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Background & Aims: Polycystic liver disease (PLD) manifests as numerous fluid-filled cysts scattered throughout the liver parenchyma. PLD most commonly develops in females, either as an extra-renal manifestation of autosomal-dominant polycystic kidney disease (ADPKD) or as isolated autosomal-dominant polycystic liver disease (ADPLD). Despite known genetic causes, clinical variability challenges patient counselling and timely risk prediction is hampered by a lack of genotype-phenotype correlations and prognostic imaging classifications. Methods: We performed targeted next-generation sequencing and multiplex ligation-dependent probe amplification to identify the underlying genetic defect in a cohort of 80 deeply characterized patients with PLD. Identified genotypes were correlated with total liver and kidney volume (assessed by CT or MRI), organ function, co-morbidities, and clinical endpoints. Results: Monoallelic diagnostic variants were identified in 60 (75%) patients, 38 (48%) of which pertained to ADPKD-gene variants (PKD1, PKD2, GANAB) and 22 (27%) to ADPLD-gene variants (PRKCSH, SEC63). Disease severity defined by age at waitlisting for liver transplantation and first PLD-related hospitalization was significantly more pronounced in mutation carriers compared to patients without genetic diagnoses. While current imaging classifications proved unable to differentiate between severe and moderate courses, grouping by estimated age-adjusted total liver volume progression yielded significant risk discrimination. Conclusion: This study underlines the predictive value of providing a molecular diagnosis for patients with PLD. In addition, we propose a novel risk-classification model based on age- and height-adjusted total liver volume that could improve individual prognostication and personalized clinical management. Lay summary: Polycystic liver disease (PLD) is a highly variable condition that can be asymptomatic or severe. However, it is currently difficult to predict clinical outcomes such as hospitalization, symptom burden, and need for transplantation in individual patients. In the current study, we aimed to investigate the clinical value of genetic confirmation and an age-adjusted total liver volume classification for individual disease prediction. While genetic confirmation generally pointed to more severe disease, estimated age-adjusted increases in liver volume could be useful for predicting clinical outcomes.

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BACKGROUND & AIMS: Polycystic liver disease (PLD) is characterised by increased autophagy and reduced miRNA levels in cholangiocytes. Given that autophagy has been implicated in miRNA regulation, we tested the hypothesis that increased autophagy accounts for miRNA reduction in PLD cholangiocytes (PLDCs) and accelerated hepatic cystogenesis. METHODS: We assessed miRNA levels in cultured normal human cholangiocytes (NHCs), PLDCs, and isolated PLDC autophagosomes by miRNA-sequencing (miRNA-seq), and miRNA targets by mRNA-seq. Levels of miR-345 and miR-345-targeted proteins in livers of animals and humans with PLD, in NHCs and PLDCs, and in PLDCs transfected with pre-miR-345 were assessed by in situ hybridisation (ISH), quantitative PCR, western blotting, and fluorescence confocal microscopy. We also assessed cell proliferation and cyst growth in vitro, and hepatic cystogenesis in vivo. RESULTS: In total, 81% of miRNAs were decreased in PLDCs, with levels of 10 miRNAs reduced by more than 10 times; miR-345 was the most-reduced miRNA. In silico analysis and luciferase reporter assays showed that miR-345 targets included cell-cycle and cell-proliferation-related genes [i.e. cell division cycle 25A (CDC25A), cyclin-dependent kinase 6 (CDK6), E2F2, and proliferating cell nuclear antigen (PCNA)]; levels of 4 studied miR-345 targets were increased in PLDCs at both the mRNA and protein levels. Transfection of PLDCs with pre-miR-345 increased miR-345 and decreased the expression of miR-345-targeted proteins, cell proliferation, and cyst growth in vitro. MiR-345 accumulated in autophagosomes in PLDCs but not NHCs. Inhibition of autophagy increased miR-345 levels, decreased the expression of miR-345-targeted proteins, and reduced hepatic cystogenesis in vitro and in vivo. CONCLUSION: Autophagy-mediated reduction of miR-345 in PLDCs (i.e. miRNAutophagy) accelerates hepatic cystogenesis. Inhibition of autophagy restores miR-345 levels, decreases cyst growth, and is beneficial for PLD. LAY SUMMARY: Polycystic liver disease (PLD) is an incurable genetic disorder characterised by the progressive growth of hepatic cysts. We found that hepatic cystogenesis is increased when the levels of miR-345 in PLD cholangiocytes (PLDCs) are reduced by autophagy. Restoration of miR-345 in PLDCs via inhibition of autophagy decreases hepatic cystogenesis and thus, is beneficial for PLD.

