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Objectives: To identify predictive variables of treatment response following aspiration sclerotherapy of large symptomatic hepatic cysts., Methods: We collected individual patient data from two tertiary referral centres and included all patients treated with aspiration sclerotherapy of a large (>5 cm), symptomatic hepatic cyst. At six months, clinical response was defined as complete or incomplete. Secondary, suboptimal technical response was defined as lower quartile of cyst reduction. Predictive variables of clinical and technical response were analyzed by logistic regression analysis., Results: We included 86 patients (58 ± 10 years; female 90 %). Complete clinical response rate was 55 %. Median cyst diameter and volume reduction were 71 % (IQR 50-87 %) and 98 % (IRQ 88-100 %), respectively. Patients with complete clinical response had a significantly higher cyst reduction compared to incomplete responders (OR 1.02, 95 % CI 1.00-1.04). Aspiration of haemorrhagic cyst fluid (OR 4.39, 95 % CI 1.34-14.39) or a lower cyst reduction at one month (OR 1.06, 95 % CI 1.02-1.10) was associated with a suboptimal technical response at six months., Conclusion: Complete clinical response is associated with effective cyst reduction. Aspiration of haemorrhagic cyst fluid or a restricted diameter reduction at one month predicts a suboptimal technical treatment response, however, these variables did not predict symptom disappearance., Key Points: • Aspiration sclerotherapy of hepatic cysts shows excellent clinical and technical efficacy. • Optimal clinical responders have a markedly higher cyst reduction. • Haemorrhagic aspirate and a strong fluid reaccumulation predict suboptimal cyst reduction.

Introduction and Aims: The DIPAK-1 Study investigates the reno- and hepatoprotective efficacy of the somatostatin analog lanreotide compared with standard care in patients with later stage autosomal dominant polycystic kidney disease (ADPKD). During this trial, we witnessed several episodes of hepatic cyst infection, all during lanreotide treatment. We describe these events and provide a review of the literature., Methods: The DIPAK-1 Study is an ongoing investigator-driven, randomized, controlled, open-label multicenter trial. Patients (ADPKD, ages 18-60 years, estimated glomerular filtration rate 30-60 mL/min/1.73 m 2 ) were randomized 1:1 to receive lanreotide 120 mg subcutaneously every 28 days or standard care during 120 weeks. Hepatic cyst infection was diagnosed by local physicians., Results: We included 309 ADPKD patients of which seven (median age 53 years [interquartile range: 48-55], 71% female, median estimated glomerular filtration rate 42 mL/min/1.73 m 2 [interquartile range: 41-58]) developed eight episodes of hepatic cyst infection during 342 patient-years of lanreotide use (0.23 cases per 10 patient-years). These events were limited to patients receiving lanreotide (p < 0.001 vs. standard care). Baseline characteristics were similar between subjects who did or did not develop a hepatic cyst infection during lanreotide use, except for a history of hepatic cyst infection (29 vs. 0.7%, p < 0.001). Previous studies with somatostatin analogs reported cyst infections, but did not identify a causal relationship., Conclusions: These data suggest an increased risk for hepatic cyst infection during use of somatostatin analogs, especially in ADPKD patients with a history of hepatic cyst infection. The main results are still awaited to fully appreciate the risk-benefit ratio. CLINICALTRIALS., Gov Identifier: NCT 01616927., Competing Interests: Compliance with Ethical Standards Funding The DIPAK-1 study is made possible by a grant from the Dutch Kidney Foundation (CP10.12), with Ipsen Farmaceutica B.V., the Netherlands acting as a minor co-sponsor. The Dutch Kidney Foundation and Ipsen had no role in the design or conduct of the study, or in the writing and submission of the manuscript. Conflict of interest Marten A. Lantinga, Hedwig M.A. D’Agnolo, Niek F. Casteleijn, Johan W. de Fijter, Esther Meijer, Annemarie L. Messchendorp, Dorien J.M. Peters, Mahdi Salih, Darius Soonawala, Folkert W. Visser, and Jack F.M. Wetzels have no conflicts of interest that are directly relevant to the content of this study. Edwin M. Spithoven has received payment for an Otsuka presentation about the epidemiology of ADPKD and future perspectives. Robert Zietse has received previous grant support from Ipsen. Joost P.H. Drenth has received previous grant support from Ipsen and Novartis. Ron T. Gansevoort holds the rights on the Orphan Designation status of lanreotide for the indication ADPKD, which was granted by the European Medicines Agency (EU/3/15/1514). Ethics approval and consent to participate All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Consent for publication Informed consent was obtained from all individual participants included in the study.

Polycystic liver disease (PLD) is a rare genetic disorder with progressive cyst growth as the primary phenotype. Therapy consists of volume reduction through invasive surgical or radiological procedures. To understand the process of treatment decision, our aim was to identify factors that increased the likelihood of treatment. We performed a cross-sectional study using an international population of patients with PLD. We collected data on the following therapies: liver transplantation, resection, fenestration, and aspiration sclerotherapy. Data on the potential determinants, sex, center, autosomal dominant polycystic kidney disease (ADPKD), autosomal dominant polycystic liver disease (ADPLD), age at diagnosis, symptoms, and phenotype, were included. We corrected for follow-up time. We included 578 patients in our study, and 35% underwent invasive therapy. Multivariate regression analysis showed that number of symptoms and age at diagnosis of PLD increased the likelihood of treatment (respectively, RR: 1.4, P < 0.001 and RR = 1.4, P = 0.03). The choice for liver transplantation or aspiration sclerotherapy was center dependent (RR: 0.7, P < 0.001 and RR: 1.1, P = 0.03, respectively). The results of our international cross-sectional study suggest that a higher number of symptoms and every 10 years of PLD diagnosis increase the risk to undergo treatment by 40%. The choice to elect a particular modality is center dependent., (© 2016 Steunstichting ESOT.)

Objective: Aspiration sclerotherapy is a percutaneous procedure indicated for treatment of symptomatic simple hepatic cysts. The efficacy and safety of this procedure have been sources of debate and disagreement for years. The purpose of this study was to assess the long-term efficacy and safety of aspiration sclerotherapy in a systematic review of the literature., Materials and Methods: A systematic search was conducted of the electronic databases PubMed MEDLINE, Embase, Web of Science, and the Cochrane Library (until August 2015). Studies of proportional volume or diameter reduction after aspiration sclerotherapy of simple hepatic cysts were included for full-text evaluation. Case reports and case series were excluded. Risk of bias was assessed by use of the Newcastle-Ottawa scale., Results: From 9357 citations, 100 were selected for full-text assessment. We included 16 studies, which included 526 patients with a total of 588 treated cysts. Overall, risk of bias was high, with 12 of 16 studies having a score of poor. Proportional cyst volume reduction ranged between 76% and 100% after a median follow-up period of 1-54 months. Change in symptoms was evaluated in 10 studies: 72-100% of patients reported symptom reduction, and 56-100% reported disappearance. Postprocedural pain occurred most frequently, at a rate of 5-90% among studies. Ethanol intoxication occurred in up to 93% of cases and was reported more frequently in studies with either high ethanol volumes (133.7-138.3 mL) or long sclerotherapy duration (120-180 minutes)., Conclusion: We found excellent results with respect to long-term efficacy and safety after aspiration sclerotherapy of hepatic cysts. Nevertheless, because of the high risk of bias in the included studies, definite conclusions regarding efficacy cannot be drawn.

