Approach Considerations
Once drug-induced megaloblastic changes and myelodysplasia-related megaloblastosis have been ruled out, most patients are treated with cobalamin or folate. Since megaloblastic anemias usually develop gradually, many patients adjust to low hemoglobin levels and do not require transfusions. Transfusion therapy should be restricted to patients with severe, uncompensated, and life-threatening anemia.
Go to Anemia, Chronic Anemia, Myelophthisic Anemia, Hemolytic Anemia, and Sideroblastic Anemias for complete information on these topics.
Cobalamin Therapy
Cobalamin (1000 µg) should be given intramuscularly daily for 2 weeks, then weekly until the hematocrit value is normal, and then monthly for life. A dose of 1000 µg is large, but it may be required in some patients. The reader should be aware that several other protocols for cobalamin therapy have been recommended. It is important to emphasize that patients with mental and neurological impairment due to cobalamin deficiency should be treated more aggressively.
Oral cobalamin (1000-2000 µg) also can be administered. Oral cobalamin is less expensive and is better tolerated by patients. A wide range of doses and schedules have been recommended. For example, a randomized controlled trial in 40 vegans and vegetarians with marginal vitamin B12 deficiency found that adequate vitamin B12 levels could be achieved with cobalamin given in either a sublingual dosage of 50 μg/day (350 μg/week) or 2000 μg/week in a single oral dose. [24]
Patients receiving oral dosages should be monitored for the desired response, since absorption can be variable and may be insufficient in some patients. Note the following [25] :
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Oral cobalamin is indicated in patients with hemophilia to avoid bleeding from intramuscular injections.
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Intramuscular cobalamin and not oral cobalamin should be used to treat patients with cobalamin-related neurological disorders.
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One advantage of parenteral over oral cobalamin is that all abnormalities in cobalamin absorption are bypassed.
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It may be practical to administer parenteral cobalamin initially and then switch to oral cobalamin.
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Proton pump inhibitors, H2-receptor antagonists, and metformin may reduce serum vitamin B-12 concentrations by inhibiting the absorption of vitamin B12. [26]
Patients who have undergone either a total or partial gastrectomy should be started on replacement therapy after the surgery to prevent the development of megaloblastosis. Oral vitamin B12 supplementation is effective and safe in patients who underwent total gastrectomy and should be considered the preferential form of supplementation. [27]
Folate Therapy
Folate should be administered orally. If this is difficult, comparable doses can be administered parenterally. [28, 29] In addition, the patient should consume a folate-enriched diet. The dosage range for folate is 1 to 5 mg daily; 1 mg/d is the usual dosage for adults with megaloblastic anemia, while a higher dosage is indicated in hemolysis, malabsorption, alcoholism, and exfoliative dermatitis. However, there is no harm in giving the higher dosage of folate.
Folate should be administered prophylactically during pregnancy, lactation, and the perinatal period. Folate is also indicated in patients with chronic hemolytic anemias, psoriasis and exfoliative dermatitis, and during extensive renal dialysis. Folate therapy has been recommended in patients with hyperhomocysteinemia who are at risk for thromboembolic complications. [30]
Fortification of foods and folic acid supplements have been recommended to reduce the risk of pancreatic, cervical, and colon cancers. Folic acid supplements are indicated in patients with kidney failure. Folate supplementation is indicated in elderly persons. However, opponents of fortification and supplementation are concerned that giving folate-fortified foods to persons with unrecognized cobalamin deficiencies will increase the frequency of cobalamin-induced neuropsychiatric disorders.
The dosage and protocol for folic acid therapy and supplementation in the various disorders mentioned above are summarized in a communication from the Mayo Clinic. [31]
Warning
Folate therapy should not be instituted in a patient with megaloblastic anemia if cobalamin deficiency has not been definitively ruled out. The danger is that folic acid will improve the anemia but not the neurological complications of cobalamin deficiency, and the neurological disorder will worsen. Both cobalamin and folate should be given if cobalamin deficiency has not been ruled out.
Monitoring Response to Therapy
Although patients may feel better as soon as therapy is started, improvements must be monitored. Laboratory tests to order include the following:
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Complete blood cell count
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Reticulocyte count
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Lactate dehydrogenase (LDH) level
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Indirect bilirubin
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Hemoglobin level
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Serum potassium level
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Serum ferritin
Elevated levels of LDH and indirect bilirubin should fall rapidly. A prolonged elevation of the LDH level indicates a failure of therapy, development of iron deficiency, or an error in diagnosis.
Reticulocytosis should be evident within 3-5 days and peaks in 4-10 days. Leukocyte and platelets counts are usually restored to normal within days after therapy has been started, but hypersegmented neutrophils may persist for 10-14 days.
The hemoglobin should rise approximately 1 g/dL each week. This rise is valuable for monitoring a complete response. If the hemoglobin does not rise appropriately and is not normal within 2 months, other causes of anemia, such as iron deficiency, should be considered.
Serum potassium levels can fall during therapy for severe cobalamin or folate deficiency, which can lead to sudden death. Therefore, potassium should be monitored and supplements may be indicated.
