Long-Term Cholic Acid Treatment in a Patient with Zellweger Spectrum Disorder

Abstract

Zellweger spectrum disorders (ZSDs) are a subgroup of peroxisomal biogenesis disorders with a generalized defect in peroxisome function. Liver disease in ZSDs has been associated with the lack of peroxisomal β-oxidation of C27-bile acid intermediates to form primary C24-bile acids, which prevents normal physiologic feedback and leads to accumulation of hepatotoxic bile acid intermediates. Primary bile acid therapy, oral cholic acid (CA), as adjunctive treatment for ZSDs, restores physiologic feedback inhibition on bile acid synthesis and inhibits formation of hepatotoxic bile acid intermediates. Our patient is a Caucasian male diagnosed with moderately severe ZSD at age 5 months, and he received long-term CA therapy from age 16 months through 19 years old. CA treatment was well tolerated, with no reports of adverse events. His liver biopsy prior to CA therapy showed cholestasis, periportal inflammation, and bridging fibrosis. Following 5 months of CA therapy, his liver biopsy showed improvement in inflammation and no change in fibrosis. Serum liver enzymes during CA therapy improved compared to pre-therapy levels but frequently were above the upper limit of normal. At age 19 years, following several years with clinical cirrhosis with severe portal hypertension, he presented with worsening jaundice, and he was diagnosed with hepatocellular cancer (HCC). Early-onset advanced liver disease associated with ZSD and natural disease progression that is not completely suppressed with CA treatment likely caused HCC in our patient. Greater awareness is needed of the possibility of development of HCC in patients with moderately severe ZSD who survive past childhood.

Keywords

• Peroxisomal biogenesis disorder
• Bile acid synthesis
• Hepatocellular carcinoma
• Neonatal adrenoleukodystrophy