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Background and Aim: Polycystic liver disease (PLD) is related to hepatomegaly which causes an increased mechanical pressure on the abdominal wall. This may lead to abdominal wall herniation (AWH). We set out to establish the prevalence of AWH in PLD and explore risk factors. Methods: In this cross‐sectional cohort study, we assessed the presence of AWHs from PLD patients with at least 1 abdominal computed tomography or magnetic resonance imaging scan. AWH presence on imaging was independently evaluated by two researchers. Data on potential risk factors were extracted from clinical files. Results: We included 484 patients of which 40.1% (n = 194) had an AWH. We found a clear predominance of umbilical hernias (25.8%, n = 125) while multiple hernias were present in 6.2% (n = 30). Using multivariate analysis, male sex (odds ratio [OR] 2.727 p <.001), abdominal surgery (OR 2.575, p <.001) and disease severity according to the Gigot classification (Type 3 OR 2.853, p <.001) were identified as risk factors. Height‐adjusted total liver volume was an independent PLD‐specific risk factor in the subgroup of patients with known total liver volume (OR 1.363, p =.001). Patients with multiple hernias were older (62.1 vs. 55.1, p =.001) and more frequently male (22.0% vs. 50.0%, p =.001). Conclusion: AWHs occur frequently in PLD with a predominance of umbilical hernias. Hepatomegaly is a clear disease‐specific risk factor. [ABSTRACT FROM AUTHOR]

Polycystic liver disease (PLD) is a rare autosomal dominant disorder including two genetically and clinically distinct forms: autosomal dominant polycystic kidney disease (ADPKD) and isolated polycystic liver disease (PCLD). The main manifestation of ADPKD is kidney cysts, while PCLD has predominantly liver presentations with mild or absent kidney cysts. Over the past decade, PRKCSH, SEC63, ALG8, and LRP5 have been candidate genes of PCLD. Recently, more candidate genes such as GANAB, SEC61B, and ALR9 were also reported in PCLD patients. This review focused on all candidate genes of PCLD, including the newly established novel candidate genes. In addition, we also discussed some other genes which might also contribute to the disease.

Abstract Background Liver transplantation (LT) remains the curative treatment for symptomatic Polycystic Liver Disease (PCLD) patients and is associated with excellent survival rates. The aim of the study is to review the Ontario experience in LT for PCLD. Methods A retrospective study was performed from pre-existing LT databases from the LT Units at Toronto General Hospital and London Health Sciences Center, which are the two LT programs in Ontario, Canada. This database contains demographic, clinical parameters and follow-up of all patients transplanted for PCLD. Data was extracted for patients who underwent LT between January 2000–April 2017 and included follow up until December 31st, 2018. Results A total of 3560 patients underwent LT, of whom 51 (1.4%) had PCLD and met inclusion criteria. 43 (84%) of these patients were female. The median physiologic Model for End Stage Liver Disease (MELD-Na) score at time of referral was 13 (IQR = 7–22), however all patients required MELD-Na exception points to receive LT. The median age of transplant was 62 years (IQR = 59–64) for male vs. 52 (IQR = 45–56) for female patients. 33 (65%) of our cohort had PCLD while 9 (17.5%) had ADPKD and 9 (17.5%) had both diseases. 39 (76%) had LT due to symptoms of mass effect, while 8 (16%) had portal hypertensive complications. After a median follow-up of 6.3 (IQR = 2.9–12.5) years, the probability of survival was 96% (95% CI: 90%, 100%). Log-rank test, comparing survival analysis between males and females did not show a statistically significant difference (p = 0.26). Conclusion Most patients underwent LT for PCLD due to symptoms of mass effect with women being more likely than men to undergo LT. LT for PCLD had excellent long-term survival.

The most common hereditary kidney illness, disease of autosomal dominant polycystic kidney disease (ADPKD), is associated with numerous cysts that induce kidney size enlargement. The most common extrarenal symptom of ADPKD is liver cysts. A condition in which patients have >20 cysts in the liver is defined as polycystic liver disease (PLD). The goal of this study was to find out how often PLD was in ADPKD patients and whether there was an association between the incidence of PLD and age, sex, and clinical manifestations using magnetic resonance imaging (MRI) results. In this study, the abdominal MRI results of 32 patients with ADPKD who underwent abdominal MRI at Hospital X between January 01, 2020 and September 30, 2021 were retrospectively evaluated by 2 radiologists. Twenty-nine (90.6%) patients had a minimum 1 cyst in the liver, whereas 12 (37.5%) patients had PLD. The women had a greater rate in of PLD than males, and a statistical difference had been observed (p = 0.033). PLD incidence was found to increase with age. The mean ages of patients with and those without PLD were 46.3 and 35.9 years, respectively, and between the foregoing mean age values, a significant difference was detected (p = 0.003). Furthermore, there was no difference between the patients with and those without PLD in terms of the clinical indicators of ADPKD, including total kidney volume and mean rate of glomerular filtration. In conclusion, the incidence of PLD in ADPKD patients was found to be high in our study, and the presence of PLD was not associated with the clinical findings of ADPKD. For this reason, we think that it may be beneficial to perform liver imaging at the time of diagnosis of ADPKD and in their routine follow-up. [ABSTRACT FROM AUTHOR]

