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

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 166; no. 5; pp. 902 - 914
• Main Authors: Schönauer, Ria, Sierks, Dana, Boerrigter, Melissa, Jawaid, Tabinda, Caroff, Lea, Audrezet, Marie-Pierre, Friedrich, Anja, Shaw, Melissa, Degenhardt, Jan, Forberger, Mirjam, de Fallois, Jonathan, Bläker, Hendrik, Bergmann, Carsten, Gödiker, Juliana, Schindler, Philipp, Schlevogt, Bernhard, Müller, Roman-U., Berg, Thomas, Patterson, Ilse, Griffiths, William J., Sayer, John A., Ambrose, John C., Arumugam, Prabhu, Bevers, Roel, Bleda, Marta, Boardman-Pretty, Freya, Boustred, Christopher R., Brittain, Helen, Caulfield, Mark J., Chan, Georgia C., Elgar, Greg, Fowler, Tom, Giess, Adam, Hamblin, Angela, Henderson, Shirley, Hubbard, Tim J.P., Jackson, Rob, Jones, Louise J., Kasperaviciute, Dalia, Kayikci, Melis, Kousathanas, Athanasios, Lahnstein, Lea, Leigh, Sarah E.A., Leong, Ivonne U.S., Lopez, Javier F., Maleady-Crowe, Fiona, McEntagart, Meriel, Minneci, Federico, Moutsianas, Loukas, Mueller, Michael, Murugaesu, Nirupa, Need, Anna C., O’Donovan, Peter, Odhams, Chris A., Patch, Christine, Pereira, Mariana Buongermino, Perez-Gil, Daniel, Pullinger, John, Rahim, Tahrima, Rendon, Augusto, Rogers, Tim, Savage, Kevin, Sawant, Kushmita, Scott, Richard H., Siddiq, Afshan, Sieghart, Alexander, Smith, Samuel C., Sosinsky, Alona, Stuckey, Alexander, Tanguy, Mélanie, Taylor Tavares, Ana Lisa, Thomas, Ellen R.A., Thompson, Simon R., Tucci, Arianna, Welland, Matthew J., Williams, Eleanor, Witkowska, Katarzyna, Wood, Suzanne M., Popp, Bernt, Torres, Vicente E., Hogan, Marie C., Somlo, Stefan, Watnick, Terry J., Nevens, Frederik, Besse, Whitney, Cornec-Le Gall, Emilie, Harris, Peter C., Drenth, Joost P.H., Halbritter, Jan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-05-2024; Elsevier
• Subjects: ADPLD; 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; Life Sciences; Liver - diagnostic imaging; Liver - pathology; Liver Diseases - diagnostic imaging; Liver Diseases - genetics; Liver Diseases - pathology; Male; Middle Aged; Molecular Chaperones; Organ Size; PCLD; PRKCSH; Prognosis; Risk Assessment; Risk Factors; RNA-Binding Proteins; SEC63; Severity of Illness Index; Sex Factors; TLV; United States - epidemiology; United States; Europe; MIM; ADPLD; CT; ADPKD; nTLV; PRKCSH; MRI; PG; HR; PCLD; SEC63; TLV; computed tomography; progression group nTLV; magnetic resonance imaging; normalized total liver volume; autosomal dominant polycystic kidney disease ADPLD; autosomal dominant polycystic liver disease; autosomal dominant polycystic kidney disease; progression group; magnetic resonance imaging PG; hazard ratio; computed tomography HR; Mendelian Inheritance in Man MRI; autosomal dominant polycystic liver disease CT; hazard ratio MIM; Mendelian Inheritance in Man
• ISSN: 0016-5085; 1528-0012; 1528-0012
• DOI: 10.1053/j.gastro.2023.12.007

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.
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Autosomal dominant polycystic liver disease is a rare genetic condition mainly due to mutated PRKCSH or SEC63. Symptomatology is highly variable, ranging from clinically silent courses to severe organ enlargement and sarcopenia. As disease prognostication at early stages is poorly developed, the predictive value of genetic confirmation and liver volumetry for individual disease prediction are investigated. Although PRKCSH defects and female sex pointed to aggravated disease, SEC63 alterations and male sex are associated with milder courses. New clinical tools to inform patients and their physicians to warrant personalized management and rational decision making are proposed.