Megaloblastic anemia is a heterogeneous group of macrocytic anemias characterized by the presence of large red blood cell precursors called megaloblasts in the bone marrow.[rx] which the bone marrow produces unusually large, structurally abnormal, immature red blood cells (megaloblasts). This condition is due to impaired DNA synthesis, which inhibits nuclear division. Cytoplasmic maturation, mainly dependent on RNA and protein synthesis, is less impaired. This leads to an asynchronous maturation between the nucleus and cytoplasm of erythroblasts, explaining the large size of the megaloblasts.[rx] The process affects hematopoiesis as well as rapidly renewing tissues such as gastrointestinal cells. Megaloblastic anemia is most often due to hypovitaminosis, specifically vitamin B12 (cobalamin) and folate deficiencies, which are necessary for the synthesis of DNA.
Bone marrow, the soft spongy material found inside certain bones, produces the main blood cells of the body -red cells, white cells, and platelets. Anemia is a condition characterized by low levels of circulating, red blood cells. Red blood cells are released from the marrow into the bloodstream where they travel throughout the body delivering oxygen to tissue. A deficiency in healthy, fully-matured red blood cells can result in fatigue, paleness of the skin (pallor), lightheadedness, and additional findings. Megaloblastic anemia has several different causes – deficiencies of either cobalamin (vitamin B12) or folate (vitamin B9) are the two most common causes. These vitamins play an essential role in the production of red blood cells.
Causes
The most common causes of megaloblastic anemia are deficiency of either cobalamin (vitamin B12) or folate (vitamin B9). These two vitamins serve as building blocks and are essential for the production of healthy cells such as the precursors to red blood cells. Without these essential vitamins, the creation (synthesis) of deoxyribonucleic acid (DNA), the genetic material found in all cells, is hampered.
Vitamin deficiency resulting in megaloblastic anemia may result from inadequate intake of cobalamin and folate in the diet, poor absorption of these vitamins by the intestines, or improper utilization of these vitamins by the body. Folate deficiency may also result from conditions that use up or require excessive amounts of folate.
Cobalamin is found in meat, fish, and eggs. Deficiency of cobalamin due to poor dietary intake is extremely rare but has occurred in some total vegetarians (vegans). The most common cause of cobalamin deficiency is impaired absorption of the vitamin by the small intestines (malabsorption). In such cases, the diet contains enough of the vitamin, but the body cannot absorb and subsequently use the vitamin. Malabsorption may result from surgery on the intestines, intestinal diseases such as Crohn’s disease or tropical sprue, or infection (bacterial growth) within the gastrointestinal tract. Pernicious anemia may also cause cobalamin deficiency. This form of anemia is characterized by a lack of intrinsic factor, a protein that binds with cobalamin and aids in its absorption by the small intestines. Without enough intrinsic factors, the body cannot absorb enough cobalamin.
In rare cases, a fish tapeworm known as Diphyllobothrium latum may take root in the small intestine and use up cobalamin, thereby depriving the body of necessary amounts of this essential vitamin. In some cases, bacteria may compete with the body for cobalamin as in blind loop syndrome, a disorder in which obstruction of the small intestines results in the abnormal build-up of bacteria in the gastrointestinal tract.
Folate, which is also known as folic acid, is a B vitamin that is normally found in green leafy vegetables, citrus fruits, and certain grains and nuts. Folate deficiency can occur in diets that supply insufficient amounts of these foods. Alcoholics may develop folate deficiency because alcohol does not contain folate and may impair the breakdown (metabolism) of folate in the body. Surgery involving the stomach or intestines can result in impaired absorption of folate. Certain intestinal disorders such as Crohn’s disease or tropical sprue can cause malabsorption and subsequent folate deficiency.
Pregnant women, women who are breastfeeding, individuals who have chronic hemolytic anemias, and individuals undergoing hemodialysis for kidney disease all have higher-than-normal demands for folate. Failure to adequately supplement folate in these individuals can potentially result in folate deficiency.
Certain medications can impair the body’s ability to absorb folate including many drugs used to treat cancer. Medications can also impair the synthesis of DNA resulting in megaloblastic anemia.
