Endocrine Abstracts

Introduction: Hyperhomocysteinemia (HHcy) is a metabolic disorder with cardiovascular, thromboembolic, and ocular complications. Nutritional deficiencies and renal impairment are common causes. HHcy without these should prompt investigation for re-methylation disorders/cystathionine β-synthase (CBS) deficiency.

Case Presentation: A 42-year-old male detected with HHcy during evaluation for CRVO. Plasma homocysteine was 62.2 (0–15 μmol/l). Vit.B12 was normal, but serum folate (3.8 μg/l) although within reference range, was below therapeutic target (>6 μg/l) recommended for HHcy. LDL was 4.1 with HDL 0.9 mmol/l. Liver, thyroid and renal function normal. He was given folic acid to meet therapeutic target. Repeat homocysteine was 27.3 μmol/l post folate supplementation with normalization of homocysteine and resolution of biochemical abnormalities. Genetic testing was planned.

Discussion: Homocysteine metabolism intersects with one carbon metabolism, methylation pathways, and amino acid homeostasis through re-methylation (requiring folate and vit.B12 and trans-sulphuration to cysteine, catalysed by CBS and requiring vit.B6. Hypothyroidism and insulin resistance can interfere with hepatic methylation leading to HHcy. Even biochemically euthyroid individuals with impaired thyroxine sensitivity can develop HHcy due to impaired re-methylation. Thyroxine replacement reduces homocysteine levels and in combination with folate offers superior therapeutic benefits. The most common genetic cause of HHcy is homozygosity for MTHFR 677C→T variant. Homozygotes develop raised homocysteine when serum folate is low. Even folate levels within normal range may be insufficient for optimal re-methylation in patients with MTHFR polymorphisms. Hence therapeutic folate targets (>6.8 μg/l) are recommended. In our case, folate supplementation led to a marked reduction in homocysteine from 62.2 to 27.3 μmol/l, confirming the critical role of optimized folate status.

Conclusion: This highlights the importance of considering genetic causes in adults with HHcy. Systematic evaluation, genetic testing, and coordinated metabolic follow-up are key to optimizing outcomes in these rare but treatable disorders.