Sex, Genotype, and Liver Volume Progression as Risk of Hospitalization Determinants in Autosomal Dominant Polycystic Liver Disease.

BACKGROUND & AIMS: Autosomal dominant polycystic liver disease is a rare condition with a female preponderance, based mainly on pathogenic variants in 2 genes, PRKCSH and SEC63. Clinically, autosomal dominant polycystic liver disease is characterized by vast heterogeneity, ranging from asymptomatic to highly symptomatic hepatomegaly. To date, little is known about the prediction of disease progression at early stages, hindering clinical management, genetic counseling, and the design of randomized controlled trials. To improve disease prognostication, we built a consortium of European and US centers to recruit the largest cohort of patients with PRKCSH and SEC63 liver disease. METHODS: We analyzed an international multicenter cohort of 265 patients with autosomal dominant polycystic liver disease harboring pathogenic variants in PRKCSH or SEC63 for genotype-phenotype correlations, including normalized age-adjusted total liver volumes and polycystic liver disease-related hospitalization (liver event) as primary clinical end points. RESULTS: Classifying individual total liver volumes into predefined progression groups yielded predictive risk discrimination for future liver events independent of sex and underlying genetic defects. In addition, disease severity, defined by age at first liver event, was considerably more pronounced in female patients and patients with PRKCSH variants than in those with SEC63 variants. A newly developed sex-gene score was effective in distinguishing mild, moderate, and severe disease, in addition to imaging-based prognostication. CONCLUSIONS: Both imaging and clinical genetic scoring have the potential to inform patients about the risk of developing symptomatic disease throughout their lives. The combination of female sex, germline PRKCSH alteration, and rapid total liver volume progression is associated with the greatest odds of polycystic liver disease-related hospitalization.

Gender Differences in Liver Transplantation Outcomes in Polycystic Liver Disease.

BACKGROUND: In this study, our objective was to determine gender differences in the outcomes of patients with PLD undergoing liver (LT) or liver/kidney transplantation (SLK). METHODS: We analyzed the UNOS datasets of all adults who had transplanted for PLD between 1988 and 2018. RESULTS: During the study period, 663 LT/SLK (51% LT only and 49% SLK) were done for PLD patients and of these 500 (75%) were in women. Women were younger (52.8 vs. 56.7 years, p < 0.001), had lower MELD at transplant (16.6 vs. 19.4, p < 0.001), had higher serum albumin (3.7 vs. 3.5, p < 0.001), and had a lower CTP class (p < 0.008). During the follow-up, 18% (n = 89) women and 29% (n = 47) men died (p = 0.002). Kaplan-Meier (KM) survival estimates showed similar survival rate for patients who had LT and SLK (p = 0.459), but survival rate was significantly higher for women compared to men (p < 0.001). Multivariable analysis showed that female gender (aHR 0.54, 95% CI 0.33-0.90) was associated with a lower mortality. Moreover, Karnofsky Performance Status was excellent for 70% of women and 55% of men (p = 0.03) after LT. Women had better survival whether they received liver or SLK. The era of transplant, whether they were transplanted with MELD exception points or whether they were on dialysis at the time of transplant, did not have an effect on the gender differences in outcomes. CONCLUSIONS: Women had 46% lower risk of mortality after adjusting for other covariates compared to men after LT/SLK for PLD.

Monoallelic Mutations to DNAJB11 Cause Atypical Autosomal-Dominant Polycystic Kidney Disease.

Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by the progressive development of kidney cysts, often resulting in end-stage renal disease (ESRD). This disorder is genetically heterogeneous with ∼7% of families genetically unresolved. We performed whole-exome sequencing (WES) in two multiplex ADPKD-like pedigrees, and we analyzed a further 591 genetically unresolved, phenotypically similar families by targeted next-generation sequencing of 65 candidate genes. WES identified a DNAJB11 missense variant (p.Pro54Arg) in two family members presenting with non-enlarged polycystic kidneys and a frameshifting change (c.166_167insTT) in a second family with small renal and liver cysts. DNAJB11 is a co-factor of BiP, a key chaperone in the endoplasmic reticulum controlling folding, trafficking, and degradation of secreted and membrane proteins. Five additional multigenerational families carrying DNAJB11 mutations were identified by the targeted analysis. The clinical phenotype was consistent in the 23 affected members, with non-enlarged cystic kidneys that often evolved to kidney atrophy; 7 subjects reached ESRD from 59 to 89 years. The lack of kidney enlargement, histologically evident interstitial fibrosis in non-cystic parenchyma, and recurring episodes of gout (one family) suggested partial phenotypic overlap with autosomal-dominant tubulointerstitial diseases (ADTKD). Characterization of DNAJB11-null cells and kidney samples from affected individuals revealed a pathogenesis associated with maturation and trafficking defects involving the ADPKD protein, PC1, and ADTKD proteins, such as UMOD. DNAJB11-associated disease is a phenotypic hybrid of ADPKD and ADTKD, characterized by normal-sized cystic kidneys and progressive interstitial fibrosis resulting in late-onset ESRD.

Severity in polycystic liver disease is associated with aetiology and female gender: Results of the International PLD Registry.

BACKGROUND & AIMS: Polycystic liver disease (PLD) occurs in two genetic disorders, autosomal-dominant polycystic kidney disease (ADPKD) and autosomal-dominant polycystic liver disease (ADPLD). The aim of this study is to compare disease severity between ADPKD and ADPLD by determining the association between diagnosis and height-adjusted total liver volume (hTLV). METHODS: We performed a cross-sectional analysis with hTLV as endpoint. Patients were identified from the International PLD Registry (>10 liver cysts) and included in our analysis when PLD diagnosis was made prior to September 2017, hTLV was available before volume-reducing therapy (measured on computed tomography or magnetic resonance imaging) and when patients were tertiary referred. Data from the registry were retrieved for age, diagnosis (ADPKD or ADPLD), gender, height and hTLV. RESULTS: A total of 360 patients (ADPKD n = 241; ADPLD n = 119) met our inclusion criteria. Female ADPKD patients had larger hTLV compared with ADPLD (P = 0.008). In a multivariate regression analysis, ADPKD and lower age at index CT were independently associated with larger hTLV in females, whereas in males a higher age was associated with larger hTLV. Young females (≤51 years) had larger liver volumes compared with older females (>51 years) in ADPKD. CONCLUSION: Aetiology is presented as a new risk factor associated with PLD severity. Young females with ADPKD represent a subgroup of PLD patients with the most severe phenotype expressed in hTLV.

Initial experience with the use of tris-acryl gelatin microspheres for transcatheter arterial embolization for enlarged polycystic liver.

PURPOSE: To assess the safety and effectiveness of transcatheter arterial embolization (TAE) with tris-acryl gelatin microspheres for patients with symptomatic enlarged polycystic liver disease (PCLD). MATERIALS AND METHODS: This prospective study was approved by our hospital's institutional review board and planned for patients with symptoms related to enlarged PCLD, such as distended abdomen, gastrointestinal obstruction and abdominal pain. Hemi-hepatic embolization with tris-acryl gelatin microspheres was performed in the hepatic artery supplying the hepatic lobe that showed the predominant presence of cysts. Each patient underwent an assessment of liver function, a questionnaire survey about symptoms, measurement of the estimated volume of the whole liver before and after TAE, and an assessment of complications associated with TAE. RESULTS: Five patients (four females, one male; mean age 52.6 ± 9.1 years) were treated. All five patients successfully completed TAE. The left lobe was treated in three patients and the right in two. After TAE, post-embolization syndrome and transient elevation of white blood cells, aspartate aminotransferase, and alanine aminotransferase occurred in all patients, but none developed hepatic insufficiency or severe complications. The mean whole liver volume was 7406 ± 2323 mL before TAE, and 6995 ± 2139 mL (95.1 ± 5.2% of the pre-therapeutic value) at 3 months and 6855 ± 2246 mL (93.3 ± 9.7%) at 12 months after TAE. Three of the five patients reported an improvement of clinical symptoms within 12 months after TAE. CONCLUSION: TAE with microspheres can be a safe and effective treatment for symptomatic enlarged PCLD.

