Cirrhosis Associated with Pyridoxal 5′-Phosphate Treatment of Pyridoxamine 5′-Phosphate Oxidase Deficiency

Abstract

We report the case of an 8-year-old boy with pyridoxamine 5 0 -phosphate oxidase (PNPO) deficiency. He developed seizures at 24 h of age that were refractory to standard anticonvulsant therapy and a trial of pyridoxine but responded to pyridoxal phosphate (PLP) at 28 days of life. Genetic testing identified compound heterozygous mutations in the PNPO gene. Management of encephalopathic episodes required escalation of PLP dose to 100 mg/kg/day by 2 years of age. Routine blood tests at this time showed significantly deranged liver function tests (LFTs). A wedge liver biopsy showed early cirrhosis with marked elevation of pyridoxal and pyridoxic acid levels in the liver sample. Despite extensive investigation, no cause other than PLP therapy could be identified for the cirrhosis. The PLP dose was weaned to 50 mg/kg/day before episodes of encephalopathy recurred. Concurrent with the reduction of his PLP dose, LFTs showed improvement. However, at 8 years of age, there is persistent evidence of hepatic fibrosis and early portal hypertension. We hypothesise that hepatic toxicity due to PLP or its degradation products is the cause of cirrhosis in this boy. Until further evidence becomes available, we would suggest that people with PNPO deficiency are treated with the minimum dose of PLP required to prevent episodes of encephalopathy.

Normal Neurodevelopmental Outcomes in PNPO Deficiency: A Case Series and Literature Review

“…Details of the initial presentation of case 4 have been reported previously (Hoffmann et al 2007;Schmitt et al 2010;Sudarsanam et al 2014). Intractable neonatal seizures occurred, with a number of different seizure types seenabnormal eye movements, abnormal smiling, multifocal myoclonic jerks, focal clonic seizures and spasms associated with screaming and irritability.…”

“…A trial of withdrawal of PLP at 8 months of age was associated with recurrence of encephalopathy, and PLP has subsequently been continued (doses ranging from 50 to 100 mg/kg/day in divided doses). However, at age 2 years, as a result of concerns about hepatotoxicity (Sudarsanam et al 2014), lower PLP doses were given more frequently (on a 4 hourly basis including an overnight dose) and the total daily dose was decreased to 50-60 mg/kg/day. During infancy, episodes of encephalopathy were relatively frequent and often associated with febrile illnesses, but after 18 months of age these became less frequent and abated with careful management of PLP dosage and timing of administration.…”

B6 and Bleeding: A Case Report of a Novel Vitamin Toxicity

“…8,9 There have also been several reports of liver toxicity with prolonged highdosage use of PLP, 10, 11 but overall pyridoxine and PLP supplementation are generally well tolerated. 7,8,10,12 To our knowledge, no bleeding symptoms have been reported in those taking either pyridoxine or PLP.…”

A preterm neonate with seizures unresponsive to conventional treatment

“…Previous reports2 have linked PLP supplementation to the risk of permanent hepatic injury. In the clinical report by Sudarsanam et al ,3 the liver biopsy showed early cirrhosis, which was attributed to the PLP therapy. The PLP dose was in fact reduced to 60 mg/kg/day and although the liver function tests improved, they did not normalise, showing persistent evidence of hepatic fibrosis and portal hypertension.…”