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Background Cat eye syndrome (CES) is a rare chromosomal disease, with estimated incidence of about 1 in 100,000 live newborns. The classic triad of iris coloboma, anorectal malformations, and auricular abnormalities is present in 40% of patients, and other congenital defects may also be observed. The typical associated cytogenetic anomaly relies on an extra chromosome, derived from an inverted duplication of short arm and proximal long arm of chromosome 22, resulting in partial trisomy or tetrasomy of such regions (inv dup 22pter-22q11.2). Case presentation We report on a full-term newborn, referred to us soon after birth. Physical examination showed facial dysmorphisms, including hypertelorism, down slanted palpebral fissures, and dysplastic ears with tragus hypoplasia and pre-auricular pit. Ophthalmologic evaluation and heart ultrasound identified left chorioretinal and iris coloboma and ostium secundum type atrial septal defect, respectively. Based on the suspicion of cat eye syndrome, a standard karyotype analysis was performed, and detected an extra small marker chromosome confirming the CES diagnosis. The chromosomal abnormality was then defined by array comparative genome hybridization (a-CGH, performed also in the parents), which identified the size of the rearrangement (3 Mb), and its de novo occurrence. Postnatally, our newborn presented with persistent hypoglycemia and cholestatic jaundice. Endocrine tests revealed congenital hypothyroidism, cortisol and growth hormone (GH) deficiencies, which were treated with replacement therapies (levotiroxine and hydrocortisone). Brain magnetic resonance imaging, later performed, showed aplasia of the anterior pituitary gland, agenesis of the stalk and ectopic neurohypophysis, confirming the congenital hypopituitarism diagnosis. She was discharged at 2 months of age, and included in a multidisciplinary follow-up. She currently is 7 months old and shows a severe global growth failure, and developmental delay. She started GH replacement treatment, and continues oral hydrocortisone, along with ursodeoxycholic acid and levothyroxine, allowing an adequate control of glycemic and thyroid profiles as well as of cholestasis. Conclusions CES phenotypic spectrum is wide and highly variable. Our report highlights how among the possible associated endocrine disorders, congenital hypopituitarism may occur, leading to persistent hypoglycemia and cholestasis. These patients should be promptly assessed for complete hormonal evaluations, in addition to major malformations and midline anomalies. Early recognition of such defects is necessary to decrease fatal events, as well as short and long-term related adverse outcomes.

Intestinal failure-associated liver disease (IFALD) is a progressive liver disease complicating intestinal failure (IF). It is a preventable and reversible condition, but at the same time, a potential cause of liver cirrhosis and an indication to combined or non-combined liver and small bowel transplantation. The diagnostic criteria are not yet standardized, so that its prevalence varies widely in the literature. Pathophysiology seems to be multifactorial, related to different aspects of intestinal failure and not only to the long-term parenteral nutrition treatment. The survival rates of children with IF have increased, so that the main problems today are preventing complications and ensuring a good quality of life. IFALD is one of the most important factors that limit long-term survival of patients with IF. For this reason, more and more interest is developing around it and the number of published articles is increasing rapidly. The purpose of this narrative review was to focus on the main aspects of the etiology, pathophysiology, management, prevention, and treatment of IFALD, based on what has been published mainly in the last 10 years. Controversies and current research gaps will be highlighted with the aim to pave the way for new project and high-quality clinical trials.