Alkaline phosphatase predicts response in polycystic liver disease during somatostatin analogue therapy: a pooled analysis.

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.

Severe Polycystic Liver Disease Is Not Caused by Large Deletions of the PRKCSH Gene.

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.

Clinical manifestation, epidemiology, genetic basis, potential molecular targets, and current treatment of polycystic liver disease.

Polycystic liver disease (PLD) is a rare condition observed in three genetic diseases, including autosomal dominant polycystic liver disease (ADPLD), autosomal dominant polycystic kidney disease (ADPKD), and autosomal recessive polycystic kidney disease (ARPKD). PLD usually does not impair liver function, and advanced PLD becomes symptomatic when the enlarged liver compresses adjacent organs or increases intra-abdominal pressure. Currently, the diagnosis of PLD is mainly based on imaging, and genetic testing is not required except for complex cases. Besides, genetic testing may help predict patients' prognosis, classify patients for genetic intervention, and conduct early treatment. Although the underlying genetic causes and mechanisms are not fully understood, previous studies refer to primary ciliopathy or impaired ciliogenesis as the main culprit. Primarily, PLD occurs due to defective ciliogenesis and ineffective endoplasmic reticulum quality control. Specifically, loss of function mutations of genes that are directly involved in ciliogenesis, such as Pkd1, Pkd2, Pkhd1, and Dzip1l, can lead to both hepatic and renal cystogenesis in ADPKD and ARPKD. In addition, loss of function mutations of genes that are involved in endoplasmic reticulum quality control and protein folding, trafficking, and maturation, such as PRKCSH, Sec63, ALG8, ALG9, GANAB, and SEC61B, can impair the production and function of polycystin1 (PC1) and polycystin 2 (PC2) or facilitate their degradation and indirectly promote isolated hepatic cystogenesis or concurrent hepatic and renal cystogenesis. Recently, it was shown that mutations of LRP5, which impairs canonical Wnt signaling, can lead to hepatic cystogenesis. PLD is currently treated by somatostatin analogs, percutaneous intervention, surgical fenestration, resection, and liver transplantation. In addition, based on the underlying molecular mechanisms and signaling pathways, several investigational treatments have been used in preclinical studies, some of which have shown promising results. This review discusses the clinical manifestation, complications, prevalence, genetic basis, and treatment of PLD and explains the investigational methods of treatment and future research direction, which can be beneficial for researchers and clinicians interested in PLD.

Genetic Spectrum of Polycystic Kidney and Liver Diseases and the Resulting Phenotypes.

Polycystic kidney diseases are a group of monogenically inherited disorders characterized by cyst development in the kidney with defects in primary cilia function central to pathogenesis. Autosomal dominant polycystic kidney disease (ADPKD) has progressive cystogenesis and accounts for 5-10% of kidney failure (KF) patients. There are two major ADPKD genes, PKD1 and PKD2, and seven minor loci. PKD1 accounts for ∼80% of patients and is associated with the most severe disease (KF is typically at 55-65 years); PKD2 accounts for ∼15% of families, with KF typically in the mid-70s. The minor genes are generally associated with milder kidney disease, but for DNAJB11 and ALG5, the age at KF is similar to PKD2. PKD1 and PKD2 have a high level of allelic heterogeneity, with no single pathogenic variant accounting for >2% of patients. Additional genetic complexity includes biallelic disease, sometimes causing very early-onset ADPKD, and mosaicism. Autosomal dominant polycystic liver disease is characterized by severe PLD but limited PKD. The two major genes are PRKCSH and SEC63, while GANAB, ALG8, and PKHD1 can present as ADPKD or autosomal dominant polycystic liver disease. Autosomal recessive polycystic kidney disease typically has an infantile onset, with PKHD1 being the major locus and DZIP1L and CYS1 being minor genes. In addition, there are a range of mainly recessive syndromic ciliopathies with PKD as part of the phenotype. Because of the phenotypic and genic overlap between the diseases, employing a next-generation sequencing panel containing all known PKD and ciliopathy genes is recommended for clinical testing.