Autosomal dominant polycystic liver disease (ADPLD) is caused by variants in PRKCSH, SEC63, and LRP5, whereas autosomal dominant polycystic kidney disease is caused by variants in PKD1 and PKD2. Liver cyst development in these disorders is explained by somatic loss-of-heterozygosity (LOH) of the wild-type allele in the developing cyst. We hypothesize that we can use this mechanism to identify novel disease genes that reside in LOH regions. In this study, we aim to map abnormal genomic regions using high-density SNP microarrays to find novel PLD genes. We collected 46 cysts from 23 patients with polycystic or sporadic hepatic cysts, and analyzed DNA from those cysts using high-resolution microarray (n=24) or Sanger sequencing (n=22). We here focused on regions of homozygosity on the autosomes (>3.0 Mb) and large CNVs (>1.0 Mb). We found frequent LOH in PRKCSH (22/29) and PKD1/PKD2 (2/3) cysts of patients with known heterozygous germline variants in the respective genes. In the total cohort, 12/23 patients harbored abnormalities outside of familiar areas. In individual ADPLD cases, we identified germline events: a 2q13 complex rearrangement resulting in BUB1 haploinsufficiency, a 47XXX karyotype, chromosome 9q copy-number loss, and LOH on chromosome 3p. The latter region was overlapping with an LOH region identified in two other cysts. Unique germline and somatic abnormalities occur frequently in and outside of known genes underlying cysts. Each liver cyst has a unique genetic makeup. LOH driver gene BUB1 may imply germline causes of genetic instability in PLD.

Background: Isolated polycystic liver disease (ADPLD) is an autosomal dominant Mendelian disorder. Heterozygous PRKCSH (where PRKCSH is protein kinase C substrate 80K-H (80 kDa protein, heavy chain; MIM*177060) mutations are the most frequent cause. Routine molecular testing using Sanger sequencing identifies pathogenic variants in the PRKCSH (15%) and SEC63 (where SEC63 is Saccharomyces cerevisiae homolog 63 (MIM*608648); 6%) genes, but about approximately 80% of patients meeting the clinical ADPLD criteria carry no PRKCSH or SEC63 mutation. Cyst tissue often shows somatic deletions with loss of heterozygosity that was recently recognized as a general mechanism in ADPLD. We hypothesized that germline deletions in the PRKCSH gene may be responsible for hepatic cystogenesis in a significant number of mutation-negative ADPLD patients., Methods: In this study, we designed a multiplex ligation-dependent probe amplification (MLPA) assay to screen for deletions of PRKCSH exons. Genomic DNA from 60 patients with an ADPLD phenotype was included., Results: MLPA analysis detected no exon deletions in mutation-negative ADPLD patients., Conclusion: Large copy number variations on germline level are not present in patients with a clinical diagnosis of ADPLD. MLPA analysis of the PRKCSH gene should not be considered as a diagnostic method to explain hepatic cystogenesis., (© 2015 Wiley Periodicals, Inc.)

Background: Hepatic cyst infection is a potentially severe complication in cystic disease. Treatment demands effective antibiotic concentrations within the infected cyst., Objectives: The aim of this study was to use elective hepatic cyst drainage as a unique pharmacokinetic model to investigate whether cefazolin, a first-generation cephalosporin, is able to penetrate hepatic cysts., Patients and Methods: Patients scheduled to undergo percutaneous aspiration sclerotherapy of a symptomatic non-infected, non-neoplastic hepatic cyst were eligible for this study. All participants received a single perioperative prophylactic dose of cefazolin (1000 mg, intravenously). We collected blood and cyst fluid samples to determine total and unbound cefazolin concentrations using HPLC. The primary outcome was hepatic cyst penetration, expressed as the ratio (%) of unbound concentration of cefazolin in cyst fluid to plasma (both in mg/L)., Results: We included eight patients [male = 25%, median age = 60 years (IQR 54-75), median estimated glomerular filtration rate = 97 mL/min/1.73 m(2) (IQR 67-102) and median serum albumin = 40 g/L (IQR 37-40)]. We detected low concentrations of unbound cefazolin in cyst fluid (≤1.0 mg/L). The median plasma unbound cefazolin peak level (immediately after cefazolin administration) was 36.6 mg/L (IQR 23.7-54.1) and the level at the time of cyst fluid aspiration was 16.1 mg/L (IQR 13.0-20.1). In total, the hepatic cyst penetration of free cefazolin was only 2.2% (IQR 0.7-5.2)., Conclusions: We developed a study model to investigate the penetration of antibiotics into hepatic cysts. Cefazolin did not reach adequate intracystic concentrations. Future studies should explore alternatives., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background & Aims: Ursodeoxycholic acid (UDCA) inhibits proliferation of polycystic human cholangiocytes in vitro and hepatic cystogenesis in a rat model of polycystic liver disease (PLD) in vivo. Our aim was to test whether UDCA may beneficially affect liver volume in patients with advanced PLD., Methods: We conducted an international, multicenter, randomized controlled trial in symptomatic PLD patients from three tertiary referral centers. Patients with PLD and total liver volume (TLV) ⩾2500ml were randomly assigned to UDCA treatment (15-20mg/kg/day) for 24weeks, or to no treatment. Primary endpoint was proportional change in TLV. Secondary endpoints were change in symptoms and health-related quality of life. We performed a post-hoc analysis of the effect of UDCA on liver cyst volume (LCV)., Results: We included 34 patients and were able to assess primary endpoint in 32 patients, 16 with autosomal dominant polycystic kidney disease (ADPKD) and 16 with autosomal dominant polycystic liver disease (ADPLD). Proportional TLV increased by 4.6±7.7% (mean TLV increased from 6697ml to 6954ml) after 24weeks of UDCA treatment compared to 3.1±3.8% (mean TLV increased from 5512ml to 5724ml) in the control group (p=0.493). LCV was not different after 24weeks between controls and UDCA treated patients (p=0.848). However, UDCA inhibited LCV growth in ADPKD patients compared to ADPKD controls (p=0.049)., Conclusions: UDCA administration for 24weeks did not reduce TLV in advanced PLD, but UDCA reduced LCV growth in ADPKD patients. Future studies might explore whether ADPKD and ADPLD patients respond differently to UDCA treatment., Lay Summary: Current therapies for polycystic liver disease are invasive and have high recurrence risks. Our trial showed that the drug, ursodeoxycholic acid, was not able to reduce liver volume in patients with polycystic liver disease. However, a subgroup analysis in patients that have kidney cysts as well showed that liver cyst volume growth was reduced in patients who received ursodeoxycholic acid in comparison to patients who received no treatment. Trial registration number https://www.clinicaltrials.gov/: NCT02021110. EudraCT Number https://www.clinicaltrialsregister.eu/: 2013-003207-19., (Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Unlabelled: 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)., (© 2016 by the American Association for the Study of Liver Diseases.)