Objectives: Progressive Familial Intrahepatic Cholestasis, is an expanding group of autosomal recessive intrahepatic cholestatic disorders. Recently, Next Generation Sequencing allowed identifying new genes responsible for new specific disorders. Two biochemical phenotypes have been identified according to gamma-glutamyltransferase (GGT) activity. Mutations of the myosin 5B gene (MYO5B) are known to cause Microvillus Inclusion Disease. Recently, different mutations in MYO5B gene have been reported in patients with low-GGT cholestasis. Methods: a multicenter retrospective and prospective study was conducted in 32 children with cryptogenic intrahepatic cholestasis. Clinical, biochemical, histological, and treatment data were analyzed in these patients. DNA from peripheral blood was extracted, and all patients were studied by Whole Exome Sequencing followed by Sanger sequencing. Results: six patients out of 32 had mutations in the MYO5B gene. Of these 6 patients, the median ageat disease onset was 0.8 years, and the median length of follow-up was 4.2 years. The most common signs were pruritus, poor growth, hepatomegaly, jaundice, and hypocholic stools. Two patients also showed intestinal involvement. Transaminases and conjugated bilirubin were moderately increased, serum bile acids elevated, and GGT persistently normal. At anti-Myo5B immunostaining, performed in liver biopsy of two patients, coarse granules were evident within the cytoplasm of hepatocytes while BSEP was normally expressed at the canalicular membrane. Six variants in homozygosity or compound heterozygosity in the MYO5B gene were identified, and three of them have never been described before. All nucleotide alterations were located on the myosin motor domain except one missense variant found in the IQ Calmodulin-binding motif. Conclusions: we identified causative mutations in MYO5B in 18.7% of a selected cohort of patients with intrahepatic cholestasis confirming a relevant role for the MYO5B gene in low-GGT cholestasis.

SARS–CoV-2 infection (COVID-19) results predominantly in pulmonary involvement but a direct, virus-induced liver damage may also occur, whose mechanisms are being actively investigated. Accordingly, it appears of utmost importance to monitor liver function and carefully evaluate hepatic safety of the various drugs administered during COVID-19. In this respect, many drugs, biological agents and novel molecules, whose efficacy in COVID-19 is under scrutiny, have also been shown to potentially cause or worsen liver damage. In this article, we review safety data of established as well as promising agents for COVID-19.

Ultrasound scan is a painless and radiation-free imaging modality and, therefore, it is widely considered the first-choice diagnostic tool in the setting of hepatopathies in paediatric patients. This article focuses on the normal ultrasound anatomy of the liver in neonatal and paediatric age and reviews the ultrasound appearance of the most common diffuse and focal liver affections.

Background ZFYVE19 (Zinc Finger FYVE-Type Containing 19) mutations have most recently been associated to a novel type of high gamma-glutamyl transpeptidase (GGT), non-syndromic, neonatal-onset intrahepatic chronic cholestasis possibly associated to cilia dysfunction. Herein, we report a new case with further studies of whole exome sequencing (WES) and immunofluorescence in primary cilia of her cultured fibroblasts which confirm the observation. Results A now 5-year-old girl born to clinically healthy consanguineous Moroccan parents was assessed at 59 days of life due to severe cholestatic jaundice with increased serum bile acids and GGT, and preserved hepatocellular synthetic function. Despite fibrosis/cirrhosis and biliary ducts proliferation on liver biopsy suggested an extrahepatic biliary obstacle, normal intra-operatory cholangiography excluded biliary atresia. Under choleretic treatment, she maintained a clinically stable anicteric cholestasis but developped hyperlipidemia. After exclusion of the main causes of cholestasis by multiple tests, abnormal concentrations of sterols and WES led to a diagnosis of hereditary sitosterolemia (OMIM #618666), likely unrelated to her cholestasis. Further sequencing investigation revealed a homozygous non-sense mutation (p.Arg223Ter) in ZFYVE19 leading to a 222 aa truncated protein and present in both heterozygous parents. Immunofluorescence analysis of primary cilia on cultured skin fibroblasts showed a ciliary phenotype mainly defined by fragmented cilia and centrioles abnormalities. Conclusions Our findings are consistent with and expands the recent evidence linking ZFYVE19 to a novel, likely non-syndromic, high GGT-PFIC phenotype with neonatal onset. Due to the possible role of ZFYVE19 in cilia function and the unprecedented coexistence of a coincidental hereditary sterol disorder in our case, continuous monitoring will be necessary to substantiate type of liver disease progression and/or possible emergence of a multisystemic involvement. What mentioned above confirms that the application of WES in children with undiagnosed cholestasis may lead to the identification of new causative genes, widening the knowledge on the pathophysiology.