Background: In patients with severe polycystic liver disease (PLD), there is a need for new treatments. Estrogens and possibly other female sex hormones stimulate growth in PLD. In some patients, liver volume decreases after menopause. Female sex hormones could therefore be a target for therapy. The AGAINST-PLD study will examine the efficacy of the GnRH agonist leuprorelin, which blocks the production of estrogen and other sex hormones, to reduce liver growth in PLD.Methods: The AGAINST-PLD study is an investigator-driven, multicenter, randomized controlled trial. Institutional review board (IRB) approval was received at the University Medical Center of Groningen and will be collected in other sites before opening these sites. Thirty-six female, pre-menopausal patients, with a very large liver volume for age (upper 10% of the PLD population) and ongoing liver growth despite current treatment options will be randomized to direct start of leuprorelin or to 18 months standard of care and delayed start of leuprorelin. Leuprorelin is given as 3.75 mg subcutaneously (s.c.) monthly for the first 3 months followed by 3-monthly depots of 11.25 mg s.c. The trial duration is 36 months. MRI scans to measure liver volume will be performed at screening, 6 months, 18 months, 24 months and 36 months. In addition, blood will be drawn, DEXA-scans will be performed and questionnaires will be collected. This design enables comparison between patients on study treatment and standard of care (first 18 months) and within patients before and during treatment (whole trial). Main outcome is annualized liver growth rate compared between standard of care and study treatment. Secondary outcomes are PLD disease severity, change in liver growth within individuals and (serious) adverse events. The study is designed as a prospective open-label study with blinded endpoint assessment (PROBE).Discussion: In this trial, we combined the expertise of hepatologist, nephrologists and gynecologists to study the effect of leuprorelin on liver growth in PLD. In this way, we hope to stop liver growth, reduce symptoms and reduce the need for liver transplantation in severe PLD. Trial registration Eudra CT number 2020-005949-16, registered at 15 Dec 2020. https://www.clinicaltrialsregister.eu/ctr-search/search?query=2020-005949-16 . [ABSTRACT FROM AUTHOR]

Autosomal dominant polycystic liver disease (ADPLD) is a rare disease with variable clinical presentations, characterized by cystic enlargement of the liver. The diagnosis is made based on family history, patient's age, and liver phenotype and is confirmed by imaging tests. The treatment aims to reduce symptoms caused by the increased liver volume and can be performed by aspiration with sclerotherapy, fenestration, and liver resection. Although ADPLD is a rare disease, it is an important differential diagnosis of cystic diseases such as polycystic kidney disease; therefore, the aim of this article was to present the diagnostic and therapeutic approach of a case of ADPLD and conducting a literature review. This is the case of a 32-year-old male patient, who was hospitalized due to abdominal pain, hepatomegaly, lack of appetite, and weight loss. Imaging propaedeutics showed a significant increase in the liver volume due to hepatic cysts. After a multidisciplinary evaluation, given the clinical changes and the location of the hepatic cysts, fenestration was performed by laparotomy. The postoperative period was uneventful. The treatment was efficient in promoting symptomatic relief and improving the quality of life in this patient. Case reports on this disease are quite limited in the currently available literature, and there are gaps in knowledge with regard to the diagnosis and management of ADPLD. The importance of this article is that it will highlight the limitations in treatment options and allow physicians to make a more informed decision when diagnosing and treating a patient with ADPLD in the future. [ABSTRACT FROM AUTHOR]

Abstract Background Polycystic liver disease (PLD) is an inherited disorder characterized by numerous cysts in the liver. Autosomal dominant polycystic kidney and liver disease (ADPKD and ADPLD, respectively) have been linked to pathogenic GANAB variants. GANAB encodes the α-subunit of glucosidase II (GIIα). Here, we report the identification of novel GANAB variants in an international cohort of patients with the primary phenotype of PLD using molecular inversion probe analysis. Results Five novel GANAB variants were identified in a cohort of 625 patients with ADPKD or ADPLD. In silico analysis revealed that these variants are likely to affect functionally important domains of glucosidase II α-subunit. Missense variant c.1835G>C p.(Arg612Pro) was predicted to disrupt the structure of the active site of the protein, likely reducing its activity. Frameshift variant c.687delT p.(Asp229Glufs*60) introduces a premature termination codon predicted to have no activity. Two nonsense variants (c.2509C>T; p.(Arg837*), and c.2656C>T; p.(Arg886*)) and splice variant c.2002+1G>C, which causes aberrant pre-mRNA splicing and affecting RNA processing, result in truncated proteins and are predicted to cause abnormal binding of α- and β-subunits of glucosidase II, thus affecting its enzymatic activity. Analysis of glucosidase II subunits in cell lines shows expression of a truncated GIIα protein in cells with c.687delT, c.2509C>T, c.2656C>T, and c.2002+1G>C variants. Incomplete colocalization of the subunits was present in cells with c.687delT or c.2002+1G>C variants. Other variants showed normal distribution of GIIα protein. Conclusions We identified five novel GANAB variants associated with PLD in both ADPKD and ADPLD patients supporting a common pathway in cystogenesis. These variants may lead to decreased or complete loss of enzymatic activity of glucosidase II which makes GANAB a candidate gene to be screened in patients with an unknown genetic background.