Background & Aims: Somatostatin 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., Methods: We 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., Results: We 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)., Conclusion: Alkaline phosphatase is a liver-specific, independent predictor of response in polycystic liver disease during somatostatin analogue therapy., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Cyst infection is one of the complications of autosomal dominant polycystic kidney disease and polycystic liver disease. The diagnosis is typically made on a mix of clinical, laboratory and imaging abnormalities but the importance of individual items is uncertain. We aimed to perform a Delphi survey amongst physicians to achieve consensus on diagnostic criteria., Methods: We retrieved diagnostic items from the literature and conducted physician and patient interviews. All items were combined to create the online questionnaire. Participants rated each item during 3 consecutive rounds. Items were rated for diagnostic helpfulness for hepatic and renal cyst infection on a 9-point scale with anchors, from extremely unimportant (n = 1) to extremely important (n = 9). We determined consensus with the disagreement index. The median rating of each item was calculated and categorized into inappropriate (≤3.4), uncertain (3.5-6.4) or appropriate (≥6.5). By combining all items that reached an appropriate consensus rating, we developed a diagnostic algorithm based on expert consensus., Results: We invited 58 physicians to participate in the survey. In total, 35 (60%) responded to round 1 of which 91% (n = 32) and 86% (n = 30) responded to round 2 and 3, respectively. The final panel included 23 nephrologists, 5 hepatologists, a nuclear medicine specialist and an infectious disease physician from 11 countries (male 67%, mean age 47 ± 11 years, median clinical experience 21 years). The panel rated the diagnostic helpfulness of 59 potential items. Ultimately, 22 hepatic and 26 renal items were rated appropriate, including positive blood cultures and fluorodeoxyglucose positron-emission CT imaging. Ultrasonography and absence of intracystic bleeding were amongst those deemed uncertain or inappropriate. Subsequently, by combining items rated appropriate, we developed a clinical tool to diagnose hepatic and renal cyst infection., Conclusions: We identified diagnostic items for hepatic and renal cyst infection and developed an expert-based diagnostic algorithm, which may aid physicians in the diagnostic work-up. A prospective study is necessary to validate this algorithm., (© 2016 S. Karger AG, Basel.)

Background & Aims: Polycystic liver diseases (PLDs) are genetic disorders characterized by progressive biliary cystogenesis. Current therapies show short-term and/or modest beneficial effects. Cystic cholangiocytes hyperproliferate as a consequence of diminished intracellular calcium levels ([Ca(2+)]i). Here, the therapeutic value of ursodeoxycholic acid (UDCA) was investigated., Methods: Effect of UDCA was examined in vitro and in polycystic (PCK) rats. Hepatic cystogenesis and fibrosis, and the bile acid (BA) content were evaluated from the liver, bile, serum, and kidneys by HPLC-MS/MS., Results: Chronic treatment of PCK rats with UDCA inhibits hepatic cystogenesis and fibrosis, and improves their motor behaviour. As compared to wild-type animals, PCK rats show increased BA concentration ([BA]) in liver, similar hepatic Cyp7a1 mRNA levels, and diminished [BA] in bile. Likewise, [BA] is increased in cystic fluid of PLD patients compared to their matched serum levels. In PCK rats, UDCA decreases the intrahepatic accumulation of cytotoxic BA, normalizes their diminished [BA] in bile, increases the BA secretion in bile and diminishes the increased [BA] in kidneys. In vitro, UDCA inhibits the hyperproliferation of polycystic human cholangiocytes via a PI3K/AKT/MEK/ERK1/2-dependent mechanism without affecting apoptosis. Finally, the presence of glycodeoxycholic acid promotes the proliferation of polycystic human cholangiocytes, which is inhibited by both UDCA and tauro-UDCA., Conclusions: UDCA was able to halt the liver disease of a rat model of PLD through inhibiting cystic cholangiocyte hyperproliferation and decreasing the levels of cytotoxic BA species in the liver, which suggests the use of UDCA as a potential therapeutic tool for PLD patients., (Copyright © 2015 European Association for the Study of the Liver. All rights reserved.)

Background: Polycystic liver disease is associated with impaired health-related quality of life (HRQL). Somatostatin analogues reduce hepatomegaly in polycystic liver disease., Aim: To determine whether somatostatin analogues improve HRQL and to identify factors associated with change in HRQL in polycystic liver disease., Methods: We 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., Results: Physical 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)., Conclusion: Somatostatin 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., (© 2015 John Wiley & Sons Ltd.)

