Drenth, Joost P.H.

ABSTRACT This international, multidisciplinary consensus report represents the first effort to systematically define and characterize fatty pancreas. A key outcome of this endeavor was the recommendation to adopt “fatty pancreas” as the standardized and inclusive term to describe all forms of fat accumulation in the pancreas. This terminological consensus provides a critical foundation for unified reporting and clinical communication. Another major contribution of the report is the consensus on diagnostic imaging findings, which was based on radiological and endoscopic modalities. The proposed criteria aim to enhance consistency in clinical assessment and support the development of standardized research protocols. In addition to establishing terminology and diagnostic frameworks, the report also synthesizes current knowledge across a wide range of relevant domains. These include the etiology and epidemiology of fatty pancreas, as well as its associations with alcohol consumption, smoking, acute and chronic pancreatitis, pancreatic exocrine insufficiency, type 2 diabetes mellitus, and surgical outcomes. The potential links between fatty pancreas and neoplastic conditions such as intraductal papillary mucinous neoplasms and pancreatic cancer are also addressed, alongside the current understanding of its metabolic implications (beta‐cell function and glucose homeostasis) and treatment strategies. Throughout the consensus process, a consistent theme emerged: the limited availability of high‐quality, prospective clinical data. Therefore, many of the recommendations in this report are based on expert consensus rather than strong empirical evidence. As such, the statements require rigorous prospective validation before they can be adopted into routine clinical practice. This underscores a critical need for further research, particularly studies aimed at clarifying causal relationships, validating diagnostic tools, and determining the clinical relevance of fatty pancreas across diverse patient populations. This report serves as both a summary of our current understanding and a roadmap for future investigations, aiming to close existing knowledge gaps and guide evidence‐based clinical practice in this emerging field.

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.

Abstract Background & Aims Polycystic liver diseases (PLDs) are genetic disorders characterized by progressive development of multiple biliary cysts. Recently, novel PLD‐causative genes, encoding for endoplasmic reticulum (ER)‐resident proteins involved in protein biogenesis and transport, were identified. We hypothesized that aberrant proteostasis contributes to PLD pathogenesis, representing a potential therapeutic target. Methods ER stress was analysed at transcriptional (qPCR), proteomic (mass spectrometry), morphological (transmission electron microscopy, TEM) and functional (proteasome activity) levels in different PLD models. The effect of ER stress inhibitors [4‐phenylbutyric acid (4‐PBA)] and/or activators [tunicamycin (TM)] was tested in polycystic (PCK) rats and cystic cholangiocytes in vitro. Results The expression levels of unfolded protein response (UPR) components were upregulated in liver tissue from PLD patients and PCK rats, as well as in primary cultures of human and rat cystic cholangiocytes, compared to normal controls. Cystic cholangiocytes showed altered proteomic profiles, mainly related to proteostasis (ie synthesis, folding, trafficking and degradation of proteins), marked enlargement of the ER lumen (by TEM) and hyperactivation of the proteasome. Notably, chronic treatment of PCK rats with 4‐PBA decreased liver weight, as well as both liver and cystic volumes, of animals under baseline conditions or after TM administration compared to controls. In vitro, 4‐PBA downregulated the expression (mRNA) of UPR effectors, normalized proteomic profiles related to protein synthesis, folding, trafficking and degradation and reduced the proteasome hyperactivity in cystic cholangiocytes, reducing their hyperproliferation and apoptosis. Conclusions Restoration of proteostasis in cystic cholangiocytes with 4‐PBA halts hepatic cystogenesis, emerging as a novel therapeutic strategy.