Intra-abdominal hemorrhage resulting from a ruptured, large hepatic cyst in a polycystic liver disease (PCLD) patient is rare and potentially fatal if not addressed promptly. Only a few isolated cases have previously been reported. The usual patient profile consists of elderly patients on anticoagulation, as is demonstrated in our case. Intra-hepatic cysts are broadly classified into congenital, traumatic, infectious, parasitic, and neoplastic. Congenital intra-hepatic cysts can consist of both simple and PCLD, as is outlined in our case. Simple cysts are usually asymptomatic, but occasionally they may achieve larger dimensions and lead to complications such as rupture, obstruction, infection, hemorrhage, and even portal hypertension. We present an uncommon case of a 78-year-old patient with PCLD on rivaroxaban who presented initially with diffuse abdominal pain, distension, and progression into hemodynamic instability. A computerized tomography (CT) scan revealed a ruptured left hepatic lobe cyst, causing hemoperitoneum and resulting in an acute abdomen. This case was complicated by the patient's anticoagulation status and anomalous hepatic vasculature pattern. Interventional radiology (IR) successfully identified the aberrant bleeding vessel and stopped the active extravasation with super-selective coil embolization., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Biswas et al.)

Purpose: We investigated the long-term safety and efficacy of hepatic transarterial embolization (TAE) in patients with symptomatic polycystic liver disease (PLD). Materials and Methods: A total of 26 patients were included, mean age of 52.3 years (range: 33–78 years), undergoing 32 TAE procedures between January 2012 and December 2019 were included in this retrospective study. Distal embolization of the segmental hepatic artery was performed with 300–500 µm embolic microspheres associated with proximal embolization using microcoils. The primary endpoint was clinical efficacy, defined by an improvement in health-related quality of life using a modified Short Form-36 Health Survey and improvement in symptoms (digestive or respiratory symptoms and chronic abdominal pain), without invasive therapy during the follow-up period. Secondary endpoints were a decrease in total liver volume and treated liver volume and complications. Results: Hepatic embolization was performed successfully in 30 of 32 procedures with no major adverse events. Clinical efficacy was 73% (19/26). The mean reduction in hepatic volume was −12.6% at 3 months and −27.8% at the last follow-up 51 ± 15.2 months after TAE (range: 30–81 months; both ps < 0.01). The mean visual analog scale pain score was 5.4 ± 2.8 before TAE and decreased to 2.7 ± 1.9 after treatment. Three patients had minor adverse events, and one patient had an adverse event of moderate severity. Conclusion: Hepatic embolization using microspheres and microcoils is a safe and effective treatment for PLD that improves symptoms and reduces the volume of hepatic cysts.

Cystic lesions of the liver are a heterogeneous group of disorders with varied etiology, prevalence, and clinical manifestations. Fibropolycystic liver disease encompasses a spectrum of related liver and biliary tract lesions caused by abnormal embryologic development of the ductal plates. These disorders include congenital hepatic fibrosis, biliary hamartomas, polycystic liver disease (PCLD), choledochal cysts, and Carolis disease. PCLD is arbitrarily defined as a liver that contains >20 cysts. Most liver cysts are incidentally found on imaging studies, and the majority of the patients with liver cysts are asymptomatic. Rarely, complications such as compression, infection, and bleeding within the cyst can occur. Under the effect of the increased pressure, the epithelial lining of the cyst undergoes necrosis and sloughing, causing injury of the fragile blood vessels, leading to intracystic bleeding. The bleeding within or from the cyst can be precipitated by anticoagulation. We present a patient with PCLD who developed intracystic bleeding after he was started on apixaban for the prevention of thromboembolism. [ABSTRACT FROM AUTHOR]

Background and Aims: Patients suffering from polycystic liver disease (PLD) can develop large liver volumes, leading to physical and psychological complaints, reducing quality of life. There is an unmet need for new therapies in these patients. Estrogen seems to be a promising target for new therapies. In this review, we summarize the available experimental and epidemiological evidence to unravel the role of estrogens and other female hormones in PLD, to answer clinical questions and identify new targets for therapy. Methods: We identified all experimental and epidemiologial studies concerning estrogens or other female hormones and PLD, to answer pre‐defined clinial questions. Results: Female sex is the most important risk factor for the presence and severity of disease; estrogen supplementation enhances liver growth and after menopause, liver growth decreases. Experimental studies show the presence of the estrogen receptors alfa and beta on cystic cholangiocytes, and increased in vitro growth after administration of estrogen. Conclusions: Based on the available evidence, female PLD patients should be discouraged from taking estrogen‐containing contraceptives or hormone replacement therapy. Since liver growth rates decline after menopause, treatment decisions should be based on measured liver growth in postmenopausal women. Finally, blockage of estrogen receptors or estrogen production is a promising target for new therapies. [ABSTRACT FROM AUTHOR]

