TY - JOUR
T1 - Sex, Genotype, and Liver Volume Progression as Risk of Hospitalization Determinants in Autosomal Dominant Polycystic Liver Disease
AU - Genomics England Research Consortium
AU - Schönauer, Ria
AU - Sierks, Dana
AU - Boerrigter, Melissa
AU - Jawaid, Tabinda
AU - Caroff, Lea
AU - Audrezet, Marie Pierre
AU - Friedrich, Anja
AU - Shaw, Melissa
AU - Degenhardt, Jan
AU - Forberger, Mirjam
AU - de Fallois, Jonathan
AU - Bläker, Hendrik
AU - Bergmann, Carsten
AU - Gödiker, Juliana
AU - Schindler, Philipp
AU - Schlevogt, Bernhard
AU - Müller, Roman U.
AU - Berg, Thomas
AU - Patterson, Ilse
AU - Griffiths, William J.
AU - Sayer, John A.
AU - Ambrose, John C.
AU - Arumugam, Prabhu
AU - Bevers, Roel
AU - Bleda, Marta
AU - Boardman-Pretty, Freya
AU - Boustred, Christopher R.
AU - Brittain, Helen
AU - Caulfield, Mark J.
AU - Chan, Georgia C.
AU - Elgar, Greg
AU - Fowler, Tom
AU - Giess, Adam
AU - Hamblin, Angela
AU - Henderson, Shirley
AU - Hubbard, Tim J.P.
AU - Jackson, Rob
AU - Jones, Louise J.
AU - Kasperaviciute, Dalia
AU - Kayikci, Melis
AU - Kousathanas, Athanasios
AU - Lahnstein, Lea
AU - Leigh, Sarah E.A.
AU - Leong, Ivonne U.S.
AU - Lopez, Javier F.
AU - Maleady-Crowe, Fiona
AU - McEntagart, Meriel
AU - Torres, Vicente E.
AU - Hogan, Marie C.
AU - Harris, Peter C.
N1 - Publisher Copyright:
© 2024 The Authors
PY - 2024
Y1 - 2024
N2 - 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.
AB - 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.
KW - ADPLD
KW - PCLD
KW - PRKCSH
KW - SEC63
KW - TLV
UR - http://www.scopus.com/inward/record.url?scp=85186887015&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85186887015&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2023.12.007
DO - 10.1053/j.gastro.2023.12.007
M3 - Article
C2 - 38101549
AN - SCOPUS:85186887015
SN - 0016-5085
VL - 166
SP - 902
EP - 914
JO - Gastroenterology
JF - Gastroenterology
IS - 5
ER -