Background & Aim: Several trials have demonstrated that somatostatin analogues decrease liver volume in mixed populations of patients with autosomal dominant polycystic kidney disease (ADPKD) and isolated polycystic liver disease. Chronic renal dysfunction in ADPKD may affect treatment efficacy of lanreotide and possibly enhances risk for adverse events. The aim of this open-label clinical trial (RESOLVE trial) was to assess the efficacy of 6-month lanreotide treatment, 120 mg, subcutaneously every 4 weeks in ADPKD patients with symptomatic polycystic liver disease., Methods: Primary outcome was change in liver volume after 6 months; secondary outcomes were changes in kidney volume, estimated glomerular filtration rate (eGFR), symptom relief and health-related quality of life (Euro-Qol5D). We excluded patients with an eGFR <30 ml/min/1.73 m(2) . We used the Wilcoxon signed-rank test or paired two-sided t-test to analyze within-group differences., Results: We included 43 ADPKD patients with polycystic liver disease (84% female, median age 50 years, mean eGFR 63 ml/min/1.73 m(2) ). Median liver volume decreased from 4859 ml to 4595 ml (-3.1%; P < 0.001), and median kidney volume decreased from 1023 ml to 1012 ml (-1.7%; P = 0.006). eGFR declined 3.5% after the first injection, remained stable up to study end, to decline again after lanreotide withdrawal. Lanreotide significantly relieved post-prandial fullness, shortness of breath and abdominal distension. Three participants had a suspected episode of hepatic or renal cyst infection during this study., Conclusion: Lanreotide reduced polycystic liver and kidney volumes and decreases symptoms in ADPKD patients. Moreover, eGFR decreased acutely after starting lanreotide, stabilized thereafter and declined again after withdrawal., Trial Registration Number: Clinical trials.gov NCT01354405 (REGISTRATION: 13 May 2011)., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Cyst infection is a severe complication of renal and hepatic cystic disease that frequently leads to hospitalization. In most cases the diagnosis of cyst infection is made empirically as a cyst aspirate is frequently unavailable. This study aims to evaluate diagnostic criteria, microbiological findings and imaging modalities needed to diagnose cyst infection. In order to do so, we evaluated reports that characterize cyst infection cases published in the English language between 1948 and January 2014. We identified 70 articles documenting a total of 215 cyst infection cases (renal n = 119; hepatic n = 96). Six studies, including 74 cases of renal and 61 cases of hepatic cyst infection, used diagnostic criteria. The criteria that led to a definite cyst infection diagnosis were consistent, whereas criteria for a 'probable diagnosis' varied considerably. Cyst infection cases commonly have abdominal pain, fever and elevated serum inflammatory markers. Urine and blood cultures frequently remained negative, even in definite cases. The diagnostic properties of (18)fluorodeoxyglucose positron-emission computed tomography ((18)F-FDG PET/CT) are probably best to diagnose cyst infection. Cyst aspirate indicating infection is currently the gold standard in diagnosing cyst infection. If not available, a combination of clinical and biochemical parameters is necessary to make a well-considered diagnosis, preferably including (18)F-FDG PET/CT., (© The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background and Objectives: Hereditary haemochromatosis (HH) is the most prevalent genetic liver disease, with an incidence of 1/200 to 1/400 in the Caucasian population. HH patients are treated by family physicians as well as different specialists. When left untreated or insufficiently treated, the complications can become life threatening. To support and evaluate qualitative care for HH, we evaluated and compared the available structured guidelines on screening, diagnosis and management of HH patients., Methods: Seven appraisers systematically reviewed the retrieved guidelines. The Appraisal of Guidelines Research and Evaluation II (AGREE II) was used to score and discuss the quality and reach consensus. The content of recommendations and the evidence behind them, were evaluated., Results: Three guidelines, developed by the American Association for the Study of Liver Diseases (AASLD), the European Association for the Study of the Liver (EASL) and a DUTCH guideline were found. Fifty-seven percent of the recommendations were not shared between the guidelines, pointing to inconsistency of their content. Only two references supporting the recommendations were shared between all three guidelines. The AASLD guideline contains no information about management and follow-up. Moreover, the methodological quality of the AASLD guideline was rated insufficient, except for 'clarity and presentation' (77%). Applicability of the guidelines was scored very low in all three (AASLD: 31%, EASL: 23%, DUTCH: 35%). The DUTCH guideline was judged best., Conclusions: Very poor consistency between available guidelines for HH hampers qualitative care and its evaluation. An updated high-quality and evidence-based guideline that covers follow-up and management of patients with HH is needed., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Background: Aspiration sclerotherapy is an effective therapeutic option for large symptomatic hepatic cysts. However, incomplete cyst reduction following aspiration sclerotherapy is frequently reported. Strong post-procedural cyst fluid secretion by cholangiocytes, which line the epithelium of the hepatic cyst, seems to be associated with lower reduction rates. Previous studies showed that somatostatin analogues curtail hepatic cyst fluid production. This trial will evaluate the effect of aspiration sclerotherapy combined with the somatostatin analogue pasireotide on cyst reduction. By combining treatment modalities we aim to improve cyst reduction leading to greater symptomatic relief and reduced rates of cyst recurrence., Methods/design: This single center, randomized, double-blind, placebo-controlled clinical trial evaluates the additional effect of pasireotide when combined with aspiration sclerotherapy in patients with a large (>5 cm) symptomatic hepatic cyst. A total of 34 participants will be randomized in a 1:1 ratio. In the active arm, patients will receive pasireotide (long-acting release, 60 mg injection) two weeks prior to and two weeks following aspiration sclerotherapy. Patients in the control arm will receive placebo injections at corresponding intervals. The primary outcome is proportional cyst diameter reduction four weeks after aspiration sclerotherapy compared to baseline measurements, obtained by ultrasonography. As secondary outcomes, proportional volume reduction, recurrence, symptomatic relief and improvement of health-related quality of life will be assessed. Furthermore, safety and tolerability of the combination of pasireotide and aspiration sclerotherapy will be evaluated., Discussion: This trial aims to improve efficacy of aspiration sclerotherapy by a combined approach of two treatment modalities. We hypothesize that pasireotide will decrease fluid re-accumulation after aspiration sclerotherapy, leading to effective hepatic cyst reduction and symptomatic relief., Trials Registration: This trial is registered with ClinicalTrials.gov (identifier: NCT02048319 ; registered on 6 January 2014) and EudraCT (identifier: 2013-003168-29; registered on 16 August 2013).

Background: Cyst infection is a severe complication of hepatic cystic disease. However, an evidence-based treatment strategy is not available., Aim: To assess the available treatment strategies and provide a treatment advice for de novo hepatic cyst infection., Methods: We systematically searched PubMed (1948-2014), EMBASE (1974-2014), and the Cochrane Library (until 2014) for studies involving humans (≥18 years) treated for a hepatic cyst infection. We extracted data on patient characteristics, treatment and follow-up., Results: We identified 41 articles; all were case series or case reports, implicating a high risk of bias. We included 54 hepatic cyst infection cases (male 39%; mean age 63 ± 12 years; diabetes 6%; dialysis 19%; transplant recipients 30%). Initial therapy consisted of antimicrobial (56%), percutaneous (31%) or surgical treatment (13%). We identified 42 antimicrobial regimens consisting of 23 different combinations. Most used antibiotic classes were quinolones (34%) and cephalosporins (34%). Antimicrobials failed in 70% of cases, eventually requiring percutaneous or surgical treatment in, respectively, 37% and 27%. Recurrent hepatic cyst infection was frequent (20%). Median time to recurrence was 8 weeks (IQR 3-24 weeks). In 46%, recurrence occurred in renal transplant recipients. Cyst infection related deaths occurred in 9%, of whom 40% were on dialysis., Conclusions: The literature shows that treatment of hepatic cyst infection is highly heterogeneous. We recommend first line treatment with oral ciprofloxacin. In case of failure, percutaneous cyst drainage needs to be considered., (© 2014 John Wiley & Sons Ltd.)

Mass-related symptoms caused by hepatic cysts are effectively treated by aspiration sclerotherapy (AS). This minimal-invasive intervention is regarded as a safe procedure. Hence, occurrence of complications is low. Transient fever is commonly reported as a side effect. However, documentation on a post-procedural hepatic cyst infection as a complication of AS is limited. We present five cases in which a tentative diagnosis of post-procedural hepatic cyst infection was made. Patients typically presented with abdominal pain and fever, had to be admitted to our hospital, and were treated with long term antibiotics. Ultimately, the cyst infection successfully resolved with ciprofloxacin in all cases.