Background: Polycystic liver disease is a clinical feature of autosomal dominant polycystic kidney disease, and it can sometimes cause health damage more serious than polycystic kidney. Dialysis therapy can be used for renal failure, but liver transplantation is the only method available for liver failure. Thus, giant and multiple hepatic cysts may affect mortality. However, liver transplantation is not indicated in many cases because of the preserved liver function.Case Presentation: A 54-year-old Japanese woman with polycystic liver disease was transferred back to our hospital for abdominal pain caused by liver cyst infection with abdominal wall herniation. She had been diagnosed with polycystic liver disease associated with sporadic autosomal dominant polycystic kidney disease 25 years earlier. Although she had several surgical interventions to reduce her liver volume, including right hepatic lobectomy and fenestration for liver cysts in another hospital, she needed further repair of the recurrent incisional herniation with patch graft surgery using fascia lata to cover the herniation site. However, new herniation sites reemerged in the fragile abdominal wall area around the patch, and therefore, she reduced the recurrent abdominal wall herniation by herself. Recurrent intestinal obstructions were luckily released by fasting with decompression treatment via nasogastric tube insertion, but multiple skin ulcers around the enlarged hernia sac gradually developed, and ascites was extremely difficult to control with any medication. At final admission, her abdominal wall was even more prominent, causing shortness of breath, and it spontaneously ruptured many times, which was accompanied by discharge of around 5 liters of ascites each time. She died from sepsis caused by drug-resistant Enterococcus.Conclusions: We report a case of autosomal dominant polycystic kidney disease with ruptured abdominal wall resulting from a hepatic cyst enlargement despite multiple laparotomy operations. Throughout the entire disease course, her liver volume increased rapidly, and her quality of life was severely impaired, but she could not undergo liver transplantation after readmission to our hospital. We will discuss the therapeutic strategy for this patient, including the timing and indication for liver transplantation. [ABSTRACT FROM AUTHOR]

Polycystic liver disease is characterized by multiple cystic lesions on the liver. Liver cysts are typically incidental findings, with occasional complications including cyst hemorrhage, infection and rupture. Polycystic liver disease may be part of autosomal dominant polycystic liver disease (ADPLD). Autosomal dominant polycystic liver disease is considered rare autosomal dominant disease, with prevalence of 1/100,000-1,000,000. Without family history of polycystic liver disease, ADPLD is defined as the presence of more than 20 liver cysts with no renal cysts, however up to third of ADPLD may have small number of renal cysts without kidney function impairment. This case of a 73-year-old woman with symptomatic polycystic liver disease, and we performed cyst fenestration-deroofing via laparoscopic. [ABSTRACT FROM AUTHOR]

The Notch signaling pathway plays a key role in the morphogenesis of the biliary tree, but its involvement in cystic biliary diseases, such as Caroli disease (CD) and polycystic liver disease (PLD), has yet to be determined. Immunostaining was performed using liver sections of CD and PLD, and the results were compared with those of congenital hepatic fibrosis (CHF) and von Meyenburg complex (VMC). The expression of Notch receptor 1 (Notch1) was increased in the nuclei of biliary epithelial cells in all cases of CD and PLD, whereas it remained at a low level in CHF and VMC. In addition, Notch2 and Notch3 were preferably expressed in the nuclei of biliary epithelial cells of PLD. Accordingly, the Notch effector Hes1 was highly expressed in biliary epithelial cells of CD and PLD, and the cell proliferative activity was significantly higher in CD and PLD. The expression of the Notch ligand Delta‐like 1 was significantly increased in biliary epithelial cells of CD and PLD, which may be causally associated with the nuclear overexpression of Notch1 and Hes1. These results indicate that aberrant activation of the Notch‐Hes1 signaling pathway may be responsible for the progression of biliary cystogenesis in CD and PLD. [ABSTRACT FROM AUTHOR]

Introduction: Intracystic haemorrhage is a rare complication of hepatic cysts, and is often mistaken for a malignant lesion. Case Report: A 55-year-old female with a history of polycystic kidney and liver disease presented with a six-month history of abdominal distension, abdominal pain, early satiety, shortness of breath and 5 kg of weight loss. Imaging revealed a 20 cm mixed solid-cystic hepatic lesion containing peripheral avascular mobile echogenic material with a flame-like morphology. After experiencing symptomatic relief from ultrasound-guided aspiration, the patient underwent cyst fenestration for more definitive treatment. Discussion: Haemorrhagic hepatic cysts are uncommon and may present on imaging as having lace-like retractile clot, internal layering or shading of separating blood products or avascular mobile flame-like excrescences. The presence of avascular mobile flame-like excrescences appears to be a unique feature of haemorrhagic hepatic cysts. Conclusion: While haemorrhagic hepatic cysts are rare and commonly mistaken for biliary cystadenomas or adenocarcinomas, the identification of particular features on high-resolution magnetic resonance imaging and contrast-enhanced ultrasound can lead to the correct diagnosis. [ABSTRACT FROM AUTHOR]

