Acute Myocardial Infarction in a Young Patient with Severe Hyperhomocysteinemia Secondary to Pernicious Anemia

Abstract

Pernicious anemia often results in vitamin B12 deficiency and is commonly associated with hyperhomocysteinemia, a known risk factor for venous and arterial thrombosis. We report on a 39-year-old man presenting with worsening angina and ST-segment elevation, found to have a large thrombus in the left main coronary artery with occlusion of the distal left anterior descending artery and macrocytic anemia. Thrombectomy achieved decreased thrombus burden and resolution of symptoms, and further laboratory evaluation demonstrated pernicious anemia and high serum homocysteine. Treatment with subcutaneous vitamin B12 led to a rapid and sustained decline in homocysteine levels with no subsequent thrombotic events through 1 year of follow-up. This case demonstrates that pernicious anemia may cause significant cardiovascular complications due to hyperhomocysteinemia, and should be considered in the diagnosis of a patient with a thrombotic event and no evident atherosclerotic risk factors.

Introduction

Pernicious anemia is a common cause of vitamin B12 deficiency, due to a lack of intrinsic factor, a protein produced by gastric parietal cells and necessary for absorption of vitamin B12 in the terminal ileum.¹ The hallmarks of the disease are macrocytic anemia, neurological symptoms, and atrophic gastritis; however, venous and arterial thromboses have been reported as presenting symptoms as well.^2,3 

The link between B12 deficiency and thrombosis resides in the elevation of plasma homocysteine, which without cobalamin-dependent enzymes, cannot be converted to methionine. Elevated plasma homocysteine may result from nutritional deficiencies of vitamin B6, vitamin B12, or folic acid, or from genetic abnormalities in methionine metabolism, such as cystathionine beta-synthetase deficiency or methylenetetrahydrofolate reductase (MTFR) gene mutations.⁴

Studies have shown an association between homocysteine levels and atherosclerosis^5,6; however, the cardiovascular complications of undiagnosed or untreated pernicious anemia may be overlooked. We describe the case of a young man, presenting with ST-segment elevation myocardial infarction and no known cardiovascular risk factors, ultimately diagnosed with severe hyperhomocysteinemia and B12 deficiency secondary to pernicious anemia, and successfully managed with vitamin supplementation. 

Case report

 A 39-year-old man with a past medical history of hypothyroidism presented with a 2-day history of worsening angina. Initial vital signs were stable. Electrocardiogram revealed ST-segment elevation in the inferior leads. The patient received 325 mg of aspirin, 600 mg of clopidogrel, and a bolus of unfractionated heparin, and was taken for urgent coronary angiography. The initial angiographic images revealed a large left main thrombus with complete occlusion of the distal left anterior descending artery (LAD), and a dominant right coronary artery without evidence of disease. Thrombectomy of the left main thrombus was attempted with an Export aspiration catheter (Medtronic) and AngioJet catheter (Medrad). After multiple attempts, significant residual thrombus remained. The distal LAD lesion was considered not amenable to percutaneous intervention due to significant proximal thrombus burden. The patient’s chest pain resolved during the procedure and he was transferred to the cardiac intensive care unit on continuous infusions of heparin and eptifibitide.

Following the procedure, further history was obtained, in which the patient complained of paresthesias in his hands and feet for a few months prior to the admission. Laboratory assessment was notable for macrocytic anemia with a mean corpuscular volume of 105 fL and hemoglobin of 11.2 g/dL. Cardiac troponin I peaked at 26 ng/mL. Transesophageal echocardiogram showed a mildly depressed left ventricular ejection fraction with mild hypokinesis of the inferior wall and no evidence of an atrial septal defect or patent foramen ovale. Doppler ultrasound of the lower extremities did not show evidence of deep venous thrombosis.  

The patient’s young age, neuropathy, anemia, and significant thrombus burden prompted an extensive laboratory investigation for hyperocagulability risk factors (Table 1). The patient was found to have a severely elevated homocysteine level of 105 µmol/L and marked vitamin B12 deficiency. Genetic testing for MFTR C677T gene mutation was negative. A positive anti-parietal cell antibody test confirmed the diagnosis of pernicious anemia as the underlying etiology. Daily parenteral vitamin B12 was initiated, in addition to routine pharmacotherapy for acute myocardial infarction.