Background & Aims: Polycystic 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., Methods: Pooled 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., Results: Demographics 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., Conclusion: Polycystic 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., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Polycystic liver disease (PLD) is the result of embryonic ductal plate malformation of the intrahepatic biliary tree. The phenotype consists of numerous cysts spread throughout the liver parenchyma. Cystic bile duct malformations originating from the peripheral biliary tree are called Von Meyenburg complexes (VMC). In these patients embryonic remnants develop into small hepatic cysts and usually remain silent during life. Symptomatic PLD occurs mainly in the context of isolated polycystic liver disease (PCLD) and autosomal dominant polycystic kidney disease (ADPKD). In advanced stages, PCLD and ADPKD patients have massively enlarged livers which cause a spectrum of clinical features and complications. Major complaints include abdominal pain, abdominal distension and atypical symptoms because of voluminous cysts resulting in compression of adjacent tissue or failure of the affected organ. Renal failure due to polycystic kidneys and non-renal extra-hepatic features are common in ADPKD in contrast to VMC and PCLD. In general, liver function remains prolonged preserved in PLD. Ultrasonography is the first instrument to assess liver phenotype. Indeed, PCLD and ADPKD diagnostic criteria rely on detection of hepatorenal cystogenesis, and secondly a positive family history compatible with an autosomal dominant inheritance pattern. Ambiguous imaging or screening may be assisted by genetic counseling and molecular diagnostics. Screening mutations of the genes causing PCLD (PRKCSH and SEC63) or ADPKD (PKD1 and PKD2) confirm the clinical diagnosis. Genetic studies showed that accumulation of somatic hits in cyst epithelium determine the rate-limiting step for cyst formation. Management of adult PLD is based on liver phenotype, severity of clinical features and quality of life. Conservative treatment is recommended for the majority of PLD patients. The primary aim is to halt cyst growth to allow abdominal decompression and ameliorate symptoms. Invasive procedures are required in a selective patient group with advanced PCLD, ADPKD or liver failure. Pharmacological therapy by somatostatin analogues lead to beneficial outcome of PLD in terms of symptom relief and liver volume reduction.

Polycystic livers are found in autosomal dominant polycystic kidney disease (ADPKD), caused by polycystic kidney disease (PKD)1 and PKD2 mutations in virtually all cases, and in isolated polycystic liver disease (PCLD), where 20% of cases are caused by mutations in Protein kinase C substrate 80K-H (PRKCSH) or SEC63. Loss of heterozygosity in single hepatoblasts leads to underlying cystogenic ductal plate malformations. Crucially, actual components driving this development remain elusive. Recent advances have unraveled the roles of transforming growth factor (TGF)-β, Notch and Wnt signaling, transcriptional regulators such as hepatocyte nuclear factor (HNF)6 and HNF1β, as well as cilium function in hepatobiliary organogenesis. In polycystic liver disease, mutation or defective co-translational processing of key elements required for primary cilium formation have been implicated. This review recapitulates liver patterning factors in hepatobiliary development and extracts molecular players in hepatic cystogenesis., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Polycystic livers are seen in the rare inherited disorder isolated polycystic liver disease (PCLD) and are recognized as the most common extrarenal manifestation in autosomal dominant polycystic kidney disease. Hepatic cystogenesis is characterized by progressive proliferation of cholangiocytes, ultimately causing hepatomegaly. Genetically, polycystic liver disease is a heterogeneous disorder with incomplete penetrance and caused by mutations in PRKCSH, SEC63, PKD1, or PKD2. Genome-wide SNP typing and Sanger sequencing revealed no pathogenic variants in hitherto genes in an extended PCLD family. We performed whole-exome sequencing of DNA samples from two members. A heterozygous variant c.3562C > T located at a highly conserved amino acid position (p.R1188W) in the low density lipoprotein receptor-related protein 5 (LRP5) gene segregated with the disease (logarithm of odds score, 4.62) but was not observed in more than 1,000 unaffected individuals. Screening of LRP5 in a PCLD cohort identified three additional mutations in three unrelated families with polycystic livers (p.V454M, p.R1529S, and p.D1551N), again all undetected in controls. All variants were predicted to be damaging with profound structural effects on LRP5 protein domains. Liver cyst tissue and normal hepatic tissue samples from patients and controls showed abundant LRP5 expression by immunohistochemistry. Functional activity analyses indicated that mutant LRP5 led to reduced wingless signal activation. In conclusion, we demonstrate that germ-line LRP5 missense mutations are associated with hepatic cystogenesis. The findings presented in this study link the pathophysiology of PCLD to deregulation of the canonical wingless signaling pathway.

Background: Long-acting lanreotide (LAN) 120 mg every 4 weeks reduces liver volume (LV) in patients with polycystic liver diseases (PCLD). Animal studies demonstrated that the inhibition of hepatic and renal cystogenesis is dose dependent., Aim: To investigate the safety and efficacy of two different LAN doses in PCLD patients., Methods: The 6-month results of the LOCKCYST I trial, its extension study and the LOCKCYST II trial were pooled. LV at baseline and month 6 was measured by CT-scan and blindly re-analysed by two independent radiologists., Results: The study population [132 treatment periods, age 49 years (IQR: 45-55), 114 women] consisted of three groups. Each received treatment every 4 weeks during 6 months: placebo (n = 26); LAN 90 mg (n = 55) or LAN 120 mg (n = 51). The inter-observer variability and agreement in the calculation of LV were excellent. Severe side effects occurred with placebo, LAN 90 mg and LAN 120 mg in respectively 0%, 7% and 16%. Change in LV's after 6 months in these three groups were respectively: increase of +36 mL [(-45)-(+138)]; decrease of -82 mL [(-285)-(+92)] and decrease of -123 mL [(-312)-(+4)] (Kruskal-Wallis One Way anova on Ranks; P = 0.002). Based on ROC analysis, a reduction of ≥120 mL in LV has a positive predictive value of 64% for improving symptoms (ROC analysis AUC: 0.729; sensitivity 73%, specificity 69%, P < 0.0001)., Conclusions: Both LAN 90 mg and LAN 120 mg reduce liver volume. LAN 90 mg has less side effects. This suggests that in case of intolerance to LAN 120 mg, a dose reduction to LAN 90 mg is meaningful., (© 2013 John Wiley & Sons Ltd.)