Novel α-1,3-Glucosyltransferase Variants and Their Broad Clinical Polycystic Liver Disease Spectrum.

Protein-truncating variants in α-1,3-glucosyltransferase (ALG8) are a risk factor for a mild cystic kidney disease phenotype. The association between these variants and liver cysts is limited. We aim to identify pathogenic ALG8 variants in our cohort of autosomal dominant polycystic liver disease (ADPLD) individuals. In order to fine-map the phenotypical spectrum of pathogenic ALG8 variant carriers, we performed targeted ALG8 screening in 478 ADPLD singletons, and exome sequencing in 48 singletons and 4 patients from two large ADPLD families. Eight novel and one previously reported pathogenic variant in ALG8 were discovered in sixteen patients. The ALG8 clinical phenotype ranges from mild to severe polycystic liver disease, and from innumerable small to multiple large hepatic cysts. The presence of <5 renal cysts that do not affect renal function is common in this population. Three-dimensional homology modeling demonstrated that six variants cause a truncated ALG8 protein with abnormal functioning, and one variant is predicted to destabilize ALG8. For the seventh variant, immunostaining of the liver tissue showed a complete loss of ALG8 in the cystic cells. ALG8-associated ADPLD has a broad clinical spectrum, including the possibility of developing a small number of renal cysts. This broadens the ADPLD genotype-phenotype spectrum and narrows the gap between liver-specific ADPLD and kidney-specific ADPKD.

Heterozygosity of ALG9 in Association with Autosomal Dominant Polycystic Liver Disease.

α-1,2-mannosyltransferase (ALG9) germline variants are linked to autosomal dominant polycystic kidney disease (ADPKD). Many individuals affected with ADPKD possess polycystic livers as a common extrarenal manifestation. We performed whole exome sequencing in a female with autosomal dominant polycystic liver disease (ADPLD) without kidney cysts and established the presence of a heterozygous missense variant (c.677G>C p.(Gly226Ala)) in ALG9. In silico pathogenicity prediction and 3D protein modeling determined this variant as pathogenic. Loss of heterozygosity is regularly seen in liver cyst walls. Immunohistochemistry indicated the absence of ALG9 in liver tissue from this patient. ALG9 expression was absent in cyst wall lining from ALG9- and PRKCSH-caused ADPLD patients but present in the liver cyst lining derived from an ADPKD patient with a PKD2 variant. Thus, heterozygous pathogenic variants in ALG9 are also associated with ADPLD. Somatic loss of heterozygosity of the ALG9 enzyme was seen in the ALG9 patient but also in ADPLD patients with a different genetic background. This expanded the phenotypic spectrum of ADPLD to ALG9.

Modelling polycystic liver disease progression using age-adjusted liver volumes and targeted mutational analysis.

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.

Polycystic liver disease genes: Practical considerations for genetic testing.

The development of a polycystic liver is a characteristic of the monogenic disorders: autosomal dominant polycystic kidney disease (ADPKD), autosomal recessive polycystic kidney disease (ARPKD), and autosomal dominant polycystic liver disease (ADPLD). Respectively two and one genes mainly cause ADPKD and ARPKD. In contrast, ADPLD is caused by at least six different genes which combined do not even explain the disease development in over half of the ADPLD population. Genetic testing is mainly performed to confirm the likelihood of developing PKD and if renal therapy is essential. However, pure ADPLD patients are frequently not genetically screened as knowledge about the genotype-phenotype correlation is currently limited. This paper will clarify the essence of genetic testing in ADPLD patients.

Association of a novel PKHD1 mutation in a family with autosomal dominant polycystic liver disease.

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.

Autophagy-mediated reduction of miR-345 contributes to hepatic cystogenesis in polycystic liver disease.

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.

Epidemiology of autosomal-dominant polycystic liver disease in Olmsted county.

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.

Bacterial Cholangitis in Autosomal Dominant Polycystic Kidney and Liver Disease.

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.

Impact of liver volume on polycystic liver disease-related symptoms and quality of life.

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.