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BACKGROUND: Autosomal dominant polycystic liver disease (ADPLD) is characterized by multiple cysts in the liver without (or only occasional) renal cysts. At least seven genes are associated with high risk for developing ADPLD; however, clear genetic involvement is undetermined in more than 50% of ADPLD patients. METHODS: To identify additional ADPLD-associated genes, we collected 18 unrelated Chinese ADPLD cases, and performed whole exome sequencing on all the participants. After filtering the sequencing data against the human gene mutation database (HGMD) professional edition, we identified new mutations. We then sequenced this gene in family members of the patient. RESULTS: Among the 18 ADPLD cases analyzed by whole exome sequencing, we found 2 cases with a PRKCSH mutation (~11.1%), 2 cases with a PKD2 mutation (~11.1%), 1 case with both PKHD1 and PKD1 mutations (~5.6%), 1 case with GANAB mutation (~5.6%), 1 case with PKHD1 mutation (~5.6%), and 1 case with PKD1 mutations (~5.6%). We identified a new PKHD1 missense mutation in an ADPLD family, in which both patients showed innumerable small hepatic cysts, as reported previously. Additionally, we found that PRKCSH and SEC63 mutation frequencies were lower in the Chinese population compared with those in European and American populations. CONCLUSIONS: We report a family with ADPLD associated with a novel PKHD1 mutation (G1210R). The genetic profile of ADPLD in the Chinese population is different from that in European and American populations, suggesting that further genetic research on genetic mutation of ADPLD in the Chinese population is warranted.

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BACKGROUND & AIMS: Isolated autosomal-dominant polycystic liver disease (ADPLD) is generally considered a rare disease. However, the frequency of truncating mutations to ADPLD genes in large, population sequencing databases is 1:496. With the increasing use of abdominal imaging, incidental detection of hepatic cysts and ADPLD has become more frequent. The present study was performed to ascertain the incidence and point prevalence of ADPLD in Olmsted County, MN, USA, and how these are impacted by the increasing utilisation of abdominal imaging. METHODS: The Rochester Epidemiology Project and radiology databases of Mayo Clinic and Olmsted Medical Center were searched to identify all subjects meeting diagnostic criteria for definite, likely, or possible ADPLD. Annual incidence rates were calculated using incident cases during 1980-2016 as numerator, and age- and sex-specific estimates of the population of Olmsted County as denominator. Point prevalence was calculated using prevalence cases as numerator, and age- and sex-specific estimates of the population of Olmsted County on 1 January 2010 as denominator. RESULTS: The incidence rate and point prevalence of combined definite and likely ADPLD were 1.01 per 100,000 person-years and 9.5 per 100,000 population, respectively. Only 15 of 35 definite and likely incident ADPLD cases had received a diagnostic code, and only 8 had clinically significant hepatomegaly. The incidence rates were much higher when adding possible cases, mainly identified through radiology databases, particularly in recent years and in older patients because of the increased utilisation of imaging studies. CONCLUSIONS: Clinically significant isolated ADPLD is a rare disease with a prevalence <1:10,000 population. The overall prevalence of ADPLD, however, to a large extent not clinically significant, is likely much higher and closer to the reported genetic prevalence. LAY SUMMARY: Isolated autosomal-dominant polycystic liver disease (ADPLD) is generally considered a rare disease. However, we demonstrate that it is a relatively common disease, which is rarely (<1:10,000 population) clinically significant.

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Introduction: Polycystic liver disease (PLD) is a rare disease defined by the growth of hepatic cysts and occurs either isolated or as an extrarenal manifestation of polycystic kidney disease. While surgery has been the mainstay in treatment of symptomatic PLD, recently discovered regulatory mechanisms affecting hepatic cystogenesis provide potential new therapies to reduce hepatic cyst burden.Areas covered: This review summarizes intracellular pathways and therapeutic targets involved in hepatic cystogenesis. While drugs that target cAMP, mTOR and bile acids were evaluated in clinical trials, investigation in autophagy, Wnt and miRNA signaling pathways are still in the pre-clinical phase. Recent epidemiological data present female hormones as a promising therapeutic target. Additionally, therapeutic advances in renal cystogenesis are reviewed for their potential application in treatment of hepatic cysts.Expert opinion: Further elucidation of the pathophysiology of hepatic cystogenesis is needed to provide additional targets and improve the efficacy of current treatments. The most promising therapeutic target in PLD is the female hormone pathway, given the increased severity in women and the harmful effects of exogenous estrogens. In addition, combining current pharmaceutical and surgical therapies can lead to improved outcomes. Lastly, the rarity of PLD creates the need to share expertise internationally.

