MacrocyticZMegaloblastic Anemia

GENERAL PRINCIPLES

Definition

Megaloblastic anemia is a term used to describe disorders of impaired DNA synthesis in hematopoietic cells, but this also affects other normally proliferating cells such as in the GI tract.

Etiology

• Vitamin B₁₂ (cobalamin) deficiency occurs insidiously over several years because daily vitamin B₁₂ requirements are low compared to total body stores. Vitamin B₁₂ is absorbed in the terminal ileum.

î Most cases of megaloblastic anemia are due to vitamin B₁₂ deficiency.

° Vitamin B₁₂ deficiency occurs in up to 20% of untreated patients within 8 years of partial gastrectomy and in almost all patients with total gastrectomy or pernicious anemia (PA). Older patients with gastric atrophy may develop a food-bound vitamin B₁₂ deficiency in which vitamin B₁₂ absorption is impaired. In nonvegan adults, vitamin B₁₂ deficiency is almost always due to malabsorption.

î PA usually occurs in individuals older than 40 years (mean age of onset, 60 years). Up to 30% of patients have a positive family history. PA is an immune-mediated disorder associated with other autoimmune disorders (Graves disease 30%, Hashimoto thyroiditis 11%, and Addison disease 5%- 10%). In patients with PA, 90% have antiparietal cell antibodies, and 60% have anti-intrinsic factor antibodies.

î Other etiologies of vitamin B₁₂ deficiency include pancreatic insufficiency, bacterial overgrowth, celiac disease, medications (metformin, proton pump inhibitors, nitrous oxide), and intestinal parasites (Diphyllobothrium latum).

• Folate deficiency results from a negative folate balance arising from malnutrition, malabsorption, or increased requirement (pregnancy, hemolytic anemia). In contrast to B₁₂ deficiency, it can develop more rapidly (weeks to months) given limited body stores.

î Folate deficiency is now rare in the US because of fortification of grains with folic acid.

° Patients on weight-losing diets, alcoholics, the elderly, and psychiatric patients are particularly at risk for nutritional folate deficiency.

î Folate deficiency may be seen in several settings:

#9632; Pregnancy and lactation in which there is a three- to fourfold increased daily folate requirements.

#9632; Folate malabsorption can occur secondary to celiac disease or bariatric surgery.

#9632; Drugs that can interfere with folate absorption include ethanol, trimethoprim, methotrexate, pyrimethamine, diphenylhydantoin, barbiturates, and sulfasalazine.

#9632; Dialysis-dependent patients require more folate intake because of increased folate losses.

#9632; Patients with hemolytic anemia, such as sickle cell anemia, require increased folate for accelerated erythropoiesis and can present with aplastic crisis (rapidly falling RBC counts) with folate deficiency.

DIAGNOSIS

Clinical Presentation

• In addition to symptoms of anemia, vitamin B₁₂ deficiency may demonstrate neurologic symptoms, such as peripheral neuropathy, paresthesias, lethargy, hypotonia, and seizures.

• Important physical findings include signs of poor nutrition, pigmentation of skin creases and nail beds, or glossitis. Jaundice or splenomegaly may indicate ineffective and extramedullary hematopoiesis.

• Vitamin B₁₂ deficiency may cause decreased vibratory and positional sense, ataxia, paresthesias, confusion, and dementia. Neurologic complications may occur in the absence of anemia and may not fully resolve despite adequate treatment. Folic acid deficiency does not result in neurologic disease.

Diagnostic Testing

• Macrocytic anemia is usually present unless there is also a coincident cause of microcytic anemia, and leukopenia and thrombocytopenia may occur.

• The peripheral smear may show macroovalocytes; hypersegmented neutrophils (containing six or more nuclear lobes) are common.

• Lactate dehydrogenase (LDH) and indirect bilirubin are typically elevated, reflecting ineffective erythropoiesis and premature destruction of RBCs (intramedullary hemolysis).

• Serum vitamin B₁₂ and folate levels should be measured.

• Serum methylmalonic acid (MMA) and homocysteine (HC) may be useful when the vitamin B₁₂ level is 100-400 pg/mL (or borderline low as defined by the laboratory reference range). MMA and HC are elevated in vitamin B₁₂ deficiency; only HC is elevated in folate deficiency.

• Detecting antibodies to intrinsic factor is specific for the diagnosis of PA.

DIAGNOSTIC PROCEDURES

BM biopsy may be necessary to rule out MDS or acute myeloid leukemia (AML) because these disorders may present with findings similar to those of megaloblastic anemia including a hypercellular marrow with an accumulation of immature cells.

TREATMENT

• Potassium supplementation may be necessary when treatment is initiated to avoid potentially serious arrhythmias due to transient hypokalemia induced by enhanced hematopoiesis.

• Reticulocytosis should begin within 1 week of therapy, followed by a rising of Hgb over 6-8 weeks.

• Coexisting iron deficiency is present in one-third of patients and is a common cause for an incomplete response to therapy.

• Folic acid 1 mg PO daily is given until the deficiency is corrected. High doses of folic acid (5 mg daily) may be needed in patients with malabsorption syndromes.

• Vitamin B₁₂ deficiency is corrected by administering cyanocobalamin. Initial treatment (1 mg/d IM cyanocobalamin) is typically administered in the setting of severe anemia, neurologic dysfunction, or chronic malabsorption. After 1 week of daily therapy, a commonly employed regimen is 1 mg/wk given for 4 weeks and then 1 mg/mo for life.

• High-dose enteral therapy (1000-2000 #956;g#8725;d PO) may be considered after initial repletion in those without neurologic involvement or for convenience or cost.⁶