Hepatocellular Carcinoma: A Critical Complication in Patients Treated with Pyridoxal Phosphate

Background Pyridoxal-5'-phosphate (PLP) is in most patients the effective treatment for pyridox(am)ine-5'-phosphate oxidase (PNPO) deficiency, a rare autosomal recessive cause of neonatal-onset developmental and epileptic encephalopathy. Although generally considered safe, long-term high-dose PLP exposure may have hepatotoxic effects, particularly in the absence of pharmaceutical-grade formulations. Methods We report a series of four pediatric patients with vitamin B6-dependent epilepsy who received long-term PLP therapy. Two had genetically confirmed PNPO deficiency, and two were later diagnosed with ALDH7A1 deficiency. All received high-dose oral PLP, with frequent changes in formulation due to availability issues. Results Three of the four patients developed hepatocellular carcinoma (HCC) after several years of PLP treatment; one developed fully reversible severe hepatotoxicity. The shared exposure to prolonged high-dose PLP across all affected patients, despite differing metabolic conditions, suggests a possible role for PLP toxicity independent of the underlying metabolic disorder. Known toxic mechanisms include mitochondrial dysfunction, Schiff base-mediated protein modification, and accumulation of reactive PLP degradation products. In two patients, the total PLP dose was successfully reduced by over 30% through increasing administration frequency, without loss of seizure control. Conclusion These findings raise significant concerns about the long-term hepatic safety of oral PLP in patients with vitamin B6-dependent epilepsies. As intravenous PLP is unfeasable for lifelong therapy, there is an urgent need for standardized, high-quality PLP preparations and exploration of alternative delivery routes such as intranasal administration. Regular hepatic monitoring should be implemented in all patients receiving chronic PLP therapy.