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OBJECTIVE: To describe first episodes of bacterial cholangitis complicating autosomal dominant polycystic kidney disease (ADPKD) and autosomal dominant polycystic liver disease (ADPLD) and to identify risk factors for cholangitis episodes among patients with ADPKD-associated polycystic liver disease (PLD). PATIENTS AND METHODS: We searched the electronic medical records at our tertiary referral center for episodes of cholangitis in patients with ADPKD or ADPLD from January 1, 1996, through June 30, 2017. Cases were categorized as suspected or definite cholangitis by expert review. Clinical, laboratory, and radiologic data were manually abstracted. A nested case-control study was conducted to investigate risk factors for cholangitis in patients with ADPKD. RESULTS: We identified 29 cases of definite or suspected cholangitis complicating PLD (24 with ADPKD-associated PLD and 5 with ADPLD). Among patients with definite cholangitis in ADPKD-associated PLD (n=19) vs ADPLD (n=4), the mean ± SD age was 62.4±12.2 vs 55.1±8.6 years, and 9 (47.4%) vs 0 (0%), respectively, were male. The odds of gallstones (odds ratio [OR], 21.6; 95% CI, 3.17-927; P<.001), prior cholecystectomy (OR, 12.2; 95% CI, 1.59-552; P=.008), duodenal diverticulum (OR, 13.5; 95% CI, 2.44 to not estimable; P=.004), type 2 diabetes mellitus (OR, 6.41; 95% CI, 1.01 to not estimable; P=.05), prior endoscopic retrograde cholangiopancreatography (OR, 14.0; 95% CI, 1.80-631; P=.005), and prior kidney transplant (OR, 8.06; 95% CI, 1.72-76.0; P=.004) were higher in patients with ADPKD-associated PLD with definite cholangitis compared to controls. CONCLUSION: Gallstones, prior cholecystectomy, duodenal diverticulosis, type 2 diabetes mellitus, prior endoscopic retrograde cholangiopancreatography, and prior kidney transplant constituted risk factors for cholangitis among patients with ADPKD-associated PLD.

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BACKGROUND: Symptoms in polycystic liver disease (PLD) are thought to be caused by compression of organs and structures by the enlarged liver. AIM: The aim of this article is to assess the impact of liver volume on symptoms and quality of life (QoL) in PLD. METHODS: We included PLD patients from two prospective studies that used the PLD-questionnaire (PLD-Q) for symptom assessment. QoL was assessed through SF-36, summarized in a physical (PCS) and mental (MCS) component score. Liver volume was correlated with PLD-Q total scores. Patients were classified based on height-corrected liver volume in mild (<1600 ml), moderate (1600-3200 ml), and severe (>3200 ml) disease. PLD-Q and QoL (PCS and MCS) scores were compared across disease stages. RESULTS: We included 82 of 131 patients from the original studies (disease stages; mild n = 26, moderate n = 33, and severe n = 23). Patients with larger liver volume reported higher symptom burden (r = 0.516, p < 0.001). Symptom scores increased with disease progression, except for abdominal pain (p = 0.088). PCS decreased with advancing disease (p < 0.001), in contrast to MCS (p = 0.055). Moderate (p = 0.007) and severe (p < 0.001) PLD patients had lower PCS scores than the general population. CONCLUSION: PLD with larger liver volume is more likely to be symptomatic and is associated with lower QoL.

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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.

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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.

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Objective: To investigate the feasibility and outcome of partial hepatectomy and fenestration combined with renal cyst decortication for treatment of autosomal dominant polycystic liver disease (APLD) associated with autosomal dominant polycystic kidney disease (APKD). Methods: From July 2007 to Oct. 2007, three patients with APLD associated with APKD were treated by partial hepatectomy and fenestration combined with renal cyst decortication in our hospital. Their preoperative symptoms, operation procedure, operation time, complications and the clinical outcomes were retrospectively analyzed. Results: The 3 patients were successfully treated and discharged. The operation time periods of the 3 patients were 475, 402, and 430 minutes. Pleural effusion and ascites occurred in all the 3 patients and disappeared after puncture and drainage. Follow-up was conducted 5, 6, and 9 mouths later; the symptoms disappeared in all patients and the renal function became normal. The blood pressure of 2 patients recovered to normal level after operation. Conclusion: Partial hepatectomy and fenestration combined with renal cyst decortication is a safe and acceptable procedure for treatment APLD associated with APKD. The complication rate is comparatively more and the long-term outcomes need to be evaluated further.