Background & aims Obeticholic acid (OCA) is the second-line treatment approved for patients with primary biliary cholangitis (PBC) and an inadequate response or intolerance to ursodeoxycholic acid. We aimed to evaluate the effectiveness and safety of OCA under real-world conditions. Methods Patients were recruited into the Italian PBC Registry, a multicentre, observational cohort study that monitors patients with PBC at national level. The primary endpoint was the biochemical response according to Poise criteria; the secondary endpoint was the biochemical response according to normal range criteria, defined as normal levels of bilirubin, alkaline phosphatase (ALP), and alanine aminotransferase (ALT) at 12 months. Safety and tolerability were also assessed. Results We analysed 191 patients until at least 12 months of follow-up. Median age was 57 years, 94% female, 61 (32%) had cirrhosis, 28 (15%) had histologically proven overlap with autoimmune hepatitis (PBC-AIH). At 12 months, significant median reductions of ALP (-32.3%), ALT (-31.4%), and bilirubin (-11.2%) were observed. Response rates were 42.9% according to Poise criteria, and 11% by normal range criteria. Patients with cirrhosis had lower response than patients without cirrhosis (29.5% vs. 49.2%, p = 0.01), owing to a higher rate of OCA discontinuation (30% vs. 12%, p = 0.004), although with similar ALP reduction (29.4% vs. 34%, p = 0.53). Overlap PBC-AIH had a similar response to pure PBC (46.4% vs. 42.3%, p = 0.68), with higher ALT reduction at 6 months (-38% vs. -29%, p = 0.04). Thirty-three patients (17%) prematurely discontinued OCA because of adverse events, of whom 11 experienced serious adverse events. Treatment-induced pruritus was the leading cause of OCA discontinuation (67%). Conclusions Effectiveness and safety of OCA under real-world conditions mirror those in the Poise trial. Patients with cirrhosis had lower tolerability. Overlap PBC-AIH showed higher ALT reduction at 6 months compared with patients with pure PBC. Lay summary Obeticholic acid (OCA) was shown to be effective in more than one-third of patients not responding to ursodeoxycholic acid in a real-world context in Italy. Patients with cirrhosis had more side effects with OCA, and this led to suspension of the drug in one-third of patients. OCA was also effective in patients who had overlap between autoimmune hepatitis and primary biliary cholangitis., Graphical abstract, Highlights • Under real-world conditions, OCA was effective in ~43% of patients who were non-responders to UDCA, according to Poise criteria. • Patients with cirrhosis showed lower efficacy (29.5%), mainly attributed to reduced tolerability and higher discontinuation rate. • Patients with overlap AIH-PBC showed a comparable efficacy to pure PBC, with a higher ALT reduction at 6 months. • Most patients with PBC are still in need of additional therapy if aiming to normalise liver biochemistry.

Background & aims Several symptoms impair the quality of life (QoL) of patients with primary biliary cholangitis (PBC). They are reported to vary significantly in different countries. Aim of our study was to explore whether there is a geographical clustering that accounts for symptoms in PBC. Methods Data was analysed from four cohorts of PBC patients from the UK, Spain, Japan and Italy using the PBC-27 scale. Results Overall, 569 patients from four cohorts were identified, including 515 females (90.5%) with a mean age of 61 years. The analysis provided evidence for strict factorial invariance of the scale, a robust indicator of its validity for cross-cultural research. The mean of the fatigue domain of British patients was significantly greater than that of the Japanese (p ​, Graphical abstract Image 1, Highlights • Primary Biliary Cholangitis (PBC) is a rare liver disease characterised by several symptoms that impair quality of life; • This study includes data from questionnaires provided to individuals with PBC in Italy, Japan, Spain and United Kingdom; • It shows a clear geographical pattern of distribution of PBC-related symptoms, with a significant difference based on latitude.