Iron deficiency can occur in the course of treatment due to the consumption of iron stores for red blood cell production. The development of iron deficiency can impede the response to cobalamin or folate therapy. Iron therapy may be indicated.
Treatment of Other Related Conditions
Other related conditions, if present, should be addressed as follows:
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Blind loop syndrome should be treated with antibiotics.
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Patients with transcobalamin II (TCII) deficiency may require higher doses of cobalamin.
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Tropical sprue should be treated with both cobalamin and folate.
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Acute megaloblastic anemias due to nitrous oxide exposure can be treated with folate and cobalamin.
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Fish tapeworm infection, pancreatitis, Zollinger-Ellison syndrome, and inborn errors should be treated with appropriate measures.
Dietary Measures
Patients with folate or cobalamin deficiency should receive dietary education on the choice of foods and instructions on how to prepare foods.
Patients should have diets rich with folic acid. Examples of such foods include asparagus, broccoli, spinach, lettuce, lemons, bananas, melons, liver, and mushrooms. To prevent loss of folate, foods should not be cooked excessively and should not be diluted in large amounts of water. To prevent cobalamin deficiency, vegetarians should include dairy products and eggs in their meals. Patients should know that goat milk contains little folate.
Consultations
A hematologist should be consulted to assist with the diagnosis and management of patients with megaloblastic anemias.
A neurologist should be consulted for patients with potential neurological complications of cobalamin and folate deficiencies.
A gastroenterologist should be consulted since an endoscopy may be indicated to rule out atrophic gastritis and to evaluate patients for gastric carcinoma with periodic endoscopies.
A pediatrician with expertise in inborn errors should be consulPernicious anaemia (PA) is associated with increased gastric cancer risk,ted to help treat children with hereditary megaloblastosis.
Long-Term Monitoring
Patients should be monitored for recurrence of megaloblastosis by periodic testing for hemoglobin levels and, if necessary, LDH and indirect bilirubin levels.
Patients with pernicious anemia should periodically undergo endoscopic screening, as they are at increased risk for gastric cancer. In addition, a systematic review found that the incidence of biliary tract cancers and hematological malignancies (multiple myeloma, Hodgkin lymphoma, non-Hodgkin lymphoma, and leukemia) was also increased in these patients. [32]
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Megaloblastic anemia. View of red blood cells
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Megaloblastic anemia. The structure of cyanocobalamin is depicted. The cyanide (Cn) is in green. Other forms of cobalamin (Cbl) include hydroxocobalamin (OHCbl), methylcobalamin (MeCbl), and deoxyadenosylcobalamin (AdoCbl). In these forms, the beta-group is substituted for Cn. The corrin ring with a central cobalt atom is shown in red and the benzimidazole unit in blue. The corrin ring has 4 pyrroles, which bind to the cobalt atom. The fifth substituent is a derivative of dimethylbenzimidazole. The sixth substituent can be Cn, CC3, hydroxycorticosteroid (OH), or deoxyadenosyl. The cobalt atom can be in a +1, +2, or +3 oxidation state. In hydroxocobalamin, it is in the +3 state. The cobalt atom is reduced in a nicotinamide adenine dinucleotide (NADH)–dependent reaction to yield the active coenzyme. It catalyzes 2 types of reactions, which involve either rearrangements (conversion of l methylmalonyl coenzyme A [CoA] to succinyl CoA) or methylation (synthesis of methionine).
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Megaloblastic anemia. Inherited disorders of cobalamin (Cbl) metabolism are depicted. The numbers and letters correspond to the sites at which abnormalities have been identified, as follows: (1) absence of intrinsic factor (IF); (2) abnormal Cbl intestinal adsorption; and (3) abnormal transcobalamin II (TC II), (a) mitochondrial Cbl reduction (Cbl A), (b) cobalamin adenosyl transferase (Cbl B), (c and d) cytosolic Cbl metabolism (Cbl C and D), (e and g) methyl transferase Cbl utilization (Cbl E and G), and (f) lysosomal Cbl efflux (Cbl F).
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Megaloblastic anemia. Cobalamin (Cbl) is freed from meat in the acidic milieu of the stomach where it binds R factors in competition with intrinsic factor (IF). Cbl is freed from R factors in the duodenum by proteolytic digestion of the R factors by pancreatic enzymes. The IF-Cbl complex transits to the ileum where it is bound to ileal receptors. The IF-Cbl enters the ileal absorptive cell, and the Cbl is released and enters the plasma. In the plasma, the Cbl is bound to transcobalamin II (TC II), which delivers the complex to nonintestinal cells. In these cells, Cbl is freed from the transport protein.
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Peripheral smear of blood from a patient with pernicious anemia. Macrocytes are observed, and some of the red blood cells show ovalocytosis. A 6-lobed polymorphonuclear leukocyte is present.
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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.
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Response to therapy with cobalamin (Cbl) in a previously untreated patient with pernicious anemia. A reticulocytosis occurs within 5 days after an injection of 1000 mcg of Cbl and lasts for about 2 weeks. The hemoglobin (Hgb) concentration increases at a slower rate because many of the reticulocytes are abnormal and do not survive as mature erythrocytes. After 1 or 2 weeks, the Hgb concentration increases about 1 g/dL per week.