Background & Aims: Clinical trials have shown that in patients with polycystic liver disease (PLD), short-term treatment with somatostatin analogues (SAs) reduces liver volumes by 4.5%-5.9%, compared with placebo. However, the effects of SA therapy vary among individuals. We collected data from individual patients with PLD to identify subgroups that benefit most from SA therapy., Methods: We analyzed data from 107 patients with PLD from 3 randomized placebo-controlled trials (67 received SAs, 52 received placebo). We used multiple linear regression analysis to determine the effects of SAs based on patients' age, sex, baseline liver volume, and diagnosis (autosomal dominant polycystic liver or kidney disease). The primary outcome was change in liver volume after 6-12 months of treatment., Results: The effects of SA therapy did not differ significantly among patients with different diagnoses or baseline liver volumes; the overall difference in liver volume between groups receiving SAs therapy vs placebo was 5.3% (P < .001). Among subjects given placebo, young women (48 years old or younger) had the greatest increase in polycystic liver volume (4.8%; 95% confidence interval: 2.2%-7.4%), and mean liver volumes did not increase in older women and men. Women 48 years old or younger had a greater response to therapy (a reduction in liver volume of 8.0% compared with placebo; P < .001) than older women (a reduction in liver volume of 4.1% compared with placebo; P = .022)., Conclusions: Based on a pooled analysis of data from individual patients with PLD, treatment with somatostatin analogues is equally effective for patients with autosomal dominant polycystic kidney disease or polycystic liver disease; efficacy does not depend on size of the polycystic liver. Young female patients appear to have the greatest benefit from 6-12 months of SA therapy, which might avert the progressive course of the disease in this specific group., (Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Polycystic liver disease (PLD) is associated with autosomal dominant polycystic kidney disease (ADPKD) or autosomal dominant polycystic liver disease (PCLD). The resulting hepatomegaly compromises quality of life. Somatostatin analogues reduce PLD volume by approximately 5% when given for 6-12 months. A pilot trial in 16 ADPKD patients demonstrated that sirolimus, an mTOR inhibitor, reduced PLD volume by 26%. The aim of this study was to assess the PLD volume reducing effect of everolimus and octreotide relative to octreotide monotherapy., Methods: We designed a randomized controlled trial that compared 48 weeks of everolimus 2.5 mg daily, combined with octreotide 40 mg intramuscularly every 4 weeks, to octreotide monotherapy. We included PCLD and ADPKD patients. Exclusion criteria were MDRD-GFR <60 ml/min/1.73 m(2) and liver volume <2500 ml. Primary outcome was change in liver volume measured with CT-volumetry., Results: We randomized 44 PLD patients (29 PCLD, 15 ADPKD, 89% female) to treatment with octreotide (n=23) or octreotide-everolimus (n=21). Liver volume decreased by 3.5% (p<0.01) in the monotherapy arm, compared to 3.8% with combination therapy (p<0.01). The difference between treatment arms was not significant (p=0.73)., Conclusions: Adding everolimus to octreotide in PLD does not increase the liver volume reducing effect of octreotide., (Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Hepatic cysts are increasingly found as a mere coincidence on abdominal imaging techniques, such as ultrasonography (USG), computed tomography (CT) and magnetic resonance imaging (MRI). These cysts often present a diagnostic challenge. Therefore, we performed a review of the recent literature and developed an evidence-based diagnostic algorithm to guide clinicians in characterising these lesions. Simple cysts are the most common cystic liver disease, and diagnosis is based on typical USG characteristics. Serodiagnostic tests and microbubble contrast-enhanced ultrasound (CEUS) are invaluable in differentiating complicated cysts, echinococcosis and cystadenoma/cystadenocarcinoma when USG, CT and MRI show ambiguous findings. Therefore, serodiagnostic tests and CEUS reduce the need for invasive procedures. Polycystic liver disease (PLD) is arbitrarily defined as the presence of > 20 liver cysts and can present as two distinct genetic disorders: autosomal dominant polycystic kidney disease (ADPKD) and autosomal dominant polycystic liver disease (PCLD). Although genetic testing for ADPKD and PCLD is possible, it is rarely performed because it does not affect the therapeutic management of PLD. USG screening of the liver and both kidneys combined with extensive family history taking are the cornerstone of diagnostic decision making in PLD. In conclusion, an amalgamation of these recent advances results in a diagnostic algorithm that facilitates evidence-based clinical decision making.

Polycystic liver disease (PLD) is arbitrarily defined as a liver that contains >20 cysts. The condition is associated with two genetically distinct diseases: as a primary phenotype in isolated polycystic liver disease (PCLD) and as an extrarenal manifestation in autosomal dominant polycystic kidney disease (ADPKD). Processes involved in hepatic cystogenesis include ductal plate malformation with concomitant abnormal fluid secretion, altered cell-matrix interaction and cholangiocyte hyperproliferation. PLD is usually a benign disease, but can cause debilitating abdominal symptoms in some patients. The main risk factors for growth of liver cysts are female sex, exogenous oestrogen use and multiple pregnancies. Ultrasonography is very useful for achieving a correct diagnosis of a polycystic liver and to differentiate between ADPKD and PCLD. Current radiological and surgical therapies for symptomatic patients include aspiration-sclerotherapy, fenestration, segmental hepatic resection and liver transplantation. Medical therapies that interact with regulatory mechanisms controlling expansion and growth of liver cysts are under investigation. Somatostatin analogues are promising; several clinical trials have shown that these drugs can reduce the volume of polycystic livers. The purpose of this Review is to provide an update on the diagnosis and management of PLD with a focus on literature published in the past 4 years.

Background: Autosomal recessive polycystic kidney disease (ARPKD) shows a great phenotypic variability between patients, ranging from perinatal demise to mildly affected adults. Autosomal dominant polycystic liver disease (PCLD) does not manifest in childhood., Case-Diagnosis/treatment: A boy was reported with the co-occurrence of ARPKD and PCLD. He presented at the age of 16 days with pyelonephritis and urosepsis. Subsequent investigations showed enlarged kidneys and hyperechogenic renal medulla and liver parenchyma. Genetic analysis revealed compound heterozygous mutations in the PKHD1 gene (p.Arg496X and p.Ser1862Leu). After his mother was diagnosed with PCLD, the finding of a liver cyst on ultrasound prompted analysis of the PRKCSH gene, revealing a missense mutation (p.Arg139His). At the most recent follow-up at 13 years of age, the patient's course and clinical examination was uneventful with normal renal and liver function without evidence of portal hypertension., Conclusions: The patient with ARPKD and PCLD has so far demonstrated a benign clinical outcome, consistent with the great phenotypic variability of ARPKD and, apart from the liver cyst, asymptomatic manifestation of PCLD in childhood. However, close long-term follow-up is mandatory.

Background: A large proportion of patients with autosomal dominant polycystic kidney disease (ADPKD) suffers from polycystic liver disease. Symptoms arise when liver volume increases. The somatostatin analogue lanreotide has proven to reduce liver volume in patients with polycystic liver disease. However, this study also included patients with isolated polycystic liver disease (PCLD). The RESOLVE trial aims to assess the efficacy of lanreotide treatment in ADPKD patients with symptomatic polycystic livers. In this study we present the design of the RESOLVE trial., Methods/design: This open-label clinical trial evaluates the effect of 6 months of lanreotide in ADPKD patients with symptomatic polycystic livers. Primary outcome is change in liver volume determined by computerised tomography-volumetry. Secondary outcomes are changes in total kidney volume, kidney intermediate volume and renal function. Furthermore, urinary (NGAL, α1-microglobulin, KIM-1, H-FABP, MCP-1) and serum (fibroblast growth factor 23) biomarkers associated with ADPKD disease severity are assessed to investigate whether these biomarkers predict treatment responses to lanreotide. Moreover, safety and tolerability of the drug in ADPKD patients will be assessed., Discussion: We anticipate that lanreotide is an effective therapeutic option for ADPKD patients with symptomatic polycystic livers and that this trial aids in the identification of patient related factors that predict treatment response., Trial Registration Number: Clinical trials.gov NCT01354405.

Polycystic liver disease (PCLD) is an autosomal dominant disorder characterised by multiple fluid filled cysts in the liver. This rare disease is caused by heterozygous germline mutations in PRKCSH and SEC63. We previously found that, in patients with a PRKCSH mutation, over 76% of the cysts acquired a somatic 'second-hit' mutation in the wild type PRKCSH allele. We hypothesise that somatic second-hit mutations are a general mechanism of cyst formation in PCLD which also plays a role in PCLD patients carrying a SEC63 germline mutation. We collected cyst epithelial cells from 52 liver cysts from three different SEC63 patients using laser microdissection. DNA samples were sequenced to identify loss of heterozygosity (LOH) mutations and other somatic mutations in cyst epithelial DNA. We discovered somatic SEC63 mutations in patient 3 (1/14 cysts), but not in patient 1 and 2 (38 cysts). Upon review we found that the germline mutation of patient 1 and 2 (SEC63 c.1703&#95;1705delAAG) was present in the same frequency in DNA samples from healthy controls, suggesting that this variant is not causative of PCLD. In conclusion, as somatic second-hit mutations also play a role in cyst formation in patients with a SEC63 germline mutation, this appears to be a general mechanism of cyst formation in PCLD.

