Milkiewicz, Piotr

Background & Aims: Liver transplantation (LT) remains the only cure for severe polycystic liver disease (PLD). However, LT indications and strategies vary across Europe, resulting in (unwanted) practice variation and unequal access to care for patients with PLD. This study aimed to (1) identify existing PLD-specific LT criteria across European countries, (2) assess which criteria are considered relevant by specialist, and (3) map the variation in liver-kidney transplant strategies among patients with autosomal dominant polycystic kidney disease (ADPKD). Methods: National PLD-specific LT criteria were collected, and if unavailable ERN RARE-Liver representatives from that country were asked to provide information. An online survey was conducted amongst hepatologists, LT surgeons, and nephrologists managing patients with PLD. The survey assessed relevant LT indications/listing requirements, clinical case evaluations, and explored preferences for liver-kidney transplantation in patients with ADPKD. Results: Defined LT criteria for patients with PLD were available in only 8 of the 17 assessed countries and showed substantial variation. Sixty-nine clinicians (43 hepatologists, 15 surgeons, 11 nephrologists), predominantly from LT centers (75.4%), completed the survey. Key LT indications were recurrent liver cyst infections (78.3%), significant impaired quality of life (75.4%), and severe malnutrition (75.4%). In ADPKD simultaneous liver-kidney transplantation (SLK) was preferred by 40.4% of respondents, primarily due the favorable immunological profile (47.6%) and prevention of renal failure (33.3%). In contrast, those favoring a liver-first approach (30.8%), followed by sequential kidney transplant, highlighted the potential harm to the kidney graft during SLK (62.5%). Conclusions: Uniform PLD-specific LT criteria in Europe are lacking. While recurrent liver cyst infections, decreased quality of life, and malnutrition are widely recognized as crucial LT indications, they are insufficiently reflected in existing criteria, contributing to unequal access to LT. Moreover, considerable variation exists in liver-kidney transplantation for ADPKD patients, with a current lack of evidence to support one approach over another.

Objective Primary sclerosing cholangitis (PSC) is a genetically complex, inflammatory bile duct disease of largely unknown aetiology often leading to liver transplantation or death. Little is known about the genetic contribution to the severity and progression of PSC. The aim of this study is to identify genetic variants associated with PSC disease progression and development of complications. Design We collected standardised PSC subphenotypes in a large cohort of 3402 patients with PSC. After quality control, we combined 130 422 single nucleotide polymorphisms of all patients—obtained using the Illumina immunochip—with their disease subphenotypes. Using logistic regression and Cox proportional hazards models, we identified genetic variants associated with binary and time-to-event PSC subphenotypes. Results We identified genetic variant rs853974 to be associated with liver transplant-free survival (p=6.07×10–9). Kaplan-Meier survival analysis showed a 50.9% (95% CI 41.5% to 59.5%) transplant-free survival for homozygous AA allele carriers of rs853974 compared with 72.8% (95% CI 69.6% to 75.7%) for GG carriers at 10 years after PSC diagnosis. For the candidate gene in the region, RSPO3, we demonstrated expression in key liver-resident effector cells, such as human and murine cholangiocytes and human hepatic stellate cells. Conclusion We present a large international PSC cohort, and report genetic loci associated with PSC disease progression. For liver transplant-free survival, we identified a genome-wide significant signal and demonstrated expression of the candidate gene RSPO3 in key liver-resident effector cells. This warrants further assessments of the role of this potential key PSC modifier gene.

Cholangiocarcinoma (CCA) includes a heterogeneous group of biliary cancers with poor prognosis. Several conditions, such as primary sclerosing cholangitis (PSC), are risk factors. Noninvasive differential diagnosis between intrahepatic CCA and hepatocellular carcinoma (HCC) is sometimes difficult. Accurate noninvasive biomarkers for PSC, CCA, and HCC are not available. In the search for novel biomarkers, serum extracellular vesicles (EV) were isolated from CCA (n = 43), PSC (n = 30), or HCC (n = 29) patients and healthy individuals (control, n = 32); and their protein content was characterized. By using nanoparticle tracking analysis, serum EV concentration was found to be higher in HCC than in all the other groups. Round morphology (by transmission electron microscopy), size (∼180 nm diameter by nanoparticle tracking analysis), and markers (clusters of differentiation 9, 63, and 81 by immunoblot) indicated that most serum EV were exosomes. Proteome profiles (by mass spectrometry) revealed multiple differentially expressed proteins among groups. Several of these proteins showed high diagnostic values with maximum area under the receiver operating characteristic curve of 0.878 for CCA versus control, 0.905 for CCA stage I‐II versus control, 0.789 for PSC versus control, 0.806 for noncirhottic PSC versus control, 0.796 for CCA versus PSC, 0.956 for CCA stage I‐II versus PSC, 0.904 for HCC versus control, and 0.894 for intrahepatic CCA versus HCC. Proteomic analysis of EV derived from CCA human cells in vitro revealed higher abundance of oncogenic proteins compared to EV released by normal human cholangiocytes. Orthotopic implant of CCA human cells in the liver of immunodeficient mice resulted in the release to serum of EV containing some similar human oncogenic proteins. Conclusion : Proteomic signatures found in serum EV of CCA, PSC, and HCC patients show potential usefulness as diagnostic tools. (H epatology 2017;66:1125‐1143).