Macrocytic

DEFINITION: Macrocytic = abnormally large RBCs, MCV >100 fL (normal ~80-100). Macrocytic anemia = low hemoglobin plus MCV >100 fL.

CLASSIFICATION: 1) MEGALOBLASTIC (impaired DNA synthesis with nuclear-cytoplasmic asynchrony) - Vitamin B12 (cobalamin) deficiency: pernicious anemia (autoimmune loss of intrinsic factor from parietal cells; anti-intrinsic factor and anti-parietal cell antibodies; associated with atrophic gastritis and increased gastric cancer risk), strict vegan diet, Diphyllobothrium latum (fish tapeworm), terminal ileum disease (Crohn disease, resection), chronic pancreatitis, bacterial overgrowth, metformin or PPI use. - Folate (B9) deficiency: alcoholism, malnutrition, pregnancy (increased demand), hemolysis, proximal small bowel (jejunum) malabsorption (celiac disease, tropical sprue), drugs (phenytoin, methotrexate, trimethoprim-sulfamethoxazole). Body stores last only about 3-4 months, whereas B12 stores last years. - Orotic aciduria: a pyrimidine synthesis defect (UMP synthase). It causes megaloblastic anemia that does not respond to B12 or folate. Orotic acid in the urine, no hyperammonemia. Treat with uridine. - Drugs that block DNA synthesis: methotrexate (DHFR inhibitor), hydroxyurea, 5-FU, zidovudine, azathioprine, 6-MP.

Findings in megaloblastic anemia: macro-ovalocytes, hypersegmented neutrophils (>5 lobes), low reticulocyte count, pancytopenia in severe cases, ineffective erythropoiesis (increased LDH and indirect bilirubin, increased homocysteine).

B12 vs folate: - Both: increased homocysteine. - B12 deficiency only: increased methylmalonic acid (MMA) and neurologic findings. B12 is a cofactor for methylmalonyl-CoA mutase (MMA to succinyl-CoA) and homocysteine methyltransferase. Impaired myelin synthesis causes subacute combined degeneration (dorsal columns and lateral corticospinal tracts: paresthesias, loss of vibration and proprioception, spastic paralysis), plus dementia and neuropathy. - Folate deficiency: normal MMA, no neurologic findings. - Treatment trap: giving folate alone to a B12-deficient patient corrects the anemia but allows the neurologic damage to progress. Always rule out or treat B12 deficiency first. - Schilling test (historic) distinguishes causes of B12 malabsorption.

2) NON-MEGALOBLASTIC (normal DNA synthesis, round macrocytes, no hypersegmented neutrophils) - Alcohol use disorder (direct marrow toxicity plus folate deficiency; a common cause of isolated macrocytosis) - Liver disease (membrane lipid changes, target cells and macrocytes) - Hypothyroidism - Reticulocytosis (hemolysis, acute blood loss), because reticulocytes are larger - Myelodysplastic syndromes (look for dysplasia, ringed sideroblasts, pseudo-Pelger-Huet cells) - Drugs: hydroxyurea, zidovudine - Others: aplastic anemia, Diamond-Blackfan anemia (congenital pure red cell aplasia with macrocytosis, short stature, and thumb or craniofacial anomalies; mutations in ribosomal proteins) - Newborns have physiologic macrocytosis.

APPROACH: Confirm MCV >100, check reticulocyte count and peripheral smear (hypersegmented neutrophils suggest megaloblastic). Then measure B12, folate, and MMA/homocysteine as needed. Also check TSH, LFTs, and alcohol history. Consider bone marrow biopsy if the cause remains unclear (MDS).

CLINICAL PEARLS: - A low reticulocyte count with high MCV points to a production problem (B12/folate, MDS, drugs). A high reticulocyte count points to hemolysis or bleeding. - Pernicious anemia can also cause a smooth, beefy red tongue (glossitis). - Mnemonic for megaloblastic causes: "Folate from the Jejunum, B12 from the Ileum."