B-12 deficiency, abnormalities of the gastrointestinal tract and nervous system are also present. The underlying cause of megaloblastic anemia must be determined in each case. Failure to recognize B-12 deficiency, even in the presence of concomitant folate deficiency, may result in permanent neurologic damage. Treatment with folate alone in these cases may aggravate this situation.

Folate is ingested in the diet in many different types of food. It enters the enterocyte and is transported into the portal circulation by a carrier molecule. It circulates in the plasma as, mostly, 5 methyl tetrahydrofolate (THF). It enters the cell via a carrier (methotrexate competes with this carrier). In the cell, folate binds to and acts as a coenzyme with enzymes responsible for single carbon metabolism.

Folate deficiency can be caused by decreased ingestion (eg, poor dietary intake, alcoholism, infancy), impaired absorption (eg, intestinal short circuits, tropical sprue, congenital malabsorption, certain drugs such as sulfasalazine), impaired utilization (eg, use of folic acid antagonists such as methotrexate), increased requirements (eg, pregnancy, infancy, hyperthyroidism, chronic hemolytic disease, cancer), or increased loss (eg, hemodialysis).

Folic acid is available in a wide variety of food groups. Approximately one third of dietary folate is estimated to come from cereals and grains, another third from fruits and vegetables, and another third from meats and fish. Folic acid deficiency is commonly observed in children who are fed a severely restricted diet. This usually occurs with a diet restricted to goat's milk, which is deficient in folic acid. It may also be observed in children with celiac sprue and other malabsorption disorders that affect the proximal small intestine.

Deficiency of metabolically active folate metabolites is frequently observed in patients who receive antifolate drugs, such as sulfa antibiotics and methotrexate. A relative deficiency of metabolically active folate metabolites may also be observed in patients who are experiencing increased red cell destruction. These patients require a greater amount of folate than is usually present in the diet and develop macrocytic changes in their erythrocytes. Increased folate intake is also important during pregnancy, in which deficiencies have been associated with neural tube defects.

Pathophysiology

Megaloblastic anemia is caused by various DNA synthesis defects. In folate deficiency, purine biosynthesis is affected because folic acid is essential in this process.

Folic acid is essential for purine biosynthesis. Folic acid absorbed from the diet must be activated to produce active tetrahydrofolic acid (THF). THF is necessary for single carbon transfers in the synthesis of pyrimidine nucleotides. Without adequate levels of biologically active THF, the ability to repair and replicate DNA is decreased. Vitamin B-12 is a cofactor for the activation of folic acid in a step that also converts homocysteine to methionine.

In the case of inadequate folic acid intake, THF production is depleted, and DNA synthesis is slowed. The effect on hematopoiesis is to reduce the rate of cell production, resulting in pancytopenia. In the cells that are produced, the effect created is an arrest of nuclear maturation. In other words, the cells that are produced have immature nuclei compared to the degree of maturation of the cytoplasm.

Frequency

International

The prevalence of megaloblastic anemia in childhood has not been established, vitamin B-12 deficiency is a worldwide problem, particularly in the newborn period due to the combined effects of poor maternal diet and congenital deficiencies of transcobalamin. Pernicious anemia is a common cause of megaloblastic anemia especially in persons of European or African descent. Dietary vitamin B-12 deficiency is a serious problem in India, Mexico, Central America, South America, and some areas of Africa. The increase in vegetarianism is related to an increase in vitamin B-12 deficiency, especially concerning in breastfed infants of vitamin B-12–deficient mothers.

Mortality/Morbidity

• Mortality and morbidity from megaloblastosis depend on the etiology of the megaloblastic process. Children not only experience anemia but also experience the underlying disease process that caused the anemia.
• Morbidity may include CNS toxicity, including dementia and loss of dorsal column function. Deficiency of vitamin B-12 is usually at the root of this. CNS dysfunction has been described in adult patients who have deficient vitamin B-12 levels in the absence of anemia. Although these symptoms are not as commonly described in children, no evidence suggests that they cannot occur in this age range, with the same lack of correlation between the severity of the CNS dysfunction and the severity of hematologic abnormalities.
• Hyperpigmentation may also be seen.

Race

This condition is observed in all racial and ethnic groups.

Sex

This condition is observed in both sexes.

Age

This condition is rarely observed in infants. It is usually observed only in infants who breastfeed from mothers who are themselves deficient in vitamin B-12 or in infants with a congenital deficiency of one of the carrier proteins.

