A 71-year-old man with ischemic cardiomyopathy and reduced ejection fraction (20%) presented for 1 month of intermittent substernal exertional chest pain. He also noted worsening fatigue and new imbalance when he closed his eyes. The chest pain felt similar to his myocardial infarction 6 years prior when a left heart catheterization showed 70% stenosis of the proximal right coronary artery and 75% stenosis of the left mid-circumflex artery. A drug-eluting stent was placed in the latter, resolving his symptoms at that time.
Examination revealed positive Romberg testing, absent proprioception, and absent vibratory sensation in both feet. Cardiopulmonary examination was unremarkable. He had a hemoglobin of 7.6 gm/dL (12 mg/dL 1 year prior) with a mean corpuscular volume (MCV) of 130.8 fL. Initial troponin was 0.027 ng/mL and trended to a peak of 0.040 ng/mL (<0.01 ng/mL). There were no ST-segment changes on his electrocardiogram.
After receiving a 1-unit transfusion of red blood cells, the patient’s exertional chest pain completely resolved, raising suspicion for anemia-driven demand ischemia. His reticulocyte count was 1.71% (0.5%-2.5%) with a low reticulocyte index of 0.34. Bilirubin was within normal limits and lactate dehydrogenase (LDH) was 863 U/L (84-246 U/L). The iron panel was unremarkable except for a nonspecific elevation in ferritin to 555 ng/mL (26-388 ng/mL). The folate level was 13 ng/mL (8.7-55.4 ng/mL). Vitamin B12 level was markedly low at 62 pg/mL (193-986 pg/mL). Serum intrinsic factor antibody was positive, confirming a diagnosis of pernicious anemia. He was treated with intramuscular vitamin B12 1000 mcg weekly for 5 weeks. Hemoglobin level recovered to 11.6 gm/dL and MCV to 106 fL. His chest pain did not recur. His imbalance improved, but his proprioception and vibratory sensation remained reduced. He was continued on supplemental oral vitamin B12.
Angina occurs as a result of a mismatch between cardiac muscle oxygen demand and oxygen supply caused by complete or partial blockages of the coronary vessels. In this patient with known coronary artery disease who presented with typical angina, there was a risk of premature diagnostic closure by incorrectly presuming that his coronary artery disease was worsening. This assumption may have led to invasive coronary angiography with the risk of contrast-induced nephropathy or local vascular injury.1 Although this patient’s coronary stenosis contributed to his presentation, the primary driving factor was demand ischemia from anemia, given that his symptoms resolved after a transfusion. Pernicious anemia is characterized by an inability to absorb vitamin B12 because of auto-antibodies against intrinsic factor. B12 is necessary for proper red blood cell division, without which large macrocytic megaloblastic red cells are formed. B12 is also crucial for myelin production as a cofactor for methionione synthase, which mediates the transfer of a methyl group from 5-methyl-tetrahydrofolate (THF) to homocysteine, forming methionine.2 Methionine is eventually converted to s-adenosylmethionine (SAM), a critical methylating agent in myelin maintenance and synthesis. B12 also serves as a cofactor in the conversion of L-methylmalonyl CoA (L-MMCoA) to succinyl CoA, without which excess L-MMACoA is generated and hydrolyzes to methylmalonic acid (MMA). Elevated MMA adds odd-chain and branched fatty acids to myelin, resulting in unstable myelin. This effect is greatest in the dorsal columns that carry sensory, vibratory, and proprioceptive information from the lower extremities. Subacute combined degeneration is a rare complication of B12 deficiency that presents with reduced or absent distal lower extremity sensation, vibration, and proprioception.
By tying together this patient’s hematologic and neurologic findings, the health care team suspected B12 deficiency and treated the patient appropriately without exposing him to unnecessary interventions. This case serves both as a caution against premature diagnostic closure and a reminder of the importance of a thorough history and physical examination to arrive at the correct diagnosis.
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-Michelle D. Lundholm, MDa,, Laurent Loganathan, MDa, Amit Dayal, MDb, Brian Schmitt, MDb
This article originally appeared in the November 2019 issue of The American Journal of Medicine.
