Polycystic Kidney and Liver Disease

The results of the study Prevalence Estimates of Polycystic Kidney and Liver Disease by Population Sequencing were published in the Journal of the American Society of Nephrology in August 2018 (DOI:10.1681/ASN.2018050493). Estimating the true prevalence for autosomal dominant polycystic kidney disease (ADPKD) or autosomal dominant polycystic liver disease (ADPLD) has been difficult, because of variable age-dependent penetrance and incomplete ascertainment in a general population. Especially for ADPLD, the clinical population particularly comprises patients with symptomatic disease, which could lead to an underestimation of the prevalence, and it has often been estimated to be low (at 1 in 100,000 people). This study sought to answer this question differently, by looking at whole-exome and whole-genome sequencing data in the general population of two databases (gnomAD and BRAVO). They found that truncating (nonsense) mutations in the six identified ADPLD genes (PRKCSH, SEC63, GANAB, ALG8, SEC61B, LRP5) were present in 202 per 100.000 persons (prevalence: 1:496). This was much more frequent than expected, and could be explained by a low disease penetrance or a large number of asymptomatic patients that are unaware of their hepatic cysts. When taking into account all other genes of potential relevance as cystic disease modifiers, 1% carries a truncating mutation and up to 23% carries a rare missense variant, opening the way to study the role of cyst-modifier genes in patients.

The results of the study Polycystic Liver Disease: Hepatic Venous Outflow Obstructon Lesions of the Noncystic Parenchyma Have Major Consequences were published in Hepatology in August 2018 (DOI:10.1002/hep.29582). Hepatic venous outflow obstruction (HVOO) is mostly known as a rare complication in PLD that can lead to portal hypertension, intractable ascites, variceal hemorrhage, splenomegaly and abnormal liver- and kidney function. This study focused on HVOO lesions at a histological level. This is an ill-researched topic in PLD, as liver parenchyma surrounding the multiple cysts is often considered normal because liver function is typically preserved in patients. The researchers have looked at resection specimens of patients undergoing liver resection (n=90) or liver transplantation (n=35). In a subgroup of patients, pre-operative imaging was available (n=45) to assess HVOO at imaging. The article shows that the prevalence of HVOO lesions is 92% in this (severely affected) group of PLD patients. Sinusoidal distension was present in 47.2% of patients and 56.8% had some degree of fibrosis (graded as extensive in 13.6%). Retrospective and blinded assessment of the pre-surgical imaging showed that all patients had stenosis or obstruction of at least two hepatic veins and 86.7% of all three hepatic veins. Venous intrahepatic collaterality was present in 84.4% of patients. This article brings about a paradigm shift in thinking about non-cystic parenchyma in PLD, and the vast majority of patients showed radiological or histological signs of HVOO. In addition, there was a significant correlation between severity of HVOO lesions on intra-operative bleeding, transfusions and post-operative ascites for patients undergoing liver resections, suggestive of potential clinical use of the data.

More information on the European Alpha1 Liver Study group can be found at www.alpha1-liver.eu

Lucas Bernts
Department of Gastroenterology and Hepatology, Radboud University Medical Centre, Nijmegen, the Netherlands.
Contact: lucas.bernts@radboudumc.nl