The farnesoid-X-receptor (FXR) is validated target in the cholestatic disorders treatment. Obeticholic acid (OCA), the first in class of FXR agonist approved for clinical use, causes side effects including acute liver decompensation when administered to cirrhotic patients with primary biliary cholangitis at higher than recommended doses. The V-Maf avian-musculoaponeurotic-fibrosarcoma-oncogene-homolog-G (Mafg) and nuclear factor-erythroid-2-related-factor-2 (Nrf2) mediates some of the downstream effects of FXR. In the present study we have investigated the role of FXR/MafG/NRF2 pathway in the development of liver toxicity caused by OCA in rodent models of cholestasis. Cholestasis was induced by bile duct ligation (BDL) or administration of α-naphtyl-isothiocyanate (ANIT) to male Wistar rats and FXR−/− and FXR+/+ mice. Treating BDL and ANIT rats with OCA exacerbated the severity of cholestasis, hepatocytes injury and severely downregulated the expression of basolateral transporters. In mice, genetic ablation FXR or its pharmacological inhibition by 3-(naphthalen-2-yl)-5-(piperidin-4-yl)-1,2,4-oxadiazole rescued from negative regulation of MRP4 and protected against liver injury caused by ANIT. By RNAseq analysis we found that FXR antagonism effectively reversed the transcription of over 2100 genes modulated by OCA/ANIT treatment, including Mafg and Nrf2 and their target genes Cyp7a1, Cyp8b1, Mat1a, Mat2a, Gss. Genetic and pharmacological Mafg inhibition by liver delivery of siRNA antisense or S-adenosylmethionine effectively rescued from damage caused by ANIT/OCA. In contrast, Nrf2 induction by sulforaphane was protective. Conclusions: Liver injury caused by FXR agonism in cholestasis is FXR-dependent and is reversed by FXR and Mafg antagonism or Nrf2 induction. © 2020 Elsevier B.V.

Background & Aims: Total bilirubin is a predictor of survival in primary biliary cholangitis, with the main elevated component being direct bilirubin. The purpose of this post hoc analysis was to assess the efficacy and safety of obeticholic acid across quartiles of varying baseline levels of direct bilirubin in the phase 3, randomized, placebo-controlled Primary Biliary Cholangitis Obeticholic Acid International Study of Efficacy. Methods: This analysis assessed patients on the basis of their baseline direct bilirubin level (divided by quartile). Biochemistry and safety outcomes were evaluated within each quartile over time. Results: In the quartile with the highest baseline direct bilirubin (>5.47µmol/L), there was a significant reduction in both direct and total bilirubin at Month 12 compared with placebo. Least squares mean (standard error) change from baseline in direct bilirubin at Month 12 was 4.17 (1.42) µmol/L for placebo, −3.48 (1.63) µmol/L for obeticholic acid 5-10mg and −3.66 (1.51) µmol/L for obeticholic acid 10mg (P&nbsp

Primary biliary cholangitis (PBC) is a rare progressive immune-mediated liver disease that, if not adequately treated, may culminate in end-stage disease and need for transplantation. According to current guidelines, PBC is diagnosed in the presence of antimitochondrial antibodies (AMA) or specific antinuclear antibodies, and of a cholestatic biochemical profile, while biopsy is recommended only in selected cases. All patients receive ursodeoxycholic acid (UDCA) in first line; the only registered second-line therapy is obeticholic acid (OCA) for UDCA-inadequate responders. Despite the recent advances in understanding PBC pathogenesis and developing new treatments, many grey areas remain. Six Italian experts selected the following topics as the most urgent to address in PBC management: diagnosis and natural history of PBC: as a portion of the subjects with isolated AMA, normal alkaline phosphatase (ALP) levels and no symptoms of liver disease could have PBC by histology, defining how to manage and follow this population is crucial; role of liver biopsy: recent evidence suggests that biopsy may provide relevant information for risk stratification and prediction of UDCA response, possibly facilitating personalized approaches; risk stratification: the tools for risk stratification are well established, but some issues (eg bile acid dosage in routine practice) remain controversial; and therapy: those in more advanced stages of development are nuclear receptor modulators and fibrates, but more data are needed to plan personalized strategies. In this manuscript, for each topic, current evidence, controversies and future perspectives are summarized with the possible implications for clinical practice.

