Hematology · Megaloblastic Anemia
The facts most likely to be tested
Vitamin B12 deficiency causes megaloblastic anemia characterized by hypersegmented neutrophils and an elevated mean corpuscular volume (MCV).
The hallmark neurologic manifestations include subacute combined degeneration of the spinal cord, presenting as symmetric paresthesias, ataxia, and loss of vibration/position sense.
Pernicious anemia is the most common cause of B12 deficiency, resulting from autoimmune destruction of parietal cells or intrinsic factor.
Patients with strict vegan diets or terminal ileum resection (e.g., Crohn disease) are at high risk for B12 deficiency due to impaired absorption.
Elevated levels of methylmalonic acid (MMA) and homocysteine distinguish B12 deficiency from folate deficiency, which presents with elevated homocysteine but normal MMA.
The Schilling test is historically significant but has been replaced by testing for anti-intrinsic factor antibodies to confirm the diagnosis of pernicious anemia.
Treatment requires intramuscular cyanocobalamin or high-dose oral B12 supplementation to bypass the need for intrinsic factor.
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A 68-year-old woman presents to the clinic complaining of progressive numbness and tingling in her feet and difficulty walking. Physical examination reveals atrophic glossitis, impaired proprioception, and positive Romberg sign. Laboratory studies show a hemoglobin of 9.2 g/dL, an MCV of 114 fL, and hypersegmented neutrophils on peripheral smear. Serum studies demonstrate elevated methylmalonic acid and low serum B12 levels.
What is the most likely underlying pathophysiology of this patient's condition?
Autoimmune destruction of gastric parietal cells
The patient's presentation of megaloblastic anemia with neurologic deficits and elevated MMA is diagnostic of B12 deficiency, most commonly caused by pernicious anemia (Bet 2 and Bet 3).
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Etiology / Epidemiology
Common in vegans, elderly, and patients with pernicious anemia or gastrectomy.
Clinical Manifestations
Presents with glossitis, megaloblastic anemia, and irreversible neurological deficits.
Diagnosis
Methylmalonic acid (MMA) elevation is the most sensitive test; Schilling test is historical.
Treatment
Intramuscular cyanocobalamin is the first-line treatment for malabsorption.
Prognosis
Hematologic recovery is rapid, but neurological damage may be permanent if untreated.
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Epidemiology & Etiology
Primary causes include pernicious anemia (autoimmune destruction of parietal cells) and dietary deficiency in strict vegans. Malabsorption syndromes like Crohn's disease, celiac disease, and chronic PPI/metformin use are frequent contributors. Surgical history of gastrectomy or ileal resection prevents intrinsic factor binding and absorption.
Pertinent Anatomy
Vitamin B12 requires intrinsic factor (secreted by gastric parietal cells) for absorption in the terminal ileum. Deficiency disrupts the myelin sheath of the dorsal columns and corticospinal tracts.
Pathophysiology
B12 acts as a cofactor for methionine synthase and methylmalonyl-CoA mutase. Deficiency leads to impaired DNA synthesis in rapidly dividing cells, causing megaloblastic anemia. Accumulation of methylmalonic acid causes demyelination of the central nervous system.
Clinical Manifestations
Patients present with glossitis (smooth, beefy-red tongue) and fatigue. Neurological symptoms include symmetric paresthesias, ataxia, and loss of vibration/position sense, known as subacute combined degeneration. Irreversible neurological damage occurs if treatment is delayed; psychiatric disturbances like megaloblastic madness may occur.
Diagnosis
CBC shows macrocytic anemia (MCV >100 fL) with hypersegmented neutrophils. Serum methylmalonic acid (MMA) and homocysteine levels are elevated. Anti-intrinsic factor antibodies confirm the diagnosis of pernicious anemia.
Treatment
Intramuscular cyanocobalamin is the standard for malabsorption. Oral high-dose supplementation is effective for dietary deficiency. Do not treat with folate alone as it corrects anemia but masks or worsens neurological progression.
Prognosis
Hematologic parameters normalize within 2 months. Neurological deficits may persist if present for >6 months. Monitor potassium levels during initial therapy due to risk of hypokalemia from rapid cell production.
Differential Diagnosis
Folate deficiency: normal MMA levels, no neurological symptoms
Myelodysplastic syndrome: persistent cytopenias despite B12 replacement
Hypothyroidism: macrocytosis without hypersegmented neutrophils
Liver disease: macrocytosis with abnormal LFTs
Copper deficiency: mimics B12 neurological symptoms with neutropenia