Case Presentation: A 50-year-old man with chronic alcohol use (10 beers per week) presented with three months of malaise, lower extremity edema, and 20-pound weight loss. Physical exam revealed jaundice, macroglossia, 2/6 apical systolic murmur, lung crackles, abdominal distension, and bilateral lower extremity pitting edema. Initial labs were notable for hemoglobin of 2.3 g/dL, MCV 160 fL, WBC 4500/mcL, platelets 16,000/mcL, D-dimer 648 ng/ml (normal: < 230 ng/mL), reticulocyte index 0.396% (0-2.5%), LDH 860 U/L (140-280 U/L), total bilirubin 4.4 mg/dL (0.1- 1.2 mg/dL), direct bilirubin 2.6 mg/dL (0-0.3 mg/dL) and haptoglobin < 20 mg/dL (30-200 mg/dL). A peripheral blood smear showed macrocytes and giant platelets. Vitamin B12 level was 243 pg/mL (211-946 pg/mL). Iron studies were normal, and Coombs testing was negative. Glucose-6-phosphate dehydrogenase levels were normal. Methylmalonic acid (MMA) levels, anti-intrinsic factor (IF) and parietal cell antibodies were sent. Imaging showed cardiomegaly, bilateral pleural effusions, and ascites, consistent with high-output heart failure.The patient was transfused and empirically started on folate, thiamine, and intramuscular cobalamin. Blood smear was unrevealing, however was obtained post transfusion. The patient did not show any signs of overt blood loss throughout his hospital course. He was discharged with outpatient follow-up and parenteral cyanocobalamin. After discharge, MMA levels resulted and were markedly elevated to 263,482 nmol/L (0-378 nmol/L). Anti-IF and parietal cell antibodies were positive, confirming autoimmune gastritis. The patient continued to receive parenteral cyanocobalamin with improvement in his anemia (hemoglobin: 14.9 g/dL), and is currently awaiting outpatient endoscopic evaluation.
Discussion: Vitamin B12 deficiency causes megaloblastic anemia primarily via ineffective erythropoiesis, but severe deficiency can also lead to hemolysis. The proposed mechanism of cobalamin deficiency causing non-immune hemolytic anemia is via increased homocysteine levels. Homocysteine has pro-oxidative qualities and has been found in vitro to provoke hemolysis through lipid peroxidation of cell membranes. Approximately 30-50% of patients with PA may present with falsely normal or elevated serum B12 levels. In patients with PA, anti-IF antibodies interact with assay reagents, leading to falsely elevated serum B12 results. Patients with other manifestations of B12 deficiency should undergo further testing to determine MMA levels, and if elevated, should be tested for anti-IF and anti-parietal cell antibodies. Since failure to treat B12 deficiency can have severe consequences, patients with severe deficiency or neurological symptoms should receive treatment with intramuscular cobalamin while awaiting confirmatory testing. It is important to monitor potassium levels in patients with severe deficiency receiving parenteral vitamin B12, as brisk erythropoiesis can lead to hypokalemia.
Conclusions: Clinicians should remember that normal serum levels of B12 do not exclude B12 deficiency, as was the case with our patient. In patients with a history of malabsorption, alcohol use, proton pump inhibitor or metformin use, clinicians should have a low threshold to test for MMA to avoid delays in diagnosis and treatment.