Background: Polycystic liver disease (PLD) is a phenotypical expression of autosomal dominant polycystic kidney disease and isolated polycystic liver disease. Somatostatin analogues, such as lanreotide, reduce polycystic liver volume., Aim: To establish long-term outcome and safety of lanreotide., Methods: This was an open-label, observational extension study of a 6-month, randomised, placebo-controlled trial with lanreotide (120 mg/month) in PLD. The length of total treatment was 12 months. Primary endpoint was relative change in liver volume, as determined by CT-volumetry after 12 months of treatment. We offered patients a CT scan 6 months after stopping lanreotide., Results: A total of 41/54 (76%) patients participated in the extension study. Liver volume decreased by 4% (IQR -8% to -1%) after 12 months of treatment. The greatest effect was observed during the first 6 months of treatment (decrease of 4% (IQR -6% to -1%)). Liver volume remained unchanged during the following 6 months. We found that liver volume increased by 4% (IQR 0-6%) 6 months after end of treatment (n = 22)., Conclusions: Lanreotide reduces liver volume within the first 6 months of treatment and the beneficial effect is maintained in the following 6 months. Stopping results in recurrence of polycystic liver growth. This suggests that continuous use of lanreotide is needed to maintain its effect., (© 2011 Blackwell Publishing Ltd.)

Background & Aims: Heterozygous germline mutations in PRKCSH cause autosomal dominant polycystic liver disease (PCLD), but it is not clear how they lead to cyst formation. We investigated whether mutations in cyst epithelial cells and corresponding loss of the PRKCSH gene product (hepatocystin) contributed to cyst development., Methods: Liver cyst material was collected through laparoscopic cyst fenestration from 8 patients with PCLD who had a heterozygous germline mutation in PRKCSH. Tissue sections from 71 cysts (2-14 per patient) were obtained for hepatocystin staining and mutation analysis. Cyst epithelium was acquired using laser microdissection; DNA was isolated and analyzed for loss of heterozygosity (LOH) and somatic mutations using restriction analysis and sequencing. Common single nucleotide polymorphisms (SNPs) in a 70-kilobase region surrounding the germline mutation were used to determine variations in the genomic region with LOH., Results: The wild-type allele of PRKCSH was lost (LOH) in 76% of cysts (54/71). Hepatocystin was not detected in cyst epithelia with LOH, whereas heterozygous cysts still expressed hepatocystin. The variation observed in the LOH region analysis indicates that cysts develop independently. We also detected somatic mutations in PRKCSH in 17% (2/12) of the cysts without LOH. Trans-heterozygous mutations in SEC63 were not observed., Conclusions: Among patients with PCLD who have a heterozygous germline mutation in PRKCSH, we found secondary, somatic mutations (second hits) in more than 76% of the liver cyst epithelia. PCLD is recessive at the cellular level, and loss of functional PRKCSH is an important step in cystogenesis., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Polycystic liver disease (PLD) is defined as having more than 20 liver cysts and can present as a severe and disabling condition. Most symptoms are caused by the mass effect of the liver size and include abdominal pain and distension. The somatostatin analogues octreotide and lanreotide have proven to reduce polycystic liver volume. mTOR inhibitors such as everolimus inhibit cell proliferation and might thereby reduce growth of liver cysts. This trial aims to assess the benefit of combination therapy of everolimus and octreotide compared to octreotide monotherapy. In this study we present the structure of the trial and the characteristics of the included patients., Methods/design: This is a randomized open-label clinical trial comparing the effect of 12 months of everolimus and octreotide to octreotide monotherapy in PLD patients. Primary outcome is change in liver volume determined by CT-volumetry. Secondary outcomes are changes in abdominal symptoms and quality of life. Moreover, safety and tolerability of the drugs will be assessed., Discussion: This trial will compare the relative efficacy of combination therapy with octreotide and everolimus to octreotide monotherapy. Since they apply to different pathways of cystogenesis we expect that combining octreotide and everolimus will result in a cumulative reduction of polycystic liver volume., Trial Registration Number: ClinicalTrials.gov: NCT01157858.

Autosomal dominant polycystic kidney disease (ADPKD) is a multisystem disorder. It is the most common genetic cause of end-stage renal disease. One frequent extra-renal manifestation is hepatic cyst formation. The majority of ADPKD patients develop complications as a result of renal cyst formation&semi; however, a small proportion develop extensive hepatic disease with minor renal features. Both phenotypes seem to represent the spectrum of ADPKD. This review discusses the current understanding of the pathogenesis of the disease, its manifestations and the mechanisms of cyst formation. Furthermore, it focuses on monitoring the disease and the treatment options currently available.

Fibrocystic diseases affecting the liver and often also other organs like the kidneys are a clinically and genetically heterogeneous group of disorders that may present in utero or remain clinically silent into late adulthood. During recent years, substantial progress has been made in unravelling the aetiology with primary cilia playing a central pathogenic role in many if not all of these diseases. The fibrocystogenic process shares some common features including proliferation and dilatation of epithelial bile ducts with concomitant abnormal apoptosis, fluid secretion and extracellular matrix deposition. In this review, we summarise clinical and diagnostic aspects, mechanisms of hepatic cystogenesis, and recent knowledge on potential therapies for these conditions., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Autosomal dominant polycystic liver disease (PCLD) is a rare progressive disorder characterized by an increased liver volume due to many (>20) fluid-filled cysts of biliary origin. Disease causing mutations in PRKCSH or SEC63 are found in approximately 25% of the PCLD patients. Both gene products function in the endoplasmic reticulum, however, the molecular mechanism behind cyst formation remains to be elucidated. As part of the translocon complex, SEC63 plays a role in protein import into the ER and is implicated in the export of unfolded proteins to the cytoplasm during ER-associated degradation (ERAD). PRKCSH codes for the beta-subunit of glucosidase II (hepatocystin), which cleaves two glucose residues of Glc(3)Man(9)GlcNAc(2) N-glycans on proteins. Hepatocystin is thereby directly involved in the protein folding process by regulating protein binding to calnexin/calreticulin in the ER. A separate group of genetic diseases affecting protein N-glycosylation in the ER is formed by the congenital disorders of glycosylation (CDG). In distinct subtypes of this autosomal recessive multisystem disease specific liver symptoms have been reported that overlap with PCLD. Recent research revealed novel insights in PCLD disease pathology such as the absence of hepatocystin from cyst epithelia indicating a two-hit model for PCLD cystogenesis. This opens the way to speculate about a recessive mechanism for PCLD pathophysiology and shared molecular pathways between CDG and PCLD. In this review we will discuss the clinical-genetic features of PCLD and CDG as well as their biochemical pathways with the aim to identify novel directions of research into cystogenesis., (Copyright (c) 2010. Published by Elsevier B.V.)

