AUTHOR AND EDITOR INFORMATION

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
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INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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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

Section 3 of 11  

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• Clinical
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• Follow-up
• Miscellaneous
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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.

DIFFERENTIALS

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Other Problems to be Considered

Aplastic anemia
Celiac disease
Ecchymoses
Granulocytopenia
Hyposplenism
Myeloproliferative disorders
Neutropenia
Pancytopenia
Tapeworm infection (cestodiasis)
Imerslund-Grasbeck disease
Thiamine-responsive anemia

WORKUP

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• Follow-up
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Lab Studies

• CBC count with a manual differential
• • CBC count reveals macrocytic red cell indices and evaluates for other cytopenias.
  • The manual differential is essential to rule out the possibility of circulating blast cells, which may be present in a patient with leukemia who presents with pancytopenia.
• Reticulocyte count: The reticulocyte count is important in the assessment of red cell production.
• Serum B-12 levels
• Serum and red blood cell folate levels
• • Red blood cell folate level is the best measure of metabolically active folate and includes THF in the assay.
  • Serum folate measures the circulating pool of folate but does not accurately reflect the amount of THF present in the tissues
• Methylmalonic acid and total homocysteine levels are sensitive indicators of vitamin B-12 deficiency and correlate with clinical abnormalities and therapeutic response. They are not specific to vitamin B-12 deficiency, and care should be taken in interpreting these results.
• Bone marrow evaluation: Consider bone marrow evaluation for any child with more than one abnormal cell line on the CBC. It can help to rule out other disorders such as leukemia, myelodysplasia, and aplastic anemia.
• Serum chemistry
• • Serum chemistries should include albumin and total protein urine for protein and creatinine.
  • Measurement of serum chemistries allows assessment of protein loss and nutritional status.
  • Measurement of urine proteins and IF, if possible, detects Imerslund-Grasbeck syndrome.
• Additional laboratory studies: A platelet count may be indicated.

Procedures

• When B-12 deficiency is suspected, a Shilling test may be performed to determine whether congenital absence of a binding protein is present.
• The Shilling test may be modified to avoid radiolabeled B-12 by measuring B-12 levels before and after a known B-12 dose, followed by a similar test using B-12 with accompanying IF. A comparison of B-12 levels allows detection of a deficiency of either IF or IF-binding protein.
• Shilling test findings that reveal elevation of the B-12 level with oral B-12 indicates dietary insufficiency.
• Shilling test findings that reveal improved B-12 levels with oral B-12 and IF indicates the absence of IF, which is pernicious anemia.
• Shilling test findings that reveal no improvement with IF indicates either no absorption in the ileum or transport carrier protein deficiency.

Histologic Findings

Examination of the peripheral blood smear shows macrocytosis. Hypersegmented neutrophils (in which the nucleus has 6 or more segments) can usually be observed as well. Pancytopenia has been observed in severe cases of megaloblastic anemia. A bone marrow examination demonstrates the red blood cell precursor nuclear/cytoplasmic asynchrony. Granulocyte precursors may also be abnormal.

TREATMENT

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Medical Care

Treatment of megaloblastic anemia depends on the underlying cause.

• Folate deficiency
• • Folate deficiency due to dietary deficiency or increased demands is best treated with folate supplements.
  • Folate deficiency caused by the use of sulfa drugs or other antifolate medications may be addressed by folate supplementation or by reducing or eliminating the drug.
  • Folate deficiency due to celiac sprue requires treatment of the underlying disorder and folate supplements.
• B-12 deficiency
• • B-12 deficiency is often more complex because of the nature of B-12 deficiency in childhood.
  • B-12 supplements can be administered orally, even for IF deficiency, using higher doses.
  • Often, B-12 deficiency must be treated with parenteral supplements if high-dose oral B-12 supplements are unsuccessful.
  • For those children with congenital disorders that lead to B-12 deficiency, supplementation is a lifelong necessity; therefore, concern regarding a regimen that is tolerable over time is essential to maintaining compliance.
  • Recent data, albeit from small trials, suggests that oral B-12 supplementation is as effective as parenteral supplementation in patients with nutritional deficiency. Patients with IF deficiency or who have undergone intestinal surgery should be considered for parenteral therapy because of impaired secretion or absorption of IF.