Introduction. The nuclear receptor FXR regulates the expression of genes involved in bile acids, glucose and lipid homeostasis. For its role as guardian of metabolism, FXR has been identified a promising pharmacological target in liver bile acid and lipid accumulation, such as cholestasis and non-alcoholic fatty liver disease (NAFLD). The field of FXR research is extremely competitive with a large number of patents and articles published in the last decades identifying promising hit compounds. Areas covered. The present review summarizes recent patent activity (2014-to date) filing for synthetic and natural FXR ligands, including bile acid derivatives and non-steroidal compounds, alongside their in vitro and in vivo efficacy as well as their therapeutic applications. Expert opinion. While the first FXR agonist, obeticholic acid, has gained approval, significant safety issues have been emerged. Today is unclear whether these safety issues are class related or restricted to the bile acid scaffold of this agent. Despite the significant number of patent applications claiming steroidal and non-steroidal FXR agonists, several questions on their therapeutic potential in cholestasis and NASH remain open leaving a space for the development of novel compounds.

Melatonin therapy or prolonged exposure to complete darkness reduces biliary hyperplasia and liver fibrosis in bile-duct–ligated (BDL) rats; however, no information exists in primary sclerosing cholangitis (PSC). Thus, we aimed to determine the therapeutic effects of prolonged dark therapy or melatonin administration on hepatic fibrosis in the multidrug resistance gene 2–knockout (Mdr2−/−) mouse model of PSC. Melatonin levels, biliary mass, liver fibrosis, angiogenesis and miR-200b expression were evaluated in wild-type and Mdr2−/− mice exposed to darkness or melatonin treatment or in male patients with PSC and healthy controls. Mdr2−/− mice were also treated with miR-200b inhibitor or control before evaluating biliary mass, liver fibrosis, and angiogenesis. After overexpression of arylalkylamine N-acetyltransferase (AANAT; the enzyme regulating melatonin synthesis) or inhibition of miR-200b in cholangiocytes and hepatic stellate cells in vitro, we evaluated angiogenesis and fibrosis gene expression. After exposure to darkness or administration of melatonin, Mdr2−/− mice show elevated serum melatonin levels and inhibition of biliary mass, along with reduction of liver fibrosis and angiogenesis. MicroRNA PCR analysis demonstrated that miR-200b expression increased in Mdr2−/− mice and patients with PSC compared with controls and decreased in Mdr2−/− mice subjected to dark exposure or melatonin treatment. Inhibition of miR-200b in Mdr2−/− ablates biliary proliferation, liver fibrosis, and angiogenesis. In vitro, overexpression of AANAT or inhibition of miR-200b in cholangiocytes and hepatic stellate cells decreased the expression of miR-200b, angiogenesis, and fibrosis genes. Dark therapy or targeting melatonin/miR-200b axis may be important in the management of biliary damage and liver fibrosis in cholangiopathies including PSC.—Wu, N., Meng, F., Zhou, T., Han, Y., Kennedy, L., Venter, J., Francis, H., DeMorrow, S., Onori, P., Invernizzi, P., Bernuzzi, F., Mancinelli, R., Gaudio, E., Franchitto, A., Glaser, S., Alpini G. Prolonged darkness reduces liver fibrosis in a mouse model of primary sclerosing cholangitis by miR-200b down-regulation.

