Causes of megaloblastic anemia include vitamin B 12 cobalamin or folate vitamin B 9 deficiency and specific drugs. Vitamin B 12 deficiency and associated megaloblastic anemia may be caused by pernicious anemia, in which a lack of intrinsic factor IF prevents sufficient absorption of vitamin B The initial evaluation for megaloblastic anemia includes a CBC and review of a peripheral blood smear.
Patients with megaloblastic anemia may present with symptoms of anemia such as pale skin and fatigue. In severe cases, atrophy of mucous membranes may occur and result in pain in the mouth; infants may exhibit failure to thrive. There may be jaundice as a result of hemolysis. Patients with megaloblastic anemia due to vitamin B 12 deficiency may also present with symptoms of peripheral neuropathy, such as dysesthesia and hypoesthesia.
In severe cases, ataxia and other severe peripheral and central nervous system manifestations eg, changes in mental status of prolonged vitamin B 12 deficiency may be present.
However, some patients may be asymptomatic, and certain laboratory features of megaloblastic anemia may be masked by concurrent iron deficiency or microcytic anemia. An evaluation for megaloblastic anemia is often prompted by CBC results. A peripheral blood smear may reveal macro-ovalocytes, anisocytosis, poikilocytosis, and hypersegmented neutrophils, a specific indicator of megaloblastic anemia.
Causes of megaloblastic anemia include vitamin B 12 or folate deficiency as a result of decreased intake, decreased absorption, or increased demand , specific drugs, inborn errors of metabolism, myelodysplastic syndromes , and problems with DNA synthesis eg, from chemotherapy.
However, folate fortification programs are increasingly common and have greatly reduced the prevalence of folate deficiency.
There are numerous less common causes, including nitrous oxide exposure and Diphyllobothrium latum infection. Because vitamin deficiency is a major cause of megaloblastic anemia, older individuals, persons who are malnourished, those with alcohol use disorder , and individuals who consume a vegetarian or vegan diet are at increased risk for megaloblastic anemia.
Drugs that induce megaloblastic anemia typically interfere with vitamin B 12 or folate absorption or metabolism. These drugs include immunomodulators and antineoplastic agents that act on purine metabolism or pyrimidine synthesis eg, methotrexate, fluorouracil ; antibiotics, hormones, or tuberculosis treatments that interfere with absorption eg, estrogens, tetracyclines, isoniazid ; antimalarial agents; and many others.
A detailed medical history is therefore useful in ruling out medication-related megaloblastic anemia. Testing for megaloblastic anemia is often prompted by the identification of macrocytosis from a CBC; if neurologic symptoms or other clinical features prompt testing, a CBC should be performed. Hemoglobin and hematocrit can be measured to confirm anemia. Once macrocytic anemia has been confirmed, a peripheral smear is recommended. Anisocytosis, poikilocytosis, macro-ovalocytes, and hypersegmented neutrophils may be present.
However, these peripheral smear findings are not diagnostic. A reticulocyte count is also recommended. The reticulocyte count is generally low in megaloblastic anemia; therefore, if reticulocytosis is present, consider a workup for hemolysis including lactate dehydrogenase and bilirubin tests. If megaloblastic anemia is suspected based on clinical features and the results of the CBC and peripheral smear, evaluation for possible drug-induced megaloblastic anemia through a detailed medical history is recommended.
If the megaloblastic anemia is not drug induced, testing for vitamin deficiencies should be considered. Testing for vitamin B 12 deficiency begins with a serum concentration test. Follow-up testing depends on the result of this test. Source: Green, The MMA test is a sensitive and specific indicator of vitamin B 12 deficiency that can be used if the serum vitamin B 12 concentration is borderline.
Plasma homocysteine levels may also be increased in vitamin B 12 deficiency, although this test is not specific. If vitamin B 12 deficiency is confirmed, evaluation for pernicious anemia is recommended. Testing for folate deficiency should begin with a serum or plasma folate test.
If results are not conclusive, an RBC folate test can be performed, followed by a homocysteine test if the concentration of folate is borderline. Although the homocysteine test is not specific, an increased homocysteine level is consistent with folate deficiency. The majority of patients with pernicious anemia have antibodies for parietal cells and IF. In patients with confirmed vitamin B 12 deficiency, testing for pernicious anemia is recommended.
In patients with borderline vitamin B 12 and MMA test results, this testing is considered optional. Antibodies to IF are specific to pernicious anemia and are present in the majority of patients. A positive IF antibody test confirms pernicious anemia. Parietal cell antibody tests are more sensitive than IF antibody tests, but parietal cell antibodies are less specific to pernicious anemia and may be seen in chronic gastritis.
A positive parietal cell antibody test following a negative IF test in the appropriate clinical context confirms the diagnosis of pernicious anemia.
Gastrin concentration is generally elevated in pernicious anemia but may be increased in other conditions as well. Gastrin testing can be considered to indirectly confirm pernicious anemia if a parietal cell antibody test is negative but suspicion for pernicious anemia persists.
The Schilling test is an obsolete test that measures the enteral absorption of vitamin B 12 ; it is not generally available. In some cases, medications like anticonvulsants and anticancer agents cause megaloblastic anemia related to folate deficiency by affecting folate metabolism. Vegan diets are low in vitamin B 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. Other causes of impaired vitamin B12 absorption include Zollinger-Ellison syndrome, blind loop syndrome, fish tapeworm infestation, and pancreatic insufficiency.
Clinical copper deficiency can cause microcytic, normocytic, or macrocytic anemia and neutropenia. Copper deficiency also causes myelopathy and peripheral neuropathy.
Bone marrow evaluation can reveal myelodysplasia and megaloblastic anemia. Treatment with copper replacement promptly reverses hematologic manifestations of the disease, although neurologic manifestation may take longer. Drug-induced megaloblastic anemia can occur from a variety of different medications via various different mechanisms.
Drugs known to cause megaloblastic changes in the bone marrow include: [12]. Megaloblastic anemia is not rare, but data are insufficient regarding its prevalence. Moreover, there is a variation amongst different populations, which may be dependent on universal supplementation of folate in dietary products, frequency of chronic illnesses, such as pernicious anemia and Helicobacter pylori H. In a study from the Netherlands, evaluating more than patients with anemia, only 7.
Approximately 1. The incidence of pernicious anemia is higher in the United Kingdom and Nordic countries than in other developed countries. The incidence of folate deficiency is low, especially in countries with universal supplementation of folate in dietary products.
A report from Canada, reported a prevalence of 0. The pathophysiology of this group of anemia is ineffective erythropoiesis secondary to intramedullary apoptosis of hematopoietic cell precursors, which results from DNA synthesis abnormalities.
Both vitamin B12 and folate deficiencies may cause defective DNA synthesis. Subsequently, the nucleus and cytoplasm do not mature simultaneously. The cytoplasm in which hemoglobin synthesis is unaltered mature at the normal rate, and the nucleus with impaired DNA synthesis is not fully mature. The primary role of folate is to donate methyl groups in DNA synthesis. Vitamin B12 is a cofactor in the reaction that recycles 5-methyl-tetrahydrofolate back to tetrahydrofolate THF.
The generation of THF is coupled to the conversion of homocysteine to methionine. Lack of vitamin B12 causes folate to become trapped in the 5-methyl-THF form, and it also leads to a deficiency of methionine. With altered DNA synthesis hematopoiesis is disrupted as hematopoietic precursor cells are rapidly dividing cells. As stated above, these deficiencies lead to arrested nuclear division without significant alteration in the cytoplasmic maturation cycle.
Nucleated precursor cells in the bone marrow develop immature or morphologically abnormal nuclei and giant metamyelocytes, with macrocytic red blood cells and hypersegmented neutrophils on the peripheral blood smear.
The pathophysiology behind pernicious anemia involves autoantibodies against the intrinsic factor or gastric parietal cell antigens. In a myelogram, megaloblastosis presents as large red blood cells megaloblasts and hypersegmented neutrophils, which are detectable in a peripheral blood smear. Poikilocytosis and anisocytosis are common due to ineffective erythropoiesis.
The bone marrow evaluation shows hypercellularity with abnormal maturation and proliferation of red cell precursors. Erythroblasts show a failure of nuclei maturation, maintaining open or lax chromatin and normal mature cytoplasm.
The most common presentation of megaloblastic anemia is an asymptomatic incidental finding on routine laboratory testing.
Usually, anemia develops gradually, and symptoms are present only in severely anemic patients. Common symptoms include weakness, shortness of breath primarily with exertion , palpitation, and lightheadedness. Physical examination may reveal pallor, tachycardia, functional heart murmur, Hunter glossitis, and splenomegaly. Jaundice can occur from intramedullary hemolysis. There are some minor differences between the clinical manifestations caused by cobalamin deficiency and folic acid deficiency.
In vitamin B12 deficiency, neurological manifestations are observable. The main symptoms are paresthesia and balance disorders. Patients with vitamin B12 deficiency may present lancinating pains caused by peripheral neuropathy, mainly affecting the lower extremities. Less frequently, there may be a development of visual disturbances caused by optic atrophy. The clinical exam usually shows a loss of vibratory sense and proprioception with a positive Romberg test.
Babinski reflex, hyporeflexia, and clonus are less frequent. Moreover, there are psychological disturbances that include a form of dementia. These neurological disorders may not be completely reversible after replacement therapy. Pernicious anemia frequently has associations with other autoimmune conditions such as autoimmune thyroid disease, type 1 diabetes, and vitiligo.