Surgical Care

Carefully monitor for the onset of megaloblastic anemia due to impaired absorption of B-12 or folic acid following surgical illnesses that involve the stomach, jejunum, or ileum.

Consultations

• Gastroenterologist
• • Consultation with a pediatric gastroenterologist to evaluate for inflammation of the ileum or jejunum and assist in treatment planning is often helpful for patients with newly diagnosed Crohn disease or celiac sprue.
  • Gastroenterologists may also be needed to evaluate the extent of liver disease, which may manifest with macrocytic erythrocytes.
• Hematologist: Consider consulting a hematologist to evaluate the bone marrow for evidence of other marrow diseases that can manifest with macrocytic anemia and thrombocytopenia.

Diet

• A diet rich in green, leafy vegetables is essential for normal intake of folic acid.
• Because vitamin B-12 is contained exclusively in animal products (meat), vitamin supplementation is the only means of appropriate vitamin B-12 intake in humans choosing vegetarian diets.

MEDICATION

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Drug Category: Vitamins

Vitamins are organic substances required by the body in small amounts for various metabolic processes. Vitamins may be synthesized in small or insufficient amounts in the body or not synthesized at all, thus requiring supplementation. Use folic acid and vitamin B-12 supplements as indicated.

FOLLOW-UP

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Complications

• Neurologic complications are frequent problems with B-12 deficiency. These may be observed in any age group and may be at least partially reversible with repletion of the B-12 deficit.

Prognosis

• Prognosis depends on the underlying cause of the megaloblastic anemia and the degree of compliance with therapy.
• Folic acid deficiency is relatively easy to treat; patients usually respond to added folate in their diet.
• Vitamin B-12 deficiency may be a more significant concern because some patients may need to use parenteral vitamin B-12 injections, with which they may not readily comply.
• Vitamin B-12 deficiency may be associated with severe abnormalities of neural function that may be long lasting and persist even with appropriate vitamin B-12 therapy.

Patient Education

• For the new patient, education should focus on the nature of the deficiency causing the anemia and the underlying factors that produce the deficiency.
• Educate patients or their parents about the neurologic complications of B-12 deficiency to ensure that they understand the importance of B-12 replacement.
• For excellent patient education resources, visit eMedicine's Esophagus, Stomach, and Intestine Center; Crohn Disease Center; and Blood and Lymphatic System Center. Also, see eMedicine's patient education articles Celiac Sprue, Crohn Disease, Diet and Nutrition in Crohn Disease, and Anemia.

MISCELLANEOUS

Section 9 of 11  

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Medical/Legal Pitfalls

• Misdiagnosis of vitamin B-12 deficiency
• • Avoid delaying or misdiagnosing vitamin B-12 deficiency.
  • Folic acid supplementation may be sufficient to drive the production of active THF in the absence of vitamin B-12. This results in improvement of the anemia but does not result in improvement of the function of other pathways dependent on B-12. Clinically, this is apparent as a resolution of megaloblastic anemia, with progressive dementia and long-tract neurologic deficits. This situation can be avoided by measuring levels of both vitamins, then evaluating and treating both deficiencies, if found.

Special Concerns

• Dietary B-12 deficiency in infants is extremely rare. It is often observed in infants who are breastfed by mothers who have B-12 deficiency. Consider this prospect if a breastfed infant has B-12 deficiency for an apparent dietary reason.

MULTIMEDIA

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• Multimedia
• References

Media file 1:  Bone marrow aspirate from a patient with untreated pernicious anemia. Megaloblastic maturation of erythroid precursors is shown. Two megaloblasts occupy the center of the slide with a megaloblastic normoblast above. Photo courtesy of Marcel E Conrad, MD.
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Media type:  Photo

REFERENCES

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Article Last Updated: Aug 20, 2007