Hepatic fibrosis occurs during the progression of primary sclerosing cholangitis (PSC) and is characterized by accumulation of extracellular matrix proteins. Proliferating cholangiocytes and activated hepatic stellate cells (HSCs) participate in the promotion of liver fibrosis during cholestasis. Gonadotropin-releasing hormone (GnRH) is a trophic peptide hormone synthesized by hypothalamic neurons and the biliary epithelium and exerts its biological effects on cholangiocytes by interaction with the receptor subtype (GnRHR 1 ) expressed by cholangiocytes and HSCs. Previously, we demonstrated that administration of GnRH to normal rats increased intrahepatic biliary mass (IBDM) and hepatic fibrosis. Also, miR-200b is associated with the progression of hepatic fibrosis; however, the role of the GnRH/GnRHR 1 /miR-200b axis in the development of hepatic fibrosis in PSC is unknown. Herein, using the mouse model of PSC (multidrug resistance gene 2 knockout), the hepatic knockdown of GnRH decreased IBDM and liver fibrosis. In vivo and in vitro administration of GnRH increased the expression of miR-200b and fibrosis markers. The GnRH/GnRHR 1 axis and miR-200b were up-regulated in human PSC samples. Cetrorelix, a GnRHR 1 antagonist, inhibited the expression of fibrotic genes in vitro and decreased IBDM and hepatic fibrosis in vivo . Inhibition of miR-200b decreased the expression of fibrosis genes in vitro in cholangiocyte and HSC lines. Targeting the GnRH/GnRHR 1 /miR-200b axis may be key for the management of hepatic fibrosis during the progression of PSC.

Abnormal liver tests occur in 3-5% of pregnancies and show many different causes. Although alterations of liver enzymes could be a physiological phenomenon, it may also reflect potential severe liver injury, necessitating further assessment and accurate management. The work-up has to consider liver diseases specific of pregnancy and non pregnancy-related liver damage (coincidental and pre-existing to pregnancy). Pre-existing liver diseases during pregnancy are relatively uncommon, as pregnant women are generally young and healthy. Liver diseases unique to pregnancy are intrahepatic cholestasis of pregnancy, the HELLP syndrome (haemolysis, elevated liver enzymes, low platelets) and acute fatty liver of pregnancy. These disorders may result in foetal distress, severe liver damage and sometime hepatic failure; for these reasons the diagnostic work-up and treatment must be very fast. This review focuses on the management of pregnant women with altered liver function tests. Furthermore, the main liver diseases specific of pregnancy are described.

Paediatric biliary tract and gallbladder diseases include a variety of entities with a wide range of clinical presentations. Cholestasis represents an impaired secretion of bilirubin by hepatocytes, manifesting with high blood levels of conjugated bilirubin and jaundice. Various causes may be involved, which can be recognised analysing blood tests and hepatobiliary imaging, while sometimes liver biopsy or surgery may be necessary. High-resolution real-time ultrasonography is an important tool for differentiation of obstructive and non-obstructive causes of jaundice in infants and children. In this paper, we briefly review the normal anatomy and the ultrasound aspects of main pathologies affecting gallbladder and biliary tree in neonatal and paediatric age.

OBJECTIVE: To investigate patient factors predictive of gamma glutamyltransferase (GGT) normalization following ursodeoxycholic acid (UDCA) therapy in children with primary sclerosing cholangitis. STUDY DESIGN: We retrospectively reviewed patient records at 46 centers. We included patients with a baseline serum GGT level ≥50 IU/L at diagnosis of primary sclerosing cholangitis who initiated UDCA therapy within 1 month and continued therapy for at least 1 year. We defined "normalization" as a GGT level

We describe the case of a childbearing-age woman presenting with spontaneous recurrent functional ovarian cysts and, more interestingly, chronic and asymptomatic elevation of cholestatic parameters. The patient showed no history of chronic viral infections, immunological and metabolic disorders, alcohol abuse and environmental toxins exposition. Hepatic ultrasonography and cholangio-pancreatography-magnetic-resonance excluded any morphological and structural abnormalities, while liver biopsy evidenced only minimal and not specific features of inflammation. Cholestasis indices obtained prompt recovery after each cycle of synthetic hormone therapy, implanted to treat functional ovarian cysts. She has continuously experienced the off-therapy asynchronous recurrence of liver laboratory abnormalities and functional ovarian cysts. The favorable effect of the synthetic hormone therapy to obtaining a stