Sex, Genotype, and Liver Volume Progression as Risk of Hospitalization Determinants in Autosomal Dominant Polycystic Liver Disease

Gastroenterology. 2024 May;166(5):902-914. doi: 10.1053/j.gastro.2023.12.007. Epub 2023 Dec 13.

Abstract

Background & aims: Autosomal dominant polycystic liver disease is a rare condition with a female preponderance, based mainly on pathogenic variants in 2 genes, PRKCSH and SEC63. Clinically, autosomal dominant polycystic liver disease is characterized by vast heterogeneity, ranging from asymptomatic to highly symptomatic hepatomegaly. To date, little is known about the prediction of disease progression at early stages, hindering clinical management, genetic counseling, and the design of randomized controlled trials. To improve disease prognostication, we built a consortium of European and US centers to recruit the largest cohort of patients with PRKCSH and SEC63 liver disease.

Methods: We analyzed an international multicenter cohort of 265 patients with autosomal dominant polycystic liver disease harboring pathogenic variants in PRKCSH or SEC63 for genotype-phenotype correlations, including normalized age-adjusted total liver volumes and polycystic liver disease-related hospitalization (liver event) as primary clinical end points.

Results: Classifying individual total liver volumes into predefined progression groups yielded predictive risk discrimination for future liver events independent of sex and underlying genetic defects. In addition, disease severity, defined by age at first liver event, was considerably more pronounced in female patients and patients with PRKCSH variants than in those with SEC63 variants. A newly developed sex-gene score was effective in distinguishing mild, moderate, and severe disease, in addition to imaging-based prognostication.

Conclusions: Both imaging and clinical genetic scoring have the potential to inform patients about the risk of developing symptomatic disease throughout their lives. The combination of female sex, germline PRKCSH alteration, and rapid total liver volume progression is associated with the greatest odds of polycystic liver disease-related hospitalization.

Keywords: ADPLD; PCLD; PRKCSH; SEC63; TLV.

Publication types

  • Research Support, Non-U.S. Gov't
  • Multicenter Study

MeSH terms

  • Adult
  • Calcium-Binding Proteins
  • Cysts / diagnostic imaging
  • Cysts / genetics
  • Cysts / pathology
  • Disease Progression
  • Europe
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Genotype
  • Glucosidases / genetics
  • Hepatomegaly / diagnostic imaging
  • Hepatomegaly / genetics
  • Hospitalization* / statistics & numerical data
  • Humans
  • Liver / diagnostic imaging
  • Liver / pathology
  • Liver Diseases* / diagnostic imaging
  • Liver Diseases* / genetics
  • Liver Diseases* / pathology
  • Male
  • Middle Aged
  • Molecular Chaperones
  • Organ Size
  • Prognosis
  • RNA-Binding Proteins
  • Risk Assessment
  • Risk Factors
  • Severity of Illness Index
  • Sex Factors
  • United States / epidemiology

Substances

  • Calcium-Binding Proteins
  • Glucosidases
  • Molecular Chaperones
  • PRKCSH protein, human
  • RNA-Binding Proteins
  • SEC63 protein, human

Supplementary concepts

  • Polycystic liver disease