Background: Alpha-1 antitrypsin (A1AT) deficiency, caused by the Z allele (p.E342K) and S allele (p.E264V) in the SERPINA1 gene, can induce liver and pulmonary disease. Different mechanisms appear to be responsible for the pathogenesis of these divergent disease expressions. The c.-1973T >C polymorphism located in the SERPINA1 promoter region is found more frequent in A1AT deficiency patients with liver disease compared to patients with pulmonary disease, but data are lacking regarding contribution to the development of liver diseases caused by other aetiologies., Aim: To study the prevalence of c.-1973T >C, Z allele and S allele in a cohort of patients with liver disease of various aetiologies compared with healthy controls and to evaluate its effect on disease progression., Methods: A total of 297 patients with liver disease from various aetiologies and 297 age and gender matched healthy controls were included. The c.-1973T >C polymorphism and Z and S alleles of the SERPINA1 gene were analyzed by real-time PCR., Results: c.-1973T >C was similarly distributed between patients with liver disease of various origins and healthy controls. Furthermore, the distribution of c.-1973T >C was independent from aetiology subgroup. In patients with liver disease mean ages at of onset of liver disease were 44.4, 42.3 and 40.7 years for the c.-1973 T/T, T/C and C/C genotype respectively (NS). S allele heterozygosity was increased in patients with drug induced liver injury (DILI), (OR 4.3; 95%CI 1.1-17.2)., Conclusion: In our study, c.-1973T >C polymorphism was not a risk factor for liver disease of various aetiologies. In addition, S allele heterozygosity might contribute to the development of DILI.

Glycogenic hepatopathy (GH) is a rare cause of serum transaminase elevations in type 1 diabetes mellitus (DM). We describe a 29-year-old woman with a history of poorly controlled type 1 DM who presented with hepatomegaly and severe transaminase flares. Liver histology confirmed GH, with glycogen accumulation due to severe fluctuations in both glucose and insulin. GH can be regarded as an adult variant of Mauriac's syndrome. Despite severe laboratory abnormalities, it does not cause liver cirrhosis. Treatment consists of improving glycaemic control.

Background & Aims: Therapy for polycystic liver is invasive, expensive, and has disappointing long-term results. Treatment with somatostatin analogues slowed kidney growth in patients with polycystic kidney disease (PKD) and reduced liver and kidney volume in a PKD rodent model. We evaluated the effects of lanreotide, a somatostatin analogue, in patients with polycystic liver because of autosomal-dominant (AD) PKD or autosomal-dominant polycystic liver disease (PCLD)., Methods: We performed a randomized, double-blind, placebo-controlled trial in 2 tertiary referral centers. Patients with polycystic liver (n = 54) were randomly assigned to groups given lanreotide (120 mg) or placebo, administered every 28 days for 24 weeks. The primary end point was the difference in total liver volume, measured by computerized tomography at weeks 0 and 24. Analyses were performed on an intention-to-treat basis., Results: Baseline characteristics were comparable for both groups, except that more patients with ADPKD were assigned to the placebo group (P = .03). The mean liver volume decreased 2.9%, from 4606 mL (95% confidence interval (CI): 547-8665) to 4471 mL (95% CI: 542-8401 mL), in patients given lanreotide. In the placebo group, the mean liver volume increased 1.6%, from 4689 mL (95% CI: 613-8765 mL) to 4895 mL (95% CI: 739-9053 mL) (P < .01). Post hoc stratification for patients with ADPKD or PCLD revealed similar changes in liver volume, with statistically significant differences in patients given lanreotide (P < .01 for both diseases)., Conclusions: In patients with polycystic liver, 6 months of treatment with lanreotide reduces liver volume.

Background/aims: Carbohydrate antigen 19-9 (CA19-9) is used as a biomarker to differentiate benign from malignant gastrointestinal disorders. We examined the value of CA19-9 measurement in polycystic livers after observing high CA19-9 cyst fluid levels in a benign polycystic liver case., Methods: We determined CA19-9 levels in serum (n=120) and hepatic cyst fluid (n=81), from patients with polycystic livers (n=109) and simple hepatic cysts (n=24). Further, we analysed CA19-9 expression in normal and polycystic liver tissue (n=17)., Results: Cyst fluid CA19-9 levels from both polycystic livers and simple hepatic cysts were extremely high (median 91 000 U/ml, range 14-15 870 000 U/ml; median 85 000 U/ml, range 332-1 744 000 U/ml respectively). Serum CA19-9 levels were significantly higher in polycystic liver patients (median 30 U/ml, range 0-1200 U/ml) compared with patients with simple hepatic cysts (median 10 U/ml, range 3-200 U/ml, P=0.0011). Serum CA19-9 levels correlated with those in cyst fluid (r=0.3979, P=0.0399), polycystic liver volume (r=0.3870, P=0.0025) and the size of the largest cyst (simple cysts group; r=0.5319, P=0.0280). Cyst epithelia showed strong CA19-9 expression. Evacuation of cyst fluid in four patients resulted in a dramatic decrease in the serum CA19-9 levels (60-95%)., Conclusions: CA19-9 levels are high in the cyst fluid and serum of polycystic liver disease patients due to production and secretion by cyst epithelia. It does not reflect malignancy in these patients and may be of value as a biomarker for intervention efficiency assessment.

The pathogenesis of polycystic liver disease is not well understood. The putative function of the associated proteins, hepatocystin and Sec63p, do not give insight in their role in cystogenesis and their tissue-wide expression does not fit with the liver-specific phenotype of the disease. We designed this study with the specific aim to dissect whether pathways involved in polycystic kidney diseases are also implicated in polycystic liver disease. Therefore, we immunohistochemically stained cyst tissue specimen with antibodies directed against markers for apoptosis, proliferation, growth receptors, signaling and adhesion. We analyzed genotyped polycystic liver disease cyst tissue (n=21) compared with normal liver tissue (n=13). None of the cysts showed proliferation of epithelial cells. In addition, anti-apoptosis marker Bcl-2 revealed slight increase in expression, with variable increase of apoptosis marker active caspase 3. Growth factor receptors, EGFR and c-erbB-2, were overexpressed and mislocalized. We found EGFR staining in the nuclei of cyst epithelial cells regardless of mutational state of the patient. Further, in hepatocystin-mutant polycystic liver disease patients, apical membranous staining of c-erbB-2 and adhesion markers, MUC1 and CEA, was lost and the proteins appeared to be retained in cytoplasm of cyst epithelia. Finally, we found loss of adhesion molecules E-cadherin and Ep-CAM in cyst epithelium of all patients. Nevertheless, we observed normal beta-catenin expression. Our results show that polycystic liver disease cystogenesis is different from renal cystogenesis. Polycystic liver disease involves overexpression of growth factor receptors and loss of adhesion. In contrast, proliferation or deregulated apoptosis do not seem to be implicated. Moreover differential findings for PRKCSH- and SEC63-associated polycystic liver disease suggest a divergent mechanism for cystogenesis in these two groups.