Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin (corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin), Berlin, Germany; Division of Nephrology, Department of Internal Medicine, University of Leipzig Medical Center, Leipzig, Germany.
Division of Nephrology, Department of Internal Medicine, University of Leipzig Medical Center, Leipzig, Germany; Department of Pediatric Surgery, Universitätsklinikum Leipzig, Leipzig, Germany.
Gastroenterology. 2024 May;166(5):902-914. doi: 10.1053/j.gastro.2023.12.007. Epub 2023 Dec 13.
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.
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.
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.
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.
常染色体显性遗传性多囊肝病（autosomal dominant polycystic liver disease，ADPLD）主要由 PRKCSH 和 SEC63 这 2 个基因的致病性变异引起，其发病率存在女性优势。临床上，ADPLD 表现出巨大的异质性，从无症状到高度肿大的肝脏不等。迄今为止，对于早期疾病进展的预测知之甚少，这阻碍了临床管理、遗传咨询和随机对照试验的设计。为了改善疾病预后，我们建立了一个由欧洲和美国中心组成的联盟，以招募最大的 PRKCSH 和 SEC63 肝病患者队列。
我们分析了一个国际多中心队列，其中包含 265 名携带 PRKCSH 或 SEC63 致病性变异的 ADPLD 患者，以进行基因型-表型相关性分析，包括正常年龄校正的总肝体积和多囊肝病相关住院（肝事件）作为主要临床终点。
将个体总肝体积分类为预先设定的进展组，可对未来的肝事件进行预测性风险区分，与性别和潜在遗传缺陷无关。此外，女性患者和携带 PRKCSH 变异的患者的疾病严重程度（首次肝事件的年龄）明显比携带 SEC63 变异的患者更严重。新开发的性别基因评分除了基于影像学的预后预测外，还能有效区分轻度、中度和重度疾病。
影像学和临床遗传评分都有可能告知患者其一生中发生症状性疾病的风险。女性、种系 PRKCSH 改变和总肝体积快速进展的组合与多囊肝病相关住院的可能性最高。