Clinical

History

• Dietary history: A careful dietary history is essential to the diagnosis of megaloblastic anemia. The type and quantity of foods should be documented. In the case of an infant with megaloblastic anemia, the maternal dietary history should also be obtained.
  • Document whether the child's only source of dietary folic acid is goat's milk.
  • Document dietary faddism or family-induced dietary restriction.
  • Consider symptoms associated with pica; children with a single dietary deficiency are at increased risk of other deficiencies.
  • Evaluate for coexisting frank or latent iron deficiency.
  • Breastfed infants whose mothers are B-12 deficient are at risk for vitamin B-12 deficiency. Obtain a careful history of the mother's diet. Include the mother's current diet, her diet while pregnant, and her diet before pregnancy. Vitamin B-12 deficiency is most common in women who have no meat in their diet.
• Gastrointestinal disease
  • Carefully document the presence or absence of malabsorption syndromes, sprue, and preexisting conditions such as intestinal blind-loop syndrome or bowel resection.
  • Evaluate for other acquired gastrointestinal disorders, such as fish tapeworm infestation by Diphyllobothrium latum.
  • Evaluate for Crohn disease and other causes of chronic inflammation of the ileum as potential causes of B-12 malabsorption.
• Bone or joint pain, bruising, or bleeding
  • Bone and joint pain suggest that the child may have leukemia or another malignancy, with marrow replacement as the cause of pancytopenia.
  • Bleeding and bruising are often observed in association with B-12 deficiency caused by thrombocytopenia, but these symptoms also raise suspicion of leukemia or other marrow replacement disorders.
• Medication
  • A history of sulfa exposure or use of antifolate antimetabolite chemotherapeutic agents, such as methotrexate, trimetrexate, or azathioprine, should be considered.
  • Consider the use of other antifolate drugs or drugs that affect the absorption of either folic acid or B-12. For example, certain anticonvulsants impair folate absorption.
• Family history
  • Congenital absence or deficiency of carrier proteins is a common cause of vitamin B-12 deficiency. These deficiencies occur in families. Obtaining an extended family history is usually necessary to detect other affected family members. These conditions often manifest during infancy and early childhood and are rare but important causes of megaloblastic anemia because myelopathy and developmental delays occur without treatment.
  • Evaluate for Imerslund-Grasbeck syndrome of proteinuria and excretion of cobalamin and IF.

Physical

• The physical examination is largely directed by the findings of the history. Common findings include glossitis, stomatitis, hyperpigmentation, and weight loss.
• Look for physical evidence of anemia, thrombocytopenia, and neutropenia. Pancytopenia can be observed in megaloblastic anemia, but it should raise the suspicion of a possible malignancy.
• Evaluate for lymphadenopathy, hepatosplenomegaly, and abdominal or retroperitoneal masses as evidence of a malignancy.
• Carefully document the neurologic status of a child with megaloblastic anemia. Document altered mental or neurologic status. Vibratory sensation in the extremities is frequently affected in B-12 deficiency. These changes may reflect neurotoxicity from deficient B-12 levels. Once documented, these symptoms can be monitored to determine the degree of resolution once the child is B-12 replete.

Causes

Megaloblastic anemia is caused by lack of vitamin B-12 or lack of folic acid.

• Causes of insufficient B-12 include the following:
  • Inadequate intake in diet
  • Inadequate absorption
    
    • Deficient IF
    • Deficient absorption from ileum
  • Impaired transport from the intestine
• Causes of insufficient folate include the following:
  • Inadequate dietary intake
  • Inadequate absorption from the proximal small intestine
  • Antifolate medications (eg, sulfonamides)
  • Medications that impair absorption (eg, anticonvulsants)
  • Increased use (eg, chronic hemolysis such as sickle cell disease)
  • Increased loss
• Megaloblastic anemia is caused by deficiency of THF. Vitamin B-12 is a cofactor in the activation of folic acid to THF.
• Congenital absence or deficiency of carrier proteins is a common cause of vitamin B-12 deficiency. These deficiencies occur in families, most commonly as autosomal recessive enzymopathies. These conditions often manifest during infancy and early childhood and are rare but important causes of megaloblastic anemia.
• Imerslund-Grasbeck syndrome of proteinuria and excretion of cobalamin and IF is a rare disorder, but it is an important cause of B-12 deficiency that arises in early childhood.
• Because B-12 is an enzyme cofactor, its effect on hematopoiesis can be overcome by large doses of folic acid. Thus, before treatment with folic acid, ensure that the cause of the disorder is folate deficiency and not B-12 deficiency. B-12 is involved in other enzyme pathways; if B-12 deficiency is not accurately diagnosed and treated, demyelination and myelopathy occur, with resultant CNS degeneration.
• Medications associated with megaloblastic anemia include the following:
  • Sulfonamide antibiotics may interfere with folate metabolism, particularly when they are used on a long-term basis.
  • Other antifolate antimetabolite drugs may also cause megaloblastic changes.
  • Megaloblastic changes are observed with some frequency with antineoplastic agents, such as methotrexate. Imuran may also cause megaloblastic changes.
  • The antifolate effect is usually confined to macrocytosis. A complete shift to a megaloblastic condition is uncommon.

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