Polycystic liver disease (PLD) is characterized by the growth of numerous biliary cysts and presents in patients with autosomal dominant polycystic kidney disease (ADPKD), causing significant morbidity. Interestingly, deletion of intraflagellar transport‐B (IFT‐B) complex genes in adult mouse models of ADPKD attenuates the severity of PKD and PLD. Here we examine the role of deletion of an IFT‐A gene, Thm1, in PLD of juvenile and adult Pkd2 conditional knockout mice. Perinatal deletion of Thm1 resulted in disorganized and expanded biliary regions, biliary fibrosis, increased serum bile acids, and a shortened primary cilium on cytokeratin 19+ (CK19+) epithelial cells. In contrast, perinatal deletion of Pkd2 caused PLD, with multiple CK19+ epithelial cell‐lined cysts, fibrosis, lengthened primary cilia, and increased Notch and ERK signaling. Perinatal deletion of Thm1 in Pkd2 conditional knockout mice increased hepatomegaly, liver necrosis, as well as serum bilirubin and bile acid levels, indicating enhanced liver disease severity. In contrast to effects in the developing liver, deletion of Thm1 alone in adult mice did not cause a biliary phenotype. Combined deletion of Pkd2 and Thm1 caused variable hepatic cystogenesis at 4 months of age, but differences in hepatic cystogenesis between Pkd2‐ and Pkd2;Thm1 knockout mice were not observed by 6 months of age. Similar to juvenile PLD, Notch and ERK signaling were increased in adult Pkd2 conditional knockout cyst‐lining epithelial cells. Taken together, Thm1 is required for biliary tract development, and proper biliary development restricts PLD severity. Unlike IFT‐B genes, Thm1 does not markedly attenuate hepatic cystogenesis, suggesting differences in regulation of signaling and cystogenic processes in the liver by IFT‐B and ‐A. Notably, increased Notch signaling in cyst‐lining epithelial cells may indicate that aberrant activation of this pathway promotes hepatic cystogenesis, presenting as a novel potential therapeutic target. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Ductal plate malformations are abnormalities in the liver that arise from inappropriate or incomplete remodeling of the embryologic ductal plate. Various types of ductal plate malformations are reported in the human and veterinary literature, most commonly affecting domestic mammalian species but also fish. We investigated the occurrence and described the histopathologic features of ductal plate malformations in captive snakes. Malformations were identified in 18 snakes: 10 colubrids, 6 vipers, and 2 boids. There was no sex predilection, and the mean age was 17 years. The majority of lesions were incidental with most snakes having one or more comorbidities, most commonly neoplasia or systemic inflammation, that resulted in natural death or euthanasia. Ductal plate malformations in all livers were broadly characterized by a well-demarcated nodule of irregular bile ducts embedded within a varying amount of fibrous stroma. Malformations were further categorized based on the amount of fibrous stroma and dilation of the bile ducts as von Meyenburg complexes, cystic liver disease, and/or an intermediate hybrid subtype representative of cysts arising within von Meyenburg complexes. Histochemical and immunohistochemical staining, including Gomori's trichome and pan-cytokeratin, respectively, were applied on select cases to confirm histologic features. Malignant transformation was not identified within this population. [ABSTRACT FROM AUTHOR]

Glycans are one of the four fundamental macromolecular components of living matter, and they are highly regulated in the cell. Their functions are metabolic, structural and modulatory. In particular, ER resident N-glycans participate with the Glc3Man9GlcNAc2 highly conserved sequence, in protein folding process, where the physiological balance between glycosylation/deglycosylation on the innermost glucose residue takes place, according GANAB/UGGT concentration ratio. However, under abnormal conditions, the cell adapts to the glucose availability by adopting an aerobic or anaerobic regimen of glycolysis, or to external stimuli through internal or external recognition patterns, so it responds to pathogenic noxa with unfolded protein response (UPR). UPR can affect Multiple Sclerosis (MS) and several neurological and metabolic diseases via the BiP stress sensor, resulting in ATF6, PERK and IRE1 activation. Furthermore, the abnormal GANAB expression has been observed in MS, systemic lupus erythematous, male germinal epithelium and predisposed highly replicating cells of the kidney tubules and bile ducts. The latter is the case of Polycystic Liver Disease (PCLD) and Polycystic Kidney Disease (PCKD), where genetically induced GANAB loss affects polycystin-1 (PC1) and polycystin-2 (PC2), resulting in altered protein quality control and cyst formation phenomenon. Our topics resume the role of glycans in cell physiology, highlighting the N-glycans one, as a substrate of GANAB, which is an emerging key molecule in MS and other human pathologies.

TGR5 (G protein-coupled bile acid receptor 1, GPBAR-1) is a G protein-coupled receptor with seven transmembrane domains and is widely distributed in various organs and tissues. As an important bile acid receptor, TGR5 can be activated by primary and secondary bile acids. Increased expression of TGR5 is a risk factor for polycystic liver disease and hepatobiliary cancer. However, there is evidence that the anti-inflammatory effect of the TGR5 receptor and its regulatory effect on hydrophobic bile acid confer protective effects against most liver diseases. Recent studies have shown that TGR5 receptor activation can alleviate the development of diabetic liver fibrosis, regulate the differentiation of natural killer T cells into NKT10 cells, increase the secretion of anti-inflammatory factors, inhibit the invasion of hepatitis B virus, promote white adipose tissue browning, improve arterial vascular dynamics, maintain tight junctions between bile duct cells, and protect against apoptosis. In portal hypertension, TGR5 receptor activation can inhibit the contraction of hepatic stellate cells and improve intrahepatic microcirculation. In addition, the discovery of the regulatory relationship between the TGR5 receptor and miRNA-26a provides a new direction for further studies of the molecular mechanism underlying the effects of TGR5. In this review, we describe recent findings linking TGR5 to various liver diseases, with a focus on the mechanisms underlying its effects and potential therapeutic implications. [ABSTRACT FROM AUTHOR]

