In a groundbreaking correction recently published in Pediatric Research, researchers Kahraman, Gedikbasi, Karaca, and colleagues have shed new light on the intricate relationship between choline supplementation, homocysteine metabolism, and hepatic steatosis in patients with classic homocystinuria. This study revisits earlier findings and offers nuanced insights into how choline—a vital nutrient involved in methylation and lipid metabolism—affects key biomarkers and liver pathology in this rare inherited metabolic disorder. The implications of this correction extend beyond classic homocystinuria, potentially influencing therapeutic approaches to related metabolic and hepatic conditions.
Classic homocystinuria is a hereditary disorder characterized by a defect in the enzyme cystathionine beta-synthase (CBS), which catalyzes the conversion of homocysteine to cystathionine in the transsulfuration pathway. The resulting enzymatic deficiency leads to systemic accumulation of homocysteine, a sulfur-containing amino acid that can exert toxic effects through oxidative stress and endothelial dysfunction. Elevated homocysteine levels are associated with a spectrum of clinical manifestations including thromboembolism, ocular abnormalities, skeletal deformities, and cognitive impairment. Furthermore, aberrant methionine metabolism contributes to secondary metabolic disturbances with hepatic repercussions.
Choline, an essential nutrient classified alongside B vitamins, plays a pivotal role as a methyl-group donor through its conversion to betaine, thereby supporting the remethylation of homocysteine to methionine. Additionally, choline is integral to the synthesis of phosphatidylcholine, a major component of very low-density lipoproteins (VLDL), crucial for hepatic lipid export. The interplay between choline availability, homocysteine accumulation, and lipid metabolism forms the biochemical basis for investigating choline supplementation as a therapeutic strategy in homocystinuria.
The correction put forth by Kahraman et al. addresses previous discrepancies related to the extent of choline’s impact on homocysteine concentrations and the development of hepatic steatosis within their patient cohort. Through rigorous reanalysis and refined methodological approaches, the authors clarify that choline supplementation leads to a statistically significant reduction in plasma homocysteine levels in individuals with classic homocystinuria. This outcome substantiates the methyl donor role of choline and its efficacy in modulating one-carbon metabolism, which is critically compromised in CBS deficiency.
Importantly, the study also revises earlier interpretations concerning hepatic steatosis—a pathological accumulation of triglycerides in hepatocytes frequently linked to metabolic dysfunction. Prior observations suggested that intrinsic homocysteine elevation might directly exacerbate steatosis through oxidative and inflammatory mechanisms. However, the correction elucidates that choline supplementation ameliorates hepatic steatosis, likely by enhancing VLDL synthesis and secretion, thereby mitigating hepatic lipid retention. This highlights choline’s multifaceted functionality extending beyond simple homocysteine detoxification towards correcting lipid metabolic derangements.
From a molecular perspective, choline’s impact on hepatic health is mediated through complex interlinked pathways involving the methionine cycle, folate metabolism, and phospholipid biosynthesis. The correction underscores the balance required in methylation reactions; inadequate methyl donor availability impairs remethylation of homocysteine, exacerbating hyperhomocysteinemia and associated cytotoxicity. Concurrently, insufficient phosphatidylcholine compromises hepatocellular lipid export, precipitating fatty infiltration. By restoring these processes, choline supplementation addresses the metabolic bottlenecks inherent in classic homocystinuria at multiple biochemical nodes.
Clinically, these findings warrant careful consideration in dietary management and pharmacological interventions for homocystinuria patients. Standard treatments conventionally focus on vitamin B6 supplementation and betaine therapy to lower homocysteine. The revelation that choline supplementation independently contributes to homocysteine reduction and hepatic protection opens avenues for integrated nutritional strategies. Personalized choline dosing regimens could optimize metabolic control and prevent liver-related complications, improving patient prognosis.
Moreover, the corrected data provoke broader reflections on the role of choline in nonalcoholic fatty liver disease (NAFLD) and other hepatic disorders characterized by disrupted methylation and lipid metabolism. Given the mounting prevalence of NAFLD worldwide, insights derived from the rare context of homocystinuria might offer translational value. This study prompts intensified research into choline’s therapeutic potential for mitigating steatosis across diverse metabolic contexts.
The interplay between homocysteine and hepatic lipid accumulation is complex and bidirectional. Elevated homocysteine induces oxidative stress, triggers ER stress pathways, and modulates inflammatory cascades that aggravate liver injury. Conversely, hepatic steatosis influences methionine metabolism and methyl donor dynamics, further perturbing homocysteine homeostasis. By demonstrating that choline supplementation alleviates both hyperhomocysteinemia and steatosis, the correction clarifies an interventional target that coordinates multiple pathological axes.
Future research based on these findings could examine choline supplementation dosage, timing, and long-term safety in homocystinuria patients. Additionally, integration with other methyl donors such as folate and vitamin B12 could be studied to identify synergistic effects on metabolic parameters. Given the genetic heterogeneity of homocystinuria and variable CBS enzyme activity, stratified clinical trials assessing genotype-phenotype-specific responses are warranted.
This correction also calls attention to the importance of rigorous data validation and transparency in rare disease research. The meticulous reevaluation by Kahraman and colleagues exemplifies scientific integrity and advances collective understanding, ensuring that clinical recommendations are grounded in robust evidence. As metabolic pathways often intersect with broader physiological systems, even subtle biochemical modulations can have profound implications for patient care.
Technological advances in metabolomics, transcriptomics, and imaging could deepen insights into choline’s mechanistic roles in homocystinuria and related metabolic disorders. High-resolution lipid profiling and quantification of methylation intermediates could refine biomarkers of therapeutic response. Additionally, liver biopsy analyses complemented by non-invasive imaging would better characterize steatosis progression and resolution patterns under choline therapy.
In conclusion, this correction underscores choline supplementation as a promising adjunct in managing classic homocystinuria. By significantly diminishing plasma homocysteine levels and reversing hepatic steatosis, choline concurrently targets metabolic imbalances and organ-specific pathology. These findings enhance the therapeutic landscape for this rare but severe condition and inspire wider exploration of nutrient-based interventions in complex metabolic diseases.
As homocystinuria exemplifies the intricate crosstalk between genetics, metabolism, and organ health, interventions like choline supplementation embody the future of precision medicine. Continuing efforts to unravel molecular intricacies while validating clinical outcomes will pave the way for optimized multidisciplinary care. This research correction by Kahraman et al. not only enriches our scientific understanding but may also improve quality of life for patients grappling with challenging metabolic disorders.
Subject of Research: Choline supplementation effects on homocysteine metabolism and hepatic steatosis in classic homocystinuria.
Article Title: Correction: Choline supplementation in classic homocystinuria: impact on homocysteine and hepatic steatosis.
Article References:
Kahraman, S., Gedikbasi, A., Karaca, M. et al. Correction: Choline supplementation in classic homocystinuria: impact on homocysteine and hepatic steatosis. Pediatr Res (2025). https://doi.org/10.1038/s41390-025-04549-1
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