Macrocytic Anemias

Anemias in which the MCV is > 100 femtoliters.

With age, the MCV increases slightly, but rarely enough to produce significant macrocytosis. Macrocytic anemia in the elderly is often megaloblastic because of vitamin B₁₂ or folate deficiency. Macrocytic anemia may also be caused by hypothyroidism, chronic liver disease, or hemolytic anemia as well as by certain drugs (ie, chemotherapeutic drugs and anticonvulsants).

Vitamin B₁₂ Deficiency Anemia

Vitamin B₁₂ deficiency anemia accounts for up to 9% of all anemias in the elderly, and 3 to 12% of all elderly persons have low serum vitamin B₁₂ levels. Neurologic damage and dementia may occur before anemia or any hematologic changes are found.

Etiology

In the elderly, the most common cause of low serum vitamin B₁₂ is an inability to split vitamin B₁₂ from the R (rapid electrophoretic) proteins in food, to which it is bound. This inability probably results from a deficiency of hydrochloric acid or pancreatic enzymes. Low stomach acidity is present in 15% of elderly persons and is the major known cause of vitamin B₁₂ deficiency in this population.

Vitamin B₁₂ deficiency anemia may also result from a lack of intrinsic factor, which prevents vitamin B₁₂ absorption (pernicious anemia). In this autoimmune disease, antibodies are produced against parietal cells in which intrinsic factor is synthesized or against intrinsic factor itself. Pernicious anemia occurs in about 1% of persons > 60 and is often associated with other autoimmune disorders.

Other causes of vitamin B₁₂ deficiency anemia include gastrectomy, small-bowel disease or surgery, Helicobacter pylori infection, prolonged use of antacids, intestinal bacterial overgrowth, and a strict vegan diet.

Symptoms, Signs, and Diagnosis

Vitamin B₁₂ deficiency takes years to develop, and its symptoms are subtle. Neurologic changes may or may not occur but may predate the anemia. Various neuropsychiatric syndromes, including dementia, depression, and mania, may occur with or without anemia and often remain after the deficiency is treated. The neuropsychiatric problems may be related to the elevated homocysteine level and to microvascular disease in the brain. The anemia is usually reversible, but the neurologic changes are often irreversible.

Vitamin B₁₂ deficiency has four stages: negative vitamin B₁₂ balance, vitamin B₁₂ depletion, vitamin B₁₂-deficient erythropoiesis, and vitamin B₁₂ deficiency anemia. The standard laboratory test results (eg, deoxyuridine suppression test, serum methylmalonic acid levels, serum homocysteine levels) may not be abnormal until the patient becomes anemic.

Besides macrocytic anemia, laboratory abnormalities include the presence of hypersegmented polymorphonuclear leukocytes on peripheral blood smear. The platelets are large. The MCV and RBC distribution width are typically elevated. Leukopenia and thrombocytopenia may occur. Serum levels of bilirubin, ferritin, and lactic dehydrogenase may be elevated because of ineffective erythropoiesis. When anemia is present, bone marrow examination will show megaloblastic changes. Use of the Schilling test in the elderly is rarely needed because the cause is almost always gastric hypoacidity, and the treatment is the same. If bacterial overgrowth is suspected, the full stages of the Schilling test should be performed.

Treatment

Treatment of vitamin B₁₂ deficiency in pernicious anemia or hypochlorhydria consists of lifelong vitamin B₁₂ administration. A common regimen is 1000 µg/day for the first week, then 1000 µg/week for 4 weeks or until the Hct is normal, and then 1000 µg/month for life. Sublingual (500 µg/day) or nasal vitamin B₁₂ is also effective, but at a higher cost. If the vitamin B₁₂ deficiency results from an inability to split vitamin B₁₂ from food proteins, as is the case in most elderly patients, vitamin B₁₂ may be given orally as 1000 µg/day on an empty stomach. Even in patients with pernicious anemia, this amount of vitamin B₁₂ usually corrects the deficiency by mass action absorption even in the absence of intrinsic factor, but patients should be monitored closely for improvement.

Reticulocytosis usually begins within 1 week. Anemia is usually corrected within 1 month, although abnormalities in the peripheral blood smear may persist for 1 year. Transfusion is rarely necessary. Treatment with folic acid alone may improve the hematologic disorder; however, it will not prevent or improve the neurologic changes associated with vitamin B₁₂ deficiency.

Folate Deficiency Anemia

Folate deficiency produces changes in the peripheral blood smear and bone marrow that are indistinguishable from those caused by vitamin B₁₂ deficiency. Folate deficiency is probably uncommon in the ambulatory elderly who are well nourished, but the actual incidence is unknown, partly because of varying definitions of the lower limits of the normal range and differences in radioimmunoassay and microbiologic methods used to measure serum and RBC folate levels.

Normal body stores of folate can be depleted in 3 to 6 months. Rapid folate deficiency can be caused by malabsorption, poor nutrition, alcoholism, and states of increased folate utilization, such as hemolytic anemia and neoplasia. Drugs (eg, anticonvulsants, nitrofurantoin, triamterene, trimethoprim) also can cause folate deficiency.

Symptoms, Signs, and Diagnosis

Pure folate deficiency may result in neurologic changes that are virtually indistinguishable from those caused by vitamin B₁₂ deficiency. This may be due, in part, to elevated serum levels of homocysteine in folate, vitamin B₁₂, and vitamin B₆ deficiencies.

A diagnosis of folate deficiency anemia is confirmed by the presence of macrocytic RBCs and hypersegmented neutrophils in the peripheral blood smear, a normal serum vitamin B₁₂ level (unless B₁₂ deficiency coexists), and a low serum folate level (< 2 ng/mL [< 5 nmol/L]) or a low RBC folate level (< 100 ng/mL [< 227 nmol/L]). However, serum folate levels fluctuate rapidly and do not necessarily reflect body stores; RBC folate levels are more stable and, therefore, are more clinically reliable. Serum homocysteine is elevated, but methylmalonic acid levels are normal. Bone marrow is histologically indistinguishable from that seen in vitamin B₁₂ deficiency, but bone marrow aspiration or biopsy is rarely needed.

Treatment

Therapy consists of folic acid 1 mg/day po. Higher doses are sometimes needed for resistant cases. A parenteral form is available for patients with severe malabsorption. In patients with megaloblastic anemia secondary to vitamin B₁₂ deficiency, treatment with folic acid alone may correct the anemia but will not reverse neurologic damage.