Megaloblastic Anemia
Megaloblastic anemia is a folate deficiency commonly seen in middle-aged and older adults. It has been associated with an increased risk for heart disease and end stage renal disease because of the association with elevated homocysteine levels (Morrison, 1996; Pancharuniti, 1994; Robinson, 1996). It may be due to increased needs, a deficient diet, malabsorption of folate and/or a vitamin B12 deficiency. Malabsorption of folic acid may occur in individuals with diseases of the small intestine including ileitis, tropical and nontropical sprue, overgrowth of bacteria, hemolytic anemia, liver disease, malnutrition and following biliopancreatic diversion with and without duodenal switch (BPD/DS) weight loss surgery (Aills, 2008).
Some medications are folate antagonists and interfere with nucleic acid synthesis. The most common folate antagonists are anticonvulsants, antimalarials, alcohol, aminopterin and methotrexate. Megaloblastic anemia occurs after approximately 5 months of folate depletion.
The initial clinical signs and symptoms of megaloblastic anemia are low levels of hemoglobin, hematocrit and red cell folate. However, elevated levels of serum iron, MCV, ferritin and homocysteine are common. Falsely elevated concentrations of red cell folate are seen in patients with raised reticulocyte counts and low levels occur in vitamin B12 deficiency. Plasma folate can be used to assess status however; it is affected by recent folate intake.
Treatment for megaloblastic anemia is based on its etiology. Folate supplementation of 1 mg or more daily can compensate for vitamin B12 deficiency in DNA synthesis reversing macrocytic anemia and thereby masking vitamin B12 deficiency. Undiagnosed vitamin B12 deficiency will result in progressive permanent neurological damage including permanent changes in cognitive abilities. Individuals taking known folic acid antagonists will require prescription strength supplemental folate for as long as these medications are taken. Individuals with malabsorption disorders due to disease or weight loss surgery will require supplemental folic acid for a lifetime.
Pernicious Anemia
Pernicious anemia is due to a vitamin B12 deficiency commonly seen in older adults, vegetarians and individuals who have had malabsorptive weight loss surgery. Early signs and symptoms include pallor, weakness, lightheadedness, smooth, sore tongue, diarrhea alternating with constipation, numbness and tingling of extremities, gait abnormalities, personality changes, irritability, confusion, cognitive changes, depression and numbness of the hands and feet. Permanent nerve lining damage and significant cognitive decline will result from an untreated vitamin B12 deficiency.
Absorption and utilization of vitamin B12 is a multi step process. Dietary vitamin B12 is bound to a protein carrier. An acidic environment is required for the body to cleave the protein carrier from vitamin B12. Once vitamin B12 is released from its protein carrier in the stomach, it must form a complex with intrinsic factor (IF) for absorption in the terminal ileum. IF is synthesized in the stomach in the presence of an acidic environment. Without IF, B12 cannot be absorbed, body stores are depleted and the body produces enlarged immature RBC. It is categorized as a macrocytic normochromic anemia, however about 40 percent of the cases are normocytic (Allen, 1990; Carmel, 1996; Koepke, 1997; Pennypacker, 1992).
The ability to absorb and utilize vitamin B12 decreases with age affecting about 20-50 percent of the elderly. The decline in absorption and utilization of vitamin B12 is primarily due to atrophic gastritis and/or gastric mucosa defect resulting in inadequate secretion of IF. Atrophic gastritis results in declining gastric acid and pepsinogen secretions. The increased pH in the gastrointestinal tract decreases intestinal absorption of the cobalamin protein complexes from food. In addition, the reduced acid secretion leads to an alkalinization of the small intestine, which may result in bacterial overgrowth and further decrease the bioavailability of the vitamin.
Other causes of pernicious anemia include history of gastric or ileal resections, weight loss surgery, diseases associated with malabsorption (e.g. Crohn's disease) may cause impaired vitamin B12 absorption. Medications such as proton pump inhibitors or H2 receptor antagonists inhibit the intestinal absorption of vitamin B12.
Plasma vitamin B12 test is a reflection of recent intake rather than vitamin stores. More prolonged vitamin B12 deficiency is measured by either blood or urinary methylmalonic acid (MMA). Elevated serum and urinary MMA levels are direct measure of tissue vitamin B12 activity. Urinary MMA/creatinine ratio is more accurate than the serum MMA as it indicates tissue/cellular vitamin B12 deficiency.
The etiology of vitamin B12 deficiency should be determined for appropriate treatment. Vitamin B12 deficiency can result from either inadequate diet or impaired absorption.
The Schilling test can be used to distinguish insufficient secretion of intrinsic factor from malabsorption syndromes. In this test, radioactive B12 is taken orally and urinary excretion is measured over 24 hours. A flushing dose of unlabeled B12 is given with the labeled B12 to saturate liver storage and enhance labeled B12 excretion.
Normally, >7 percent of the labeled B12 is recovered in the urine. If absorption is low, it is necessary to repeat the test with administration of intrinsic factor. The lab results for pernicious anemia are very similar to megaloblastic anemia. Lower than normal values are seen for hemoglobin, hematocrit and serum B12. However, elevated levels are seen in serum iron, serum folate, ferritin and homocysteine. MCV may be elevated or normal. The only definitive lab test appears to be MMA. This test is elevated in vitamin B12 deficiency and normal in megaloblastic anemia (Van Asselt, 1996; Savage, 1994).
Treatment for pernicious anemia is based on the etiology of the anemia. Oral B12 supplements are effective if the body can produce adequate levels of IF and the pH of the stomach is sufficient to cleave vitamin B12 from its protein carrier. However, if the body is unable to produce IF then daily B12 nasal spray, B12 patch or monthly injections of B12 are recommended. Table 7 summarizes the most commonly used tests to evaluate for different types of anemia. Not all patients’ lab results will follow the pattern provided in Table 7 due to the effects of other diseases or the use of medications. Additional information about each laboratory test is included in the next section of this text.
Table 7. Guide to Anemias
| Lab Test | Fe Deficiency | Megaloblastic Anemia (Folate) | Pernicious Anemia (B12) | Anemia of Chronic & Inflammatory Disease |
| HGB Females Males | <12 gm <14 gm | <12 gm <14 gm | <12 gm <14 gm | <12 gm <14 gm |
| HCT Females Males | <37% <42% | <37% <42% | <37% <42% | <37% <42% |
| MCV | <80 μm3 | >95 μm3 | >95 μm3 or WNL | WNL |
| MCH | <27 pg | >31 pg | >31 pg | WNL |
| Serum Fe Females Males | <60 μg/dL <80 μg/dL | >190 μg/dL >180 μg/dL | >190 μg/dL >180 μg/dL | <60 μg/dL <80 μg/dL |
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