Hepatic symptoms and histology in 13 patients with a Zellweger spectrum disorder

Abstract

Patients with a Zellweger spectrum disorder (ZSD) have a defect in the assembly or maintenance of peroxisomes, leading to a multisystem disease with variable outcome. Liver disease is an important feature in patients with severe and milder phenotypes and a frequent cause of death. However, the course and histology of liver disease in ZSD patients are ill‐defined. We reviewed the hepatic symptoms and histological findings of 13 patients with a ZSD in which one or several liver biopsies have been performed (patient age 0.2‐39 years). All patients had at least some histological liver abnormalities, ranging from minor fibrosis to cirrhosis. Five patients demonstrated significant disease progression with liver failure and early death. In others, liver‐related symptoms were absent, although some still silently developed cirrhosis. Patients with peroxisomal mosaicism had a better prognosis. In addition, we show that patients are at risk to develop a hepatocellular carcinoma (HCC), as one patient developed a HCC at the age of 36 years and one patient a precancerous lesion at the age of 18 years. Thus, regular examination to detect fibrosis or cirrhosis should be included in the standard care of ZSD patients. In case of advanced fibrosis/cirrhosis expert consultation and HCC screening should be initiated. This study further delineates the spectrum and significance of liver involvement in ZSDs.

High Dose Versus Low Dose Syngeneic Hepatocyte Transplantation in Pex1-G844D NMRI Mouse Model is Safe but Does Not Achieve Long Term Engraftment

“…Since then, successful HT protocols were reported in patients affected by chronic liver disease [28]. ZSD mouse models and patients exhibit chronic liver disease [18,29,30], and our team reported the safety of HT in a 4-year-old ZSD patient [8]. Our ZSD mouse model express a severe disease phenotype with growth retardation along with chronic liver injury and fibrosis [18,29].…”

The physiological functions of human peroxisomes

“…Clinical features of severe ZS patients include hepatomegaly, and hepatic dysfunction as revealed by prolonged neonatal jaundice, coagulopathy, cholestasis and elevated transaminases (32,253). In the milder ZSD patients, surviving into adulthood, liver pathology can be very diverse (351). It can go unnoticed because of normal transaminase levels up to liver failure as the cause of death.…”

“…Other frequent pathologies are portal stenosis, inflammation and glycogenated nuclei, copper and iron storage. In a few patients premalignant dysplastic nodules and hepatocellular carcinoma were detected (351). Patients that showed peroxisomal mosaicism in the liver, in which a fraction of hepatocytes contained normal peroxisomes, had the mildest liver pathology.…”

“…Conversely, there are also examples of patients who initially presented with strong liver involvement with hepatomegaly and more than 10-fold increased liver parameters in the neonatal period, which subsequently spontaneously resolved after a few years (351,352). Natural history studies in which metabolic parameters are associated with liver pathologies are badly needed.…”

Acute Late-Onset Cirrhosis in Zellweger Spectrum Disorder

“…ZSD can affect the liver with variable presentations including hepatomegaly, cholestasis, elevated transaminases, fibrosis, cirrhosis, and hepatocellular carcinoma [2]. In fact, liver disease is a frequent cause of death in patients with ZSD [3]. However, the clinical course of liver disease over time is poorly understood.…”