Paul Schick, MD, Emeritus Professor, Department of Internal Medicine, Thomas Jefferson University Medical College; Research Professor, Department of Internal Medicine, Drexel University College of Medicine; Adjunct Professor of Medicine, Lankenau Hospital, Wynnewood, PA
Updated: Aug 26, 2009
Megaloblastic anemias are a heterogeneous group of disorders that share common morphologic characteristics. Erythrocytes are larger and have higher nuclear-to-cytoplasmic ratios compared to normoblastic cells. Neutrophils can be hypersegmented, and megakaryocytes are abnormal. On the molecular level in megaloblastic cells, the maturation of nuclei is delayed, while cytoplasmicdevelopment is normal.
Megaloblastosis is a generalized disorder because nonhematopoietic cells, such as gastrointestinal and uterine cervical mucosal cells, can also have megaloblastic features. The etiology of megaloblastic anemias is diverse, but a common basis is impaired DNA synthesis. The most common causes of megaloblastosis are cobalamin (vitamin B-12) and folate deficiencies. The usual causesof cobalamin deficiency are pernicious anemia (PA, see Pernicious Anemia), failure of absorption of cobalamin in the terminal ileum, and the effects of medications. Folate deficiency is usually due to folate-poor diets but may also occur in patients with tropical sprue, in patients who are pregnant, and in patients on antifolate or other medications. Current routine folate replacement duringpregnancy and folate-containing multivitamin supplementation for elderly persons has led to a decline in the frequency of folate deficiency.
Some patients can be asymptomatic. The development of megaloblastic anemia is usually insidious; therefore, patients are often relatively asymptomatic because they have had time to adjust to the marked fall in hemoglobin (Hgb) levels. Patients with cobalamindeficiency may develop debilitating neurological impairment that may develop independently of anemia.
Recent trends in medical care have emphasized early therapy. Folate supplementation is recommended to prevent the atherosclerosis and thromboembolic events by reducing homocysteine levels. Folate is given during pregnancy to prevent developmental defects in the fetus. Mild cobalamin deficiencies andincipient cobalamin-related neuropsychiatric abnormalities have recently been identified in some individuals, and prompt early treatment with cobalamin is recommended to avoid progression of mental deterioration and neurological complications. One review focuses on the relation between various outcomes of human reproduction (ie, pregnancy, lactation, male reproduction) and folate nutrition andmetabolism, homocysteine metabolism, and polymorphisms of genes that encode folate-related enzymes or proteins.[1 ]
The molecular basis for megaloblastosis is a failure in the synthesis and assembly of DNA. The most common causes of megaloblastosis are cobalamin and folate deficiencies. Cobalamin metabolism and folate metabolism are intricately related, and abnormalities in thesepathways are believed to lead to the attenuated production of DNA.
Methotrexate-induced megaloblastosis has been ascribed to a deficiency in deoxythymidine triphosphate (dTTP) that is consumed by the methyl folate trap. Evidence exists that megaloblastosis is caused by interference of folate metabolism by the inhibition of methionine synthesis. However, because of dietary folate deficiency, thesize of the dTTP pool is normal or increased in persons with megaloblastosis.
Impairment in the deoxyuridine monophosphate (dUMP) – deoxythymidine monophosphate (dTMP) pathway may be responsible for nutritional megaloblastosis. Despite this information, the biochemical basis for megaloblastosis is not fully understood. This is especially true of the cobalamin-related neuropathy that can occur...