During his recovery, the patient had several episodes of chest pain, without corresponding EKG changes, which resolved with sublingual nitroglycerin. Repeat coronary angiography showed no evidence of residual thrombus and intravascular ultrasound did not identify any obstructing, vulnerable, or ruptured plaque in the territory involving the culprit lesion. After 6 days of vitamin B12 repletion, the patient’s homocysteine level decreased to 12 µmol/L. Following rehabilitation, the patient was discharged to home on the following medical regimen: subcutaneous vitamin B12 supplementation, aspirin, clopidogrel, warfarin, lisinopril, metoprolol, and levothyroxine. 

The patient was followed up to 1 year after his myocardial infarction. During that time, his neuropathy resolved and he did not demonstrate signs or symptoms of heart failure. The patient had infrequent occurrences of chest pain with exertion that resolved without therapy and no subsequent thrombotic events.   

Discussion

Homocysteine is a sulfur-containing amino acid that is converted to methionine via methionine synthase. This reaction requires vitamin B12 as a cofactor. The most common cause of severe homocysteinemia is the homozygous deficiency of cystathionine beta-synthetase, which has a prevalence of approximately 1 in 335,000 people.⁷ Additional etiologies include homozygous deficiency of MTHFR, errors of cobalamin metabolism, and vitamin B6, B12, and folic acid deficiencies.⁸ Pernicious anemia is a common cause of B12 deficiency, though its association with hyperhomocysteinemia may be overlooked in the evaluation of thrombotic events.

In 1969, Kilmer MucCully first described the link between elevated homocysteine levels and atherothrombotic disease in two children with inborn errors of methionine metabolism and diffuse arterial plaques.⁹ Fifty percent (50%) of individuals with severe elevations in homocysteine will endure a major vascular event, such as myocardial infarction, stroke, or venous thromboembolism, before the age of 30.¹⁰ Therapy with vitamin supplementation and methionine restriction may significantly reduce the risk of adverse cardiovascular events, as shown in this case¹¹; however, randomized prospective trials have failed to show this effect.^12-14

Multiple epidemiological studies and meta-analyses have shown that even a mild elevation in homocysteine is a risk factor for major vascular events.^5,6,15,16 The pathophysiologic mechanism linking hyperhomocysteinemia with vascular events remains unclear, though human and animal studies have demonstrated abnormal endothelial-dependent vasorelaxation in response to elevated serum homocysteine. It appears that increased oxidative stress may lead to decreased bioavailabilty of endothelium-derived nitric oxide.¹⁷ In addition, homocysteine contains a reactive thiol group, which can undergo disulfide reactions with cysteine residues in proteins, and potentially alter the function of those required for normal vascular function. The resulting stress to the endoplasmic reticulum may manifest as activation of inflammatory pathways, impaired insulin signaling, dysregulation of lipid metabolism, and apoptotic cell death. Homocysteine has been shown to modulate tissue plasminogen activator binding to vascular endothelial cells, activate clotting factors VIIa and V, and inhibit protein C and heparin sulfate.  This complicated interplay of endothelial dysfunction, pro-inflammatory, and pro-thrombotic events has been postulated to lead to accelerated atherosclerosis, plaque rupture, and thrombosis.^7,17 

Conclusion

Hyperhomocysteinemia secondary to vitamin B12 deficiency due to pernicious anemia should be considered in the differential diagnosis of a patient presenting with an atherothrombotic event and no evident cardiovascular risk factors. This case demonstrates that vitamin supplementation can result in a rapid reduction in homocysteine levels as well as the successful abeyance of thrombotic events. It also highlights the potential serious cardiovascular complications of undiagnosed or untreated pernicious anemia. 

Disclosures: The authors report no financial relationships or conflicts of interest regarding the content herein.

This article received a double-blind peer review from members of the Cath Lab Digest editorial board.

The authors may be contacted via Jason Litsky, DO, MS, at jason.litsky@yale.edu.

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