Early Detection of Subclinical Atherosclerosis: Hyperhomocysteinemia as a Promising Marker in Adolescents With Vitamin B Deficiency

Abstract

In recent decades, the increased incidence of cardiovascular disease (CVD) mortality among young adults has raised concerns. Although clinical manifestations of CVD typically occur later in life, the underlying pathological processes emerge early on. This review article summarizes the association between vitamin B deficiency-induced hyperhomocysteinemia and subclinical atherosclerosis in adolescents. Numerous studies have demonstrated that elevated homocysteine levels are an independent risk factor for endothelial dysfunction (ED) and arterial stiffness, which are key contributors to CVD. Notably, vitamin B deficiency, particularly in vitamin B9 and vitamin B12, emerges as a significant factor in childhood hyperhomocysteinemia, initiating the development of subclinical atherosclerosis in early life. A comprehensive review of relevant literature from prominent bibliographic databases, including PubMed/MEDLINE, PubMed Central, Google Scholar, and Cochrane, was performed. Four cross-sectional studies focusing on homocysteine levels as an exposure variable and markers of atherosclerosis as outcome measures were included and reviewed as part of our analysis. The reviewed studies demonstrate a positive correlation between homocysteine levels and markers of atherosclerosis, including increased carotid intima-media thickness (CIMT) and ED. Mainly, adolescents with vitamin B12 deficiency exhibit a significant positive correlation between homocysteine levels and CIMT. These findings underscore the potential of hyperhomocysteinemia as an early marker for detecting subclinical atherosclerosis in adolescents with vitamin B deficiency. Despite limited research in this area, recognizing the importance of early detection and management of subclinical atherosclerosis in adolescents can help mitigate the risk of severe cardiovascular events such as myocardial infarction and stroke in young adulthood.

Keywords: carotid intima-media thickness (cimt); children and adolescents; endothelial injury; homocysteine levels; hyperhomocysteinemia (hhcy); pediatric clinical cardiology; pediatric preventive medicine; pediatrics; subclinical atherosclerosis; vitamin b deficiency.

Figure 1. Role of vitamin B in homocysteine metabolism

This figure explains the role of vitamins B2, B6, B9 (folic acid), and B12 in homocysteine metabolism. Homocysteine receives a methyl group in the remethylation pathway primarily from the transformation of 5-methyl-THF into tetrahydrofolate (THF) [15]. This B12-dependent reaction requires the enzyme methionine synthase (MS). Homocysteine condenses with serine to form cystathionine in the transsulfuration pathway, catalyzed by the cystathionine synthase (CS), which requires vitamin B6 as a cofactor [15]. 5-methylene-THF is converted to 5-methyl THF, the reaction requires the enzyme methyl tetrahydrofolate reductase (MTHFR) and vitamin B2 as cofactor. MS: methionine synthase; THF: tetrahydrofolate; MTHFR: methyl tetrahydrofolate reductase; CS: cystathionine synthase; B12: vitamin B12; B6: vitamin B6; B2: vitamin B2; CH3: methyl group. Image credits: Parth S. Shirode

Figure 2. Mechanisms explaining the role of hyperhomocysteinemia (HHCY) in endothelial dysfunction (ED) and atherogenesis

Image credits: Parth S. Shirode