Background: Most patients with autosomal-dominant polycystic kidney disease (ADPKD) develop liver cysts and polycystic liver disease as they age. To date, no simple clinical indicator has been confirmed to predict polycystic liver disease exacerbation. Furthermore, the effect of the type and location of mutation on disease progression of polycystic liver disease remains unclear. Here, we aimed to establish a simple liver cyst indicator for clinical practice and investigate whether gene mutations determined liver phenotype in patients with autosomal-dominant polycystic kidney disease. Methods: In total, 129 patients with ADPKD were enrolled and liver cyst indicators were assessed based on mutation type (truncating mutation: nonsense, frameshift, and splicing mutation; non-truncating mutation: substitution) and mutation position. Liver cyst severity was determined using Gigot and Drenth classifications, based on their number, maximum diameter, and area ratio with the liver. Results: We observed an overall prevalence of 62.8% for polycystic liver disease. Patients with PKD1 nonsense mutations, a type of PKD1 truncating mutation, exhibited more severe liver disease phenotypes than those without the mutation. We identified maximum diameter as a potential liver cyst indicator. Moreover, a subgroup analysis that included a PKD1 nonsense mutation cohort revealed that genetic mutations located closer to the 5ʹ end of PKD1 were associated with a maximum diameter index value ≥ 6 cm. Conclusion: PKD1 nonsense mutations were associated with liver cyst severity, which along with maximum diameter index as a simple clinical indicator for liver cysts, may improve the treatment of polycystic liver disease associated with ADPKD. [ABSTRACT FROM AUTHOR]

Polycystic liver disease (PLD) is a hereditary liver disease in which the number of cysts increases over time, causing various abdominal symptoms and poor quality of life. Although effective treatment for PLD has not been established, we recently reported that long-term exercise ameliorated liver cyst formation and fibrosis with the activation of AMP-activated protein kinase (AMPK) in polycystic kidney (PCK) rats, a PLD model. Therefore, the aim of this study was to investigate whether metformin, an indirect AMPK activator, was effective in PCK rats. PCK rats were randomly divided into a control (Con) group and a metformin-treated (Met) group. The Met group was treated orally with metformin in drinking water. After 12 wk, liver function, histology, and signaling cascades of PLD were examined in the groups. Metformin did not affect the body weight or liver weight, but it reduced liver cyst formation, cholangiocyte proliferation, and fibrosis around the cyst. Metformin increased the phosphorylation of AMPK and tuberous sclerosis complex 2 and decreased the phosphorylation of mammalian target of rapamycin, S6, and extracellular signal-regulated kinase and the expression of cystic fibrosis transmembrane conductance regulator, aquaporin I, transforming growth factor-β, and type 1 collagen without changes in apoptosis or collagen degradation factors in the liver. Metformin slows the development of cyst formation and fibrosis with the activation of AMPK and inhibition of signaling cascades responsible for cellular proliferation and fibrosis in the liver of PCK rats. [ABSTRACT FROM AUTHOR]

Management of symptomatic polycystic liver disease (PLD) has remained primarily unchanged since the early 20th century when multiple case reports described management of non-parasitic liver cysts. In 1968, Lin et al. described the fenestration procedure, “aspiration of the cysts, incision, partial excision with or without external drainage, or marsupilization and anastomosis to the gastrointestinal tract”. Further surgical options have included cyst sclerotherapy, laparoscopic cyst aspiration, partial hepatectomy, and orthotopic liver transplant (OLT). Recently there has been discussion of medical management with somatostatin analogs to reduce hepatomegaly in PLD with varying success. There is no current consensus on treatment or standard of care for symptomatic PLD, it is largely up to surgeon preference and ability; however, there has been a movement toward early OLT with Model for End-Stage Liver Disease (MELD) score exception points. This case series reviews two female patients with normal renal and hepatic function with symptomatic PLD treated with transverse hepatectomy. We propose that patients suffering from symptomatic PLD, with retained renal and hepatic function, can be treated with transverse hepatectomy conserving limited donor livers for decompensated patients; moreover, transverse hepatectomy does not disrupt the major suprahepatic vena cava preserving potential surgical access for future OLT.

