Gevers, Tom J.G.

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.

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.

AbstractBackground & AimsPolycystic liver disease (PLD) follows a progressive course ultimately leading to severe hepatomegaly and mechanical complaints in a subset of patients. It is still unknown to what extent this compromises health‐related quality of life (HRQL). Our aim was to determine HRQL in PLD patients and investigate its association with concurrent abdominal symptoms and liver volume.MethodsPooled data of 92 severe PLD patients from two randomized clinical trials were used for our cross‐sectional analysis. HRQL was assessed using the generic short‐form health survey (SF‐36) resulting in eight scale scores and the summarizing physical (PCS) and mental component score (MCS). Subsequently, these were compared with the general population. Abdominal symptoms were measured with a standardized, 7‐point scale questionnaire in 54 patients. We dichotomized symptoms for absence or presence and compared them with the component scores. Finally, a possible correlation between liver volume and HRQL was explored.ResultsDemographics showed severe polycystic livers (mean 4906 ± 2315 ml). PCS was significantly lower compared with the general population (P < 0.001), in contrast with a similar MCS (P = 0.82). PLD patients had statistically significant (P < 0.05) diminished physical functioning, role physical, general health, vitality and social functioning scores. Upper‐ and lower abdominal pain and dyspnoea were significantly associated with a reduced PCS (P < 0.01). No correlation was found between liver volume and HRQL.ConclusionPolycystic liver disease patients had significantly lower HRQL in the physical dimension compared with the general population. Abdominal pain and dyspnoea had a significant impact on this physical dimension of HRQL.