Folate deficiency differential diagnosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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Differential Diagnosis

Macrocytosis is defined as a MCV (mean corpuscular volume) greater than 100 fL. It can be divided into megaloblastic and non-megaloblastic types. Following are the causes of Non-megaloblastic anemia i.e. MCV >100 fL without DNA replication problems and megaloblastic changes.

• Alcoholism : This is a result of dietary lack, a weak antifolate action and due to a direct toxic effect of alcohol on the bone marrow.
• Hypothyroidism : Macrocytosis is found in up to 55% patients with hypothyroidism and may result from the insufficiency of the thyroid hormones themselves and also due to 20 times increased risk of pernicious anemia in people with hypothyroidism
• Aplastic anemia : Mild macrocytosis can be observed in association with stress erythropoiesis and elevated fetal hemoglobin levels in aplastic anemia.
• Reticulocytosis : Commonly due to hemolysis or a recent history of blood loss. This is due to increased hematopoeisis and rapid release of immature RBCs from the bone marrow to replace the blood loss.
• Liver disease  : Liver enzymes play an important role in the process of normal erythropoiesis
• Myeloproliferative diseas and Myelodysplastic syndromes : due to bone marrow dysfunction
• Chronic exposure to benzene and drugs like 5- Fluorouracil.

Folate and Vitamin B12 deficiencies : These are the two most important causes of Megaloblastic macrocytic anemia associated with impaired DNA synthesis and megaloblastic changes like hypersegmented neutrophils and glossitis. History and physical examination, vitamin B₁₂ level, reticulocyte count, and a peripheral smear are helpful in delineating the underlying cause of megaloblastosis. A measurement of methylmalonic acid in the blood or urine, can provide an indirect method for partially differentiating Vitamin B₁₂ and folate deficiencies. The level of methylmalonic acid is not elevated in folic acid deficiency while it is raised in Vitamin B12 (cobalamin) deficiency. Direct measurement of blood cobalamin and folate is the gold standard to differentiate between the two causes.

CONDITIONS	SIGNS/SYMPTOMS	INVESTIGATIONS
Vitamin B12 deficiency	May be associated with neurologic and neuropsychiatric symptoms. e.g. decreased vibration sense, peripheral neuropathy, gait abnormalities.	Serum vitamin B12 levels are low. Both homocysteine and methylmalonic acid are elevated.
Alcoholic liver disease	Nutritional deficiencies and macrocytic anemia may be the presenting features. History reveals alcohol abuse.	Elevated liver enzymes e.g. ALT and AST Liver biopsy shows fatty liver or cirrhosis.
Hypothyroidism	Associated with constipation, weight gain, cold intolerance, hoarse voice, bradycardia, dry skin, delayed tendon reflexes.	Elevated TSH, low T4, and low T3. Serum folate level is normal. Homocysteine is often elevated
Hereditary orotic aciduria	Growth retardation, neurologic abnormalities, and obstructive uropathy are associated with hypochromic megaloblastic anemia, with or without congenital malformations and immune deficiency. Replacement of uridine corrects anemia and reduces the orotic crystalluria.	Orotic acid crystalluria is present. Serum folate level is normal.
Myelodysplastic syndrome	Gradual-onset fatigue often present. Patients may have splenomegaly.	Macrocytic anemia may be associated with neutropenia and thrombocytopenia. Peripheral smear may show large, hypogranular platelets; hypogranulated, hyposegmented neutrophils with Dohle bodies; and circulating myeloblasts. Bone marrow shows dyserythropoiesis; hypogranulated, hyposegmented granulocytic precursors; increased myeloblasts; and megakaryocytes showing fewer or disorganized nuclei. Ringed sideroblasts are seen in the bone marrow in certain subtypes of myelodysplastic syndrome. Cytogenetic analysis and fluorescence in-situ hybridization can identify specific chromosomal abnormalities.
Aplastic anemia	History of recent viral illness, chemical exposure, or drug use. Bleeding and symptoms of infection are usually present. Ecchymosis and signs of infection may be present.	Macrocytic anemia, neutropenia, thrombocytopenia, and reticulocytopenia are present. Bone marrow aspirate and biopsy show decreased cellularity and paucity of all 3 lineage precursor cells.
Drug-induced macrocytosis	Associated with intake of certain drugs, such as DNA synthesis-inhibiting drugs, immunosuppressive drugs, anticonvulsants, and antiviral medications.	Serum folate level is normal.
Diphyllobothriasis	Presents with abdominal discomfort, diarrhea, vomiting, weakness, weight loss, and occasionally acute abdominal pain due to intestinal obstruction, cholangitis, or cholecystitis. Additional features are megaloblastic anemia and neurologic abnormalities secondary to vitamin B12 (cobalamin) deficiency.	Stool exam reveals characteristic eggs of the fish tapeworm Serum vitamin B12 levels are low. Serum folate is normal.