Background: Liver transplantation (LT) remains the curative treatment for symptomatic Polycystic Liver Disease (PCLD) patients and is associated with excellent survival rates. The aim of the study is to review the Ontario experience in LT for PCLD.Methods: A retrospective study was performed from pre-existing LT databases from the LT Units at Toronto General Hospital and London Health Sciences Center, which are the two LT programs in Ontario, Canada. This database contains demographic, clinical parameters and follow-up of all patients transplanted for PCLD. Data was extracted for patients who underwent LT between January 2000-April 2017 and included follow up until December 31st, 2018.Results: A total of 3560 patients underwent LT, of whom 51 (1.4%) had PCLD and met inclusion criteria. 43 (84%) of these patients were female. The median physiologic Model for End Stage Liver Disease (MELD-Na) score at time of referral was 13 (IQR = 7-22), however all patients required MELD-Na exception points to receive LT. The median age of transplant was 62 years (IQR = 59-64) for male vs. 52 (IQR = 45-56) for female patients. 33 (65%) of our cohort had PCLD while 9 (17.5%) had ADPKD and 9 (17.5%) had both diseases. 39 (76%) had LT due to symptoms of mass effect, while 8 (16%) had portal hypertensive complications. After a median follow-up of 6.3 (IQR = 2.9-12.5) years, the probability of survival was 96% (95% CI: 90%, 100%). Log-rank test, comparing survival analysis between males and females did not show a statistically significant difference (p = 0.26).Conclusion: Most patients underwent LT for PCLD due to symptoms of mass effect with women being more likely than men to undergo LT. LT for PCLD had excellent long-term survival. [ABSTRACT FROM AUTHOR]

Management of symptomatic polycystic liver disease (PLD) has remained primarily unchanged since the early 20th century when multiple case reports described management of non-parasitic liver cysts. In 1968, Lin et al. described the fenestration procedure, "aspiration of the cysts, incision, partial excision with or without external drainage, or marsupilization and anastomosis to the gastrointestinal tract". Further surgical options have included cyst sclerotherapy, laparoscopic cyst aspiration, partial hepatectomy, and orthotopic liver transplant (OLT). Recently there has been discussion of medical management with somatostatin analogs to reduce hepatomegaly in PLD with varying success. There is no current consensus on treatment or standard of care for symptomatic PLD, it is largely up to surgeon preference and ability; however, there has been a movement toward early OLT with Model for End-Stage Liver Disease (MELD) score exception points. This case series reviews two female patients with normal renal and hepatic function with symptomatic PLD treated with transverse hepatectomy. We propose that patients suffering from symptomatic PLD, with retained renal and hepatic function, can be treated with transverse hepatectomy conserving limited donor livers for decompensated patients; moreover, transverse hepatectomy does not disrupt the major suprahepatic vena cava preserving potential surgical access for future OLT. [ABSTRACT FROM AUTHOR]

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

We present a case of amebic liver abscess in a patient with polycystic liver disease (PCLD). A 36-year-old woman was admitted to the hospital due to right upper quadrant pain for 8 months before the admission. She also had episodic diarrhea. At previous admission, she was diagnosed having liver abscess. In the present admission, the diagnosis of amebic liver abscess was made based on the characteristics of abscess, sterile abscess culture, and the presence of cysts and trophozoites of protozoa in the stools. The diagnosis of PCLD was established according to the Gigot and Schnelldorfer criteria. In conclusion, the diagnosis of amebic liver abscess in patient with PCLD requires a holistic investigation and comprehensive follow-up. [ABSTRACT FROM AUTHOR]

A 65 year old woman presented with acute abdomen pain, a history of chronic abdominal swelling. Physical examination found a palpable mass of the right upper quadrant extended to the umbilical quadrant, associated to generalized abdominal tenderness. Laboratory testes demonstrated an inflammatory syndrome without perturbation of serum enzymes of cholestasis. A computed tomography scan of the abdomen revealed more than 20 liver cysts, the biggest measured 20 cm. The biliary tree and the kidneys were normal. It also showed an intraperitoneal effusion. We suspected a spontaneous rupture of hepatic hydatid cysts despite negative hydatid serology. The patient was operated upon electively and the operative findings were a polycystic liver spread through several segments of the liver with a giant thin walled cyst of the right lobe measured 20cm associated to a free fluid in the hepato-diaphragmatic space, without biliary fistula. We performed the fenestration technique which combined aspiration of 4 liters of serous fluid and chocolate-like materials and deroofing of the biggest cyst. The histology has confirmed the diagnosis of a simple hepatic cyst. The outcome until 11 months after still uneventful.

Introduction: Polycystic liver disease is uncommon and usually asymptomatic. Surgery is indicated for patients with symptoms or complications. Cyst fenestration has been the main surgical option despite the relatively high recurrence rate. Open hepatectomy and fenestration provided sustainable symptomatic relief in selected patients at the cost of higher morbidity. The role of laparoscopic hepatectomy (LH) for this entity remains unclear. Methods: A retrospective review of patients with polycystic liver disease receiving LH was undertaken. LH in this study referred to the removal of part of normal liver or complex cysts by dividing Glissonean pedicles to the specimen, excluding simple cyst fenestration. Indication for surgery included symptoms related to mass effect with image-confirmed compression on stomach or duodenum and cyst infection. Results: From December 2004 to September 2016, a total of 14 patients (12 females and 2 males) with a mean age of 55.9 ± 14.0 years had been enrolled. Gigot's classification in this series includes type I in 3, type II in 8, and type III in 3 cases. Extent of liver resection includes partial S2 and S3 in 6, partial S2 and S3 with associated partial S5 and S6 or S7 in 3, partial S5, S6, and S7 in 1, partial S6 and S7 in 1, left hepatectomy in 2, and right hepatectomy in 1. Perioperative outcomes include median operation time of 240 min (60–300, interquartile range [IQR]: 150), estimated blood loss of 50 ml (5–2000, IQR: 98.8), and mean postoperative hospital stay of 5.5 days (2–77, IQR: 7.3). The 90-day postoperative complications developed in three patients, mainly bile leak and pleural effusion. There was no postoperative mortality. Conclusion: Laparoscopic liver resection and fenestration for polycystic liver disease seem safe and feasible. The perioperative outcomes were acceptable although the bile leakage rate was relatively high. Careful patient selection to choose peripheral lesions is advisable.