Clinical suspicion for megaloblastic anemia should be high in patients with unexplained macrocytic mean corpuscular volume [MCV] greater than fL anemia or hypersegmented neutrophils on a peripheral smear. An MCV of greater than 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.
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. In patients with suspected disorders of absorption or malnutrition such as excess alcohol consumption, both levels should be obtained.
Spuriously low serum vitamin B12 levels can occur in patients with multiple myeloma, HIV infection, pregnancy, oral contraceptive use, and diphenylhydantoin administration. Methylmalonic acid and homocysteine levels can be obtained in patients with borderline results from the above testing.
They are often also ordered to confirm the diagnosis of B12 deficiency. Homocysteine is elevated in both vitamin B12 and folate deficiencies. In patients with evidence of B12 deficiency from the above testing, autoantibodies assays to test for antibodies against intrinsic factors should be obtained.
Although the sensitivity of this assay is low, the specificity is quite high and a positive test is diagnostic of pernicious anemia. 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. Vitamin B12 and folic acid can be given orally or parenterally. If there is no evidence of malabsorption, the generally preferred route for supplementation is oral.
In asymptomatic cases oral supplementation is sufficient. In patients with neurologic symptoms or those with increased demand such as pregnancy and in infancy, vitamin B12 and folic acid supplementation should be initiated parenterally. Patients with symptomatic anemia may require a blood transfusion to relieve symptoms, as vitamin B12 and folic acid supplementation do not correct anemia rapidly.
Vitamin B12 is also available in a sublingual formulation, which may be appropriate for patients with intestinal malabsorption syndromes. The recommended dose for vitamin B12 supplementation in children is 50 to 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 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 mcg daily is equally effective as the above parenteral regimen, provided that there is no intestinal malabsorption issue.
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.
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. Subgroup analysis in the study revealed that absence of sensory dermatomal deficit, Romberg, and Babinski signs, age less than 50 years, and less than or equal to 7 segment involvement on magnetic resonance imaging, correlated with resolution of neurologic symptoms.
The complete blood count may show macrocytosis in non-megaloblastic macrocytic anemias. Reticulocyte count will help distinguish between two primary conditions.
If reticulocytosis is present, hemolytic anemia and acute hemorrhage are the two main conditions for which the clinician must look. If a reticulocytopenia is present, the underlying conditions may be evident in some cases, such as hypothyroidism, alcoholism, liver dysfunction, and certain drugs. In other cases, one should perform bone marrow aspiration provided that the investigations to exclude vitamin B12 or folate deficiency are carried out.
Indeed, myelodysplastic disorders and sideroblastic anemia can manifest as refractory megaloblastic anemia. The prognosis for megaloblastic anemia is favorable with proper identification of the precise etiology and the institution of appropriate treatment. There are some complications of the disease that can lead to poor outcomes in patients, such as gastric malignancy in patients with pernicious anemia as the cause of megaloblastic anemia.
Health News Posted on January 13, -. Medindia provides you with the latest news and research breakthroughs on Megaloblastic Anemia. Please find 13 such items on this topic. Vitamin B12 deficiency status is associated with depressive symptoms in older adults but folate deficiency is not associated with depression.
This finding is shown in a new study published in the British Journal of Nutrition. Deficiency of Low levels of vitamin B12 impairs fat metabolism, which could increase the risk of obesity during pregnancy, reports a new study. The findings of the study are presented at the Society for Endocrinology annual conference. Pregnant women with People with vitamin B12 deficiency are at a higher risk of having infections, reports a new study.
Using roundworms, one of Earth's simplest animals, Rice University Nutrient-enriched plants containing high levels of Vitamin B12 cobalamin can reduce vitamin B12 deficiency, discovers a new study. Scientists at the University of Kent have made a significant discovery about how the vitamin content of some Highlights Losing weight has become an obsession among people and suddenly switching to healthy eating causes vitamin B12 deficiency Orthorexia nervosa is the obsessive healthy eating disorder that can lead to social isolation, Highlights Vitamin B12 is naturally found in animal products like fish, meat, poultry, eggs and milk.
Previous research states that maternal deficiency of vitamin B12 caused low birth weight and high cholesterol levels in babies. It is believed that a deficiency of folic acid could cause several problems like spina bifida, placental abnormalities and heart disease in the offspring.
A study out today reveals that a mutation in a gene necessary for the metabolism of folic acid An article published in the Journal of Agricultural and Food Chemistry discusses how vitamin B12 deficiency can be avoided in vegetarians. Vitamin B12 or cyanocobalamine is among the important vitamins for optimal nervous tissue and
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