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

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.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.Three of the four patients developed hepatocellular carcinoma 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.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.

Duke Scholars

Author Sidney M. Gospe Jr. Pediatrics, Neurology