Ischaemic stroke with multi-focal venous and arterial thrombosis due to hyperhomocysteinemia: anabolic androgenic steroid use and MTHFR c.667 C > T variant – a case report

Severely elevated serum homocysteine is a rare cause of ischaemic stroke and extra-cranial arterial and venous thrombosis. Several factors can lead to mild elevation of homocysteine including dietary folate and B12 deficiency, and genetic variants of the methylenetetrahydrofolate reductase (MTHFR) enzyme. Use of Anabolic androgenic steroid (AAS) is under reported, but increasingly linked to ischaemic stroke and can raise homocysteine levels.

We present a case of a 49-year-old male repatriated back to the United Kingdom (UK) following a left middle cerebral artery (MCA) territory ischaemic stroke which occurred whilst abroad. The initial National Institute of Health Stroke Scale (NIHSS) was 15. His primary deficits were a severe mixed aphasia and verbal apraxia (NIHHS 2), with difficulty following two-step commands and impaired comprehension at the sentence level. He had a partial right facial paralysis (NIHSS 2) with severe right arm and leg weakness (NIHSS 4 and 2 respectively). Left MCA infarct involving frontal, temporal, and parietal lobes was demonstrated on initial CT and MRI imaging (Fig. 1). He was also found to have both a pulmonary embolism on CT pulmonary angiography and a right popliteal artery thrombus on lower limb ultrasonography.

He had a diagnosis of Crohn’s disease, that was well controlled with azathioprine and for which a colectomy and ileostomy were performed over ten years prior. There was no evidence of active Crohn’s colitis during his admission. He did not smoke or drink alcohol. However, after his stroke, it came to light that he had engaged in covert persistent anabolic androgenic steroid (AAS) use over six years for body building.

Carotid doppler studies, interval MRI and CT did not reveal any intracranial vascular abnormalities. Investigations for cardioembolic stroke including trans-thoracic and bubble echocardiography, and prolonged cardiac monitoring were negative. A CT-PET was performed that was negative for malignancy and Crohn’s disease activity.

He had an elevated total homocysteine concentration of 87 µmol/L (Reference range (RR): 5–12 µmol/L) following the acute infarct with a corresponding normal methylmalonic acid 0.11µmol/L (RR: <0.29 µmol/L), low vitamin B12 74 pg/mL (RR: 160–800 pg/mL), and low folic acid level < 2.2ng/mL (RR: >2.7 ng/mL). Serum testosterone was suppressed at 0.8nmol/L (RR: 10-30nmol/L) secondary to presumed exogenous steroid use. Subsequent genetic testing for methylenetetrahydrofolate reductase (MTHFR) variants showed that he was homozygous for the common c.677 C > T MTHFR thermolabile variant.

His admission was complicated by significant agitation due to a combination of AAS withdrawal, and combined aphasia. He was temporarily commenced on risperidone (1 mg daily). His initial antiplatelet medication was converted to apixaban due to his pulmonary and peripheral artery emboli. He was treated with hydroxocobalamin (1 mg intramuscular 3 monthly) and folate replacement (5 mg once daily), both of which normalized along with homocysteine.

He made significant improvements following several months of stroke rehabilitation. Interval MRI imaging demonstrated a mature left MCA infarct (Fig. 2). Prior to discharge he was self-caring and mobilizing independently. He had persistent speech apraxia and limited verbal output but was able to communicate using written methods. He was repatriated to a local hospital awaiting social care input and ongoing speech and language therapy.

Homocysteine is a toxic intermediate of the metabolism of the amino acid methionine, low levels are therefore typically maintained in plasma[1]. Ineffective intracellular metabolism of homocysteine leads to an increase in its plasma concentration. Homocysteine metabolism is dependent on sufficient Vitamin B6, B12, folate, and the function of the MTHFR enzyme. The recycling of homocysteine to methionine is dependent on both the MTHFR enzyme and folate as essential co-factors[2]. Hyperhomocysteinemia is one of the few conditions that may present with both arterial and venous thrombosis. The dose-dependent relationship between homocysteine concentration and risk of ischaemic stroke, as well as extracranial arterial and venous thromboembolism, is well characterized [3, 4]. Homocysteine has been shown to induce endothelial dysfunction, promote oxidative stress, and induce coagulation abnormalities such as reduced activity of tissue plasminogen activator (tPA) and increased activation of Plasminogen activator inhibitor-1( PAI-1) [5‐7]. Chronic mild elevations of homocysteine may also promote large and small vessel atherosclerosis leading to ischaemic stroke [7].

AAS use is common in the UK and is likely under-reported; in our case this was covert and only subsequently revealed. Anabolic androgenic steroid use leading to ischaemic stroke has been previously reported but primarily limited to case reports [8‐10]. Proposed prothrombotic mechanisms include dyslipidemia, platelet aggregation, and increased hematopoiesis resulting in erythrocytosis [11‐13]. A study by Graham et al. demonstrated chronic anabolic steroid use can raise homocysteine levels compared to controls independent of B12 and folate concentration[14]. Elevation of homocysteine by AAS may contribute to stroke risk, however, the exact mechanism by which AAS leads to elevated homocysteine is unknown [12, 14].

Several known variants of the MTHFR gene exist leading to reduced activity of the enzyme MTHFR. A thermolabile variant was first discovered in 1988 caused by a missense mutation, c.677 C > T (rs1801133) [15]. This variant is common with significant differences between ethnic groups, with the highest prevalence in White and Hispanic populations [16]. The estimated global prevalence of heterozygotes is between 30 and 50% and homozygotes between 3 and 15% (16). Homozygotes with this MTHFR variant have an enzymatic function at roughly 30% compared to those without the variant [17]. Homozygosity is associated with a mild elevation of homocysteine and increased stroke risk compared to heterozygotes and controls. The extent in which MTHFR variants contribute to stroke risk has been inconsistent or thought to be moderate compared to the classical stroke risk factors[18].

Plasma homocysteine can be reduced through treatment with folic acid supplementation. However, the results of large trials for stroke prevention with B vitamins and folic acid supplementation are inconsistent and largely negative [19‐21]. Analysis of stroke outcomes from the Heart Outcomes Prevention Evaluation 2 trial did suggest a reduction in stroke incidence with folic acid supplementation in sub-groups without routine folic acid fortification in food and sub-groups with higher baseline homocysteine levels [20]. Furthermore, a meta-analysis of folic acid supplementation in countries without routine fortification in foods was associated with a 25% risk reduction in stroke [22].

It is suggested that patients with MTHFR c.677 C > T variants may have increased folate requirements to maintain normal serum folate and homocysteine concentrations[23]. The China stroke primary prevention randomized control trial demonstrated reduced stroke risk with folic acid replacement in the MTHFR variant population [24]. Therefore the MTHFR variant sub-group may represent a high-risk group for intervention [23]. Routine testing of homocysteine which is typically reserved for young stroke presentations in the UK may be a useful screen to guide further MTHFR gene testing as part of our stroke management.