Background: Polycystic liver disease (PLD) is a hereditary liver disease with progressive enlargement of fluid-filled liver cysts, which causes abdominal discomfort and worsens quality of life. Long-term exercise has beneficial effects in various organs, but the effects of long-term exercise on PLD are unclear. Therefore, the aim of this study was to investigate whether long-term exercise inhibits liver cyst formation and fibrosis. Methods: Polycystic kidney (PCK) rats, a model of PLD, were randomly divided into a sedentary group and a long-term exercise group, which underwent treadmill running for 12 wk (28 m⋅min-1, 60 min⋅d-1, 5 d⋅wk-1). Sprague-Dawley (SD) rats were set as a control group. After 12 wk, exercise capacity, histology, and signaling cascades of PLD were examined. Results: Compared with control SD rats, PCK rats showed a low exercise capacity before exercise protocol. After 12 wk, the exercise improved the exercise capacity and ameliorated liver cyst formation and fibrosis. The exercise significantly decreased the number of Ki-67-positive cells; the expression of cystic fibrosis transmembrane conductance regulator, aquaporin 1, transforming growth factor β, and type 1 collagen; and the phosphorylation of extracellular signal-regulated kinase, mammalian target of rapamycin and S6. It also increased the phosphorylation of AMP-activated protein kinase in the liver of PCK rats. Conclusions: The present results indicated that long-term moderate-intensity exercise ameliorates liver cyst formation and fibrosis with the inhibition of signaling cascades responsible for cellular proliferation and fibrosis in PCK rats. [ABSTRACT FROM AUTHOR]

Patients suffering from polycystic liver disease may develop Hepatic Venous Outflow Obstruction, Portal Vein Obstruction and/or Inferior Caval Vein Syndrome because of cystic mass effect. This can cause portal hypertension, leading to ascites, variceal haemorrhage or splenomegaly. For this review, we evaluate the evidence to provide clinical guidance for physicians faced with this complication. Diagnosis is made with imaging such as ultrasound, computed tomography or magnetic resonance imaging. Therapy includes conventional therapy with diuretics and paracentesis, and medical therapy using somatostatin analogues. Based on disease phenotype various (non‐)surgical liver‐volume reducing therapies, hepatic or portal venous stenting, transjugular intrahepatic portosystemic shunts and liver transplantation may be considered. Because of complicated anatomy, use of high‐risk interventions and lack of empirical evidence, patients should be treated in expert centres. [ABSTRACT FROM AUTHOR]

The rough endoplasmic reticulum (ER) of nucleated human cells has crucial functions in protein biogenesis, calcium (Ca2+) homeostasis, and signal transduction. Among the roughly one hundred components, which are involved in protein import and protein folding or assembly, two components stand out: The Sec61 complex and BiP. The Sec61 complex in the ER membrane represents the major entry point for precursor polypeptides into the membrane or lumen of the ER and provides a conduit for Ca2+ ions from the ER lumen to the cytosol. The second component, the Hsp70-type molecular chaperone immunoglobulin heavy chain binding protein, short BiP, plays central roles in protein folding and assembly (hence its name), protein import, cellular Ca2+ homeostasis, and various intracellular signal transduction pathways. For the purpose of this review, we focus on these two components, their relevant allosteric effectors and on the question of how their respective functional cycles are linked in order to reconcile the apparently contradictory features of the ER membrane, selective permeability for precursor polypeptides, and impermeability for Ca2+. The key issues are that the Sec61 complex exists in two conformations: An open and a closed state that are in a dynamic equilibrium with each other, and that BiP contributes to its gating in both directions in cooperation with different co-chaperones. While the open Sec61 complex forms an aqueous polypeptide-conducting- and transiently Ca2+-permeable channel, the closed complex is impermeable even to Ca2+. Therefore, we discuss the human hereditary and tumor diseases that are linked to Sec61 channel gating, termed Sec61-channelopathies, as disturbances of selective polypeptide-impermeability and/or aberrant Ca2+-permeability.

A 44-year-old Japanese woman with autosomal dominant polycystic kidney disease was admitted to our hospital for evaluation of abdominal distension. Her eGFR was 53.7 mL/min/1.73 m2. Total kidney volume was 2,614 mL. Tolvaptan (60 mg/day) was started to treat renal involvement. The patient’s abdominal fullness began to improve and liver volume, indicating advanced polycystic liver disease (PLD), decreased from 9,750 mL to 8,345 mL after 17 months of tolvaptan treatment, though there was no significant change in kidney volume. This case indicates that tolvaptan may be a therapeutic option for hepatomegaly in patients with symptomatic PLD.