Hyperhomocysteinemia is a well-established and modifiable risk factor associated with cardiovascular disease, stroke, cognitive decline, and systemic inflammation. Conventional therapeutic approaches based on folate, vitamin B12, and vitamin B6 supplementation are widely implemented and frequently effective. However, a subset of patients presents persistent elevations in homocysteine levels despite adequate or supraphysiological concentrations of these cofactors. This paradox highlights the complexity of homocysteine metabolism and suggests the presence of functional metabolic dysregulation rather than simple nutrient deficiency. This narrative review provides a comprehensive and clinically oriented framework integrating biochemical pathways, conventional therapies, and advanced metabolic reasoning in cases of treatment resistance. Particular emphasis is placed on methylation imbalance, impaired transsulfuration, and the concept of functional metabolic blockade. A practical, physiology-based approach is proposed to guide clinicians in the management of refractory hyperhomocysteinemia.
Jozélio Freire de Carvalho (Thu,) studied this question.