Acute Late-Onset Cirrhosis in Zellweger Spectrum Disorder

Abstract

Zellweger spectrum disorders (ZSDs) are known to present with variable hepatic manifestations ranging from benign hepatosplenomegaly and elevated liver enzymes to advanced liver cirrhosis with hepatocellular carcinoma. However, the progression of liver disease in ZSD patients over time is poorly characterized due to scarcity of the disease. Herein, we report a case of newly diagnosed liver cirrhosis in a ZSD patient with rapid progression and fatal outcome to demonstrate key clinical learning points.

Introduction

Zellweger spectrum disorders (ZSDs) comprise a range of mild to severe clinical manifestations caused by defects in the PEX genes responsible for peroxisomal biogenesis [1]. Mild ZSD can present early in life with common signs including developmental delay, vision loss, hearing loss, ataxia, and polyneuropathy [1]. 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. Herein, we present a case of a 30-year-old male with ZSD previously diagnosed with hepatomegaly at 18 months of age found to have new-onset cholestasis and newly diagnosed cirrhosis, with no gastrointestinal or hepatobiliary symptoms prior to this encounter.

Case Presentation

A 30-year-old male with ZSD presented to the hospital with a report of 1 week of jaundice and dark urine. He was diagnosed with infantile Refsum disease (IRD), now part of the Zellweger spectrum, as a newborn and had reportedly undergone a liver biopsy at 18 months of age for congenital hepatomegaly, which was found to be normal. Aside from congenital hepatomegaly, the patient had other common clinical manifestations of ZSD including blindness, deafness, and developmental delays. Prior to admission, the patient never had any known hepatobiliary complications. The patient and his family denied use of any medications, supplements, or alcohol ingestion at home.

On admission, he was found to have a total bilirubin of 11.8 mg/dL (normal range <1.2), aspartate aminotransferase 140 U/L (normal range <8), alanine aminotransferase 27 U/L (normal range <10), alkaline phosphatase 234 U/L (normal range <116), international normalized ratio 1.3 (normal range <1.2), albumin 4.3 g/dL (normal range: 3.5–5), and platelets 290 × 10³/µL (normal range: 119–332). Prior historical data showed normal bilirubin and minimal aspartate aminotransferase elevation to 41 U/L 8 months prior. Blood and urine toxicologies were negative. Ethanol and acetaminophen levels were found to be normal. Viral hepatitis panel, HIV, IgG subclass, anti-LKM antibody, anti-mitochondrial antibody, anti-smooth muscle antibody, alpha-1 antitrypsin, and ceruloplasmin were all found to be normal/negative.

Ultrasound imaging of the abdomen was notable for an enlarged liver with coarse heterogeneous echotexture consistent with hepatocellular disease but without discrete liver lesions or masses; common bile duct dilation; or evidence of gallbladder, spleen, or kidney disease. Computerized tomography of the abdomen and pelvis without contrast found an enlarged liver with irregular contours and heterogeneous attenuation, suggestive of cirrhosis with portal hypertension and collateral vessels as well as moderate amount of ascites. These imaging findings are shown in Figure 1. A liver biopsy was recommended but ultimately not pursued due to the family’s stated goals of care. The patient was transitioned to hospice care and unfortunately died 1 month after his evaluation.

Fig. 1.

CT imaging (a–c) and ultrasound (d) findings consistent with cirrhosis. CT, computerized tomography.

Discussion and Conclusions

ZSD represents a continuum of diseases including IRD and may result in liver dysfunction. It is important to distinguish IRD/ZSD from adult Refsum disease, also referred to as classic Refsum disease, which is caused by a deficiency of phytanoyl-CoA hydroxylase that plays a role in peroxisomal oxidation, resulting in elevated serum phyantic acid levels [4]. Unlike ZSD, adult Refsum disease typically does not manifest until late childhood or adulthood and does not appear to be associated with blindness or liver disease as seen in the clinical case described above [4].

The progression of liver disease in ZSD is poorly characterized, but our case demonstrates the potential for sudden and rapid liver decompensation with fatal outcomes in patients with ZSD. Despite these potentially fatal consequences, there are no clearly defined societal guidelines on appropriate monitoring or treatment for progression of liver disease, in large part due to the scarcity of ZSD. Notably, cholic acid was approved by the FDA in 2015 as an adjunctive treatment for peroxisomal disorders such as ZSD with hepatic manifestations. A proposed mechanism for hepatic injury in ZSD is due to accumulation of cytotoxic C₂₇-bile acid intermediates and relative reduction of mature C₂₄-bile acid levels [5]. In rat models, C₂₇-bile acid intermediates have been shown to be particularly cytotoxic in hepatoma cell lines [6]. Cholic acid is hypothesized to reduce levels of cytotoxic C₂₇-bile acid intermediates via restoration of the negative feedback loop, restore C₂₄-bile acid levels to facilitate biliary excretion of bile acids, improve cholestasis, and increase intraluminal bile acid concentration which improves absorption of dietary fat and fat-soluble vitamins [5]. In fact, the use of bile acid supplementation as a proposed treatment has been suggested for many years with noted improvements to liver function and overall growth in patients [7].

While cholic acid may play a role in patients with mild liver disease (with an associated significant reduction in C₂₇-bile acid intermediates), patients with advanced fibrosis and cirrhosis may only see small reductions in C₂₇-bile acid intermediates with a concurrent increase in liver enzymes and conjugated bilirubin levels, suggesting possible detrimental effects of cholic acid in advanced liver disease [8]. Furthermore, cholic acid supplementation may delay but ultimately not prevent progression of liver disease and known complications of liver cirrhosis/portal hypertension [9]. Data for orthotopic liver transplantation in this patient population are very limited as all patients have been 3 years of age or younger upon receipt of liver transplantation, with normalization of some biochemical tests acutely, but unclear long-term outcomes [10–12].

In summary, ZSD is a rare condition with a wide spectrum of hepatic manifestations that may present congenitally but can progress insidiously into adulthood with potentially rapid and fatal manifestations such as our case. It should be recognized as a rare cause of liver cirrhosis. Given the lack of guideline-based approach for management of liver disease in ZSD, the authors propose that early liver biopsy can examine the absence of well-formed peroxisomes, establishing evidence of hepatic involvement. Early management should rely on the use of cholic acid as a well-tolerated therapy to prevent or delay progression of liver disease. However, consideration for early liver transplantation may be warranted. The CARE Checklist has been completed by the authors for this case report, attached as supplementary material (for all online suppl. material, see www.karger.com/doi/10.1159/000529353).

Statement of Ethics

Written informed consent was obtained from the patient’s father for publication of this case report and any accompanying images. A copy of the written consent is available for review by the editor if requested. Ethical approval is not required for this study in accordance with local or national guidelines.

Conflict of Interest Statement

The authors confirm that there are no known conflicts of interest associated with this publication.

Funding Sources

There has been no financial support for this work.

Author Contributions

Both Hsu M. and Subhash A. have been involved in drafting the manuscript and/or making critical revisions.

Funding Statement

There has been no financial support for this work.

Data Availability Statement

All data generated or analyzed during this study are included in this article and its supplementary materials. Further inquiries can be directed to the corresponding author.