Decoding Hypercarotenemia: Integrating Pathophysiology, Clinical Recognition, and Precision Management

Hypercarotenemia represents a complex metabolic phenotype characterized by supraphysiological circulating carotenoid concentrations exceeding 300 μg/dL for β-carotene, manifesting as distinctive cutaneous xanthochromia with preserved scleral clarity - a critical differentiating feature from hepatobiliary dysfunction. The contemporary surge in detection rates, which has increased over the past decade, correlates with global dietary paradigm shifts, including the growth in plant-based diet adoption and the concurrent rise in metabolic dysfunction. This comprehensive review synthesizes current understanding of hypercarotenemia pathophysiology through systematic literature analysis encompassing molecular mechanisms, epidemiological trends, clinical phenotypes, and therapeutic interventions, with particular emphasis on genetic discoveries and precision management approaches. Hypercarotenemia pathogenesis involves sophisticated interactions among three key mechanistic pathways: (1) intestinal absorption via SR-B1 receptors, (2) enzymatic conversion through β-carotene oxygenase 1 and 2 (Beta-carotene oxygenase 1 (BCO1)/BCO2) systems, and (3) genetic susceptibility primarily mediated by BCO1 variants (rs6564851, rs12934922, rs7501331). The condition demonstrates remarkable clinical heterogeneity influenced by individual metabolic capacity, intestinal microbiome composition, and concurrent endocrinopathies, particularly thyroid dysfunction and diabetes mellitus. The management paradigms have evolved from simple dietary restriction to precision nutrition approaches, integrating genetic profiling with individualized tolerance thresholds while preserving established health benefits of carotenoid-rich diets. Standard diagnostic criteria incorporate both biochemical thresholds and functional assessments, including the retinol:β-carotene molar ratio as a functional measure of BCO1 activity. Although traditionally considered benign, hypercarotenemia serves as a valuable biomarker for underlying metabolic dysfunction and genetic variants affecting fat-soluble vitamin homeostasis, warranting clinical attention for risk stratification and personalized dietary counseling.