Treatment of polycystic liver disease (PLD) focuses on symptom improvement. Generic questionnaires lack sensitivity to capture PLD‐related symptoms, a prerequisite to determine effectiveness of therapy. We developed and validated a disease‐specific questionnaire that assesses symptoms in PLD (PLD‐Q). We identified 16 PLD‐related symptoms (total score 0‐100 points) by literature review and interviews with patients and clinicians. The developed PLD‐Q was validated in Dutch (n = 200) and United States (US; n = 203) PLD patients. We assessed the correlation of PLD‐Q total score with European Organization for Research and Treatment of Cancer (EORTC) symptom scale, global health visual analogue scale (VAS) of EQ‐5D, and liver volume. To test discriminative validity, we compared PLD‐Q total scores of patients with different PLD severity stages (Gigot classification) and PLD‐Q total scores of PLD patients with general controls and polycystic kidney disease patients without PLD. Reproducibility was tested by comparing original test scores with 2‐week retest scores. In total, 167 Dutch and 124 US patients returned the questionnaire. Correlation between PLD‐Q total score and EORTC symptom scale (The Netherlands [NL], r = 0.788; US, r = 0.811) and global health VAS (NL, r = −0.517; US, r = −0.593) was good. There was no correlation of PLD‐Q total score with liver volume (NL, r = 0.138; P = 0.236; US, r = 0.254; P = 0.052). Gigot type III individuals scored numerically higher than type II patients (NL, 46 vs. 40; P = 0.089; US, 48 vs. 36; P = 0.055). PLD patients scored higher on the PLD‐Q total score than general controls (NL, 42 vs. 17; US, 40 vs. 13 points) and polycystic kidney disease patients without PLD (22 points). Reproducibility of PLD‐Q was excellent (NL, r = 0.94; US, 0.96). Conclusion: PLD‐Q is a valid, reproducible, and sensitive disease‐specific questionnaire that can be used to assess PLD‐related symptoms in clinical care and future research. (Hepatology 2016;64:151–160)

AbstractBackground & AimsSomatostatin analogues reduce liver volumes in polycystic liver disease. However, patients show considerable variability in treatment responses. Our aim was to identify specific patient, disease or treatment characteristics that predict response in polycystic liver disease during somatostatin analogue therapy.MethodsWe pooled the individual patient data of four trials that evaluated long‐acting somatostatin analogues (120 mg lanreotide or 40 mg octreotide) for 6–12 months in polycystic liver disease patients. We performed uni‐ and multivariate linear regression analysis with preselected patient, disease and drug variables to identify independent predictors of response, defined as per cent change in liver or kidney volume (in ADPKD subgroup). All analyses were adjusted for baseline liver volume and centre.ResultsWe included 153 polycystic liver disease patients (86% female, median liver volume 4974 ml) from three international centres, all treated with octreotide (n = 70) or lanreotide (n = 83). Mean reduction in liver volume was 4.4% (range −31.6 to +9.4%). Multivariate linear regression revealed that elevated baseline alkaline phosphatase was associated with increased liver volume reduction during therapy (−2.7%, 95% CI −5.1 to −0.2%, P = 0.04), independently of baseline liver volume. Somatostatin analogue type, underlying diagnosis and eGFR did not affect response. In our ADPKD subpopulation (n = 100), elevated alkaline phosphatase predicted liver volume reduction (−3.2%, P = 0.03) but did not predict kidney volume reduction (+0.1%, P = 0.97). Total gastro‐intestinal symptom severity decreased with therapy in a subgroup analysis (n = 95; P < 0.001).ConclusionAlkaline phosphatase is a liver‐specific, independent predictor of response in polycystic liver disease during somatostatin analogue therapy.

SummaryBackgroundPolycystic liver disease is associated with impaired health‐related quality of life (HRQL). Somatostatin analogues reduce hepatomegaly in polycystic liver disease.AimTo determine whether somatostatin analogues improve HRQL and to identify factors associated with change in HRQL in polycystic liver disease.MethodsWe pooled data from two randomized, double‐blind, placebo‐controlled trials that evaluated HRQL using the Short‐Form 36 (SF‐36) in 96 polycystic liver disease patients treated 6‐12 months with somatostatin analogues or placebo. The SF‐36 contains a summarizing physical and mental component score and was administered at baseline and at the end of treatment. We used random effect models to delineate the effect of somatostatin analogues on HRQL. We determined the effect of demographics, height‐adjusted liver volume, change in liver volume, somatostatin analogue‐associated side effects with change in HRQL. In patients with autosomal dominant polycystic kidney disease, we estimated the effect of height‐adjusted kidney volume and change in kidney volume in relation to HRQL.ResultsPhysical component scores improved with somatostatin analogues, but remained unchanged with placebo (3.41 ± 1.29 vs. −0.71 ± 1.54, P = 0.044). Treatment had no impact on the mental component score. Large liver volume was independently associated with larger HRQL decline during follow up (−4.04 ± 2.02 points per logarithm liver volume, P = 0.049). In autosomal dominant polycystic kidney disease, patients with large liver and kidney volumes had larger decline in HRQL (5.36 ± 2.54 points per logarithm liver volume; P = 0.040 and −4.00 ± 1.88 per logarithm kidney volume; P = 0.039).ConclusionSomatostatin analogues improve HRQL in symptomatic polycystic liver disease. Halting the progressive nature of polycystic liver disease is necessary to prevent further decline of HRQL in severe hepatomegaly.