Much rarer causes of megaloblastic anemia (unrelated to vitamin deficiency) have been identified including rare enzyme deficiencies known as inborn errors of metabolism and primary bone marrow disorders including myelodysplastic syndromes and acute myeloid leukemia. In some cases, the cause of megaloblastic anemia is unknown (idiopathic).
Folic acid is present in food such as green vegetables, fruits, meat, and liver. Daily adult needs range from 50 to 100 mcg. The recommended dietary allowance is 400 mcg in adults and 600 mcg in pregnant women.[rx] Folic acid is mainly absorbed in the jejunum and the body stores around 5 mg of folate in the liver, which is enough for 3 to 4 months. Folic acid deficiency may be related to decreased intake in the case of alcohol use disorder or malnutrition (elderly patients, institutionalized patients, poverty, special diets, etc.), increased demand particularly in case of pregnancy, hemolysis, hemodialysis, and malabsorption (tropical sprue, celiac disease, jejunal resection, Crohn disease, etc.). In some cases, medications like anticonvulsants and anticancer agents cause megaloblastic anemia related to folate deficiency by affecting folate metabolism.
The primary dietary sources of cobalamin/vitamin B12 are meats, fish, eggs, and dairy products. Vegan diets are low in vitamin B12. However, not all patients following a vegan diet develop clinical evidence of deficiency. Vitamin B12 is first bound within the duodenum and jejunum to the intrinsic factor (IF) produced by gastric parietal cells and is then absorbed in the terminal ileum. The body stores 2 to 3 mg of vitamin B12 in the liver (sufficient for 2 to 4 years). The most frequent cause of vitamin B12 deficiency is pernicious anemia caused by autoimmune gastric atrophy, leading to decreased intrinsic factor production.[rx] Vitamin B12 deficiency may also develop following gastrectomy, ileal resection, or ileitis of any cause. Other causes of impaired vitamin B12 absorption include Zollinger-Ellison syndrome, blind loop syndrome, fish tapeworm infestation, and pancreatic insufficiency.
Diagnosis
A diagnosis of megaloblastic anemia is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings, and a variety of blood tests. Blood tests may reveal the abnormally large, misshapen red blood cells that characterize megaloblastic anemia. Blood tests can also confirm cobalamin or folate deficiency as the cause of megaloblastic anemia. Additional tests such as a Schilling test, which confirms poor absorption as the cause of cobalamin deficiency, may be necessary.
Clinical suspicion for megaloblastic anemia should be high in patients with unexplained macrocytic (mean corpuscular volume [MCV] greater than 100 fL) anemia or hypersegmented neutrophils on a peripheral smear. An MCV of greater than 115 fL is more specific for vitamin B12 deficiency or folate deficiency than other causes of macrocytosis, however, a normal MCV does not rule out megaloblastic anemia.[rx] A reticulocyte count is also indicated in the workup of this disease. In a patient with typical peripheral blood smear findings and a low reticulocyte count, the only testing needed is a serum vitamin B12 and folate level.[rx] In a patient consuming a normal diet, folate levels can be omitted. In patients with suspected disorders of absorption or malnutrition such as excess alcohol consumption, both levels should be obtained. A B12 level above 300 pg/mL (above 221 pmol/L) is considered normal. A level between 200 to 300 pg/mL (148 to 221 pmol/L) is considered borderline and additional testing should be obtained to verify the diagnosis and elucidate the cause. A level below 200 pg/mL (below 148 pmol/L) is consistent with deficiency and further testing is only indicated if the route of administration of B12 supplementation needs clarification.[rx]
It is imperative to remember that vitamin B12 and folate deficiency testing should be done simultaneously to ensure both deficiencies are diagnosed if present. In cases where folate is replaced without vitamin B12 supplementation and underlying B12 deficiency, the neurologic manifestations of vitamin B12 deficiency will not be treated and may potentially get worse.[rx]
The 2014 Guidelines from the British Committee for Standards in Haematology[rx]
- Serum cobalamin and folate levels should be obtained simultaneously due to the close relationship in metabolism. (Grade 1A)
- Neurological symptoms due to vitamin B12 deficiency can occur in the absence of macrocytosis. In unexplained neurological symptoms consistent with B12 deficiency, cobalamin assays should be obtained. (Grade 1B)
- Methylmalonic acid and homocysteine levels should be obtained in patients with clinical suspicion of B12 deficiency but borderline serum levels. (Grade 2B)
- Homocysteine level is more sensitive for B12 deficiency but methylmalonic acid is more specific. Both have to be interpreted in relation to the patient’s renal function.
- Holotranscobalamin (HoloTC) is the ‘active’ fraction of serum cobalamin and is more specific than serum cobalamin levels.[rx] It may be used as a routine diagnostic laboratory in the future. (Grade 1B)
- All patients with clinical features suspicious for pernicious anemia should be tested for anti-IF antibodies regardless of cobalamin levels. (Grade 1A)
- Patients with low serum cobalamin levels without anemia or malabsorption syndromes to explain the result should be tested for anti-IF antibodies as they may have an early/latent presentation of pernicious anemia. (Grade 2A)
- Anti-gastric parietal cell antibody testing is not recommended. (Grade 1A)
- Red cell folate testing is not recommended in most cases. (Grade 1A)
- In the presence of strong clinical suspicion of folate deficiency and a normal serum level, a red cell folate assay can be obtained if cobalamin deficiency has already been ruled out. (Grade 2B
Treatment
The treatment of megaloblastic anemia depends upon the underlying cause of the disorder. Dietary insufficiency of cobalamin and folate can be treated with appropriate changes to the diet and the administration of supplements. In individuals who cannot absorb cobalamin or folate properly, life-long supplemental administration of these vitamins may be necessary. Prompt treatment of cobalamin deficiency is important because of the risk of neurological symptoms.
The recommended dose for vitamin B12 supplementation in children is 50 to 100 mcg parenterally once a week until the deficiency is corrected. They may require supplemental doses every month or every other month thereafter, depending on the formulation used (cyanocobalamin versus hydroxocobalamin). In adults, the recommended dose is 1000 mcg parenterally once a week until the deficiency is corrected, followed by supplemental doses every month or every other month. An oral vitamin B12 dose of 1000 mcg daily is equally effective as the above parenteral regimen, provided that there is no intestinal malabsorption issue.[rx] A 2018 Cochrane review reported oral supplementation was equally effective in raising serum B12 levels as compared to intramuscular formulations, with the added benefit of it being a low-cost treatment.[rx] The duration of treatment is dependent on the cause of the deficiency. If the root cause is correctable, supplementation can be stopped after serum B12 levels normalize. However, in cases with expected life-long deficiency (gastric bypass surgery patients, pernicious anemia, etc.) indefinite supplementation is warranted.
The recommended dose for folic acid supplementation is 1 mg orally once a day until the deficiency is corrected. If the cause of this deficiency is correctable, supplementation can be stopped after repletion. However, in cases with nonreversible causes, indefinite supplementation is recommended.[rx]
Prescribe 1000 micrograms of oral vitamin B12 daily for 1 month followed by 125 to 250 micrograms daily or administer 1000 micrograms of intramuscular B12 every week for 4 weeks then monthly to replace vitamin B12 stores, the latter of which is preferred for patients with pernicious anemia or altered gastrointestinal anatomy. Clinicians may prescribe empiric folate supplementation (400 micrograms to 1 g/day) in patients receiving vitamin B12 replacement. Reticulocytosis will improve within 1 to 2 weeks, and anemia should resolve after 4 to 8 weeks. There is no need to monitor RBC indices or recheck folate or vitamin B12 levels and their metabolites during active treatment, though some physicians check yearly complete blood counts in patients taking long-term vitamin B12 therapy.
If underlying disorders (e.g., Crohn’s disease, tropical sprue, celiac sprue, blind loop syndrome, inborn errors of metabolism) are the cause of these vitamin deficiencies, appropriate treatment for the specific disorder is required. Supplementation of either cobalamin or folate may also be required.
If medications are the cause of vitamin deficiency then the use of the medication in question should be stopped or the dosage lowered.
Preventive (prophylactic) folate supplementation may be recommended for individuals who have higher-than-normal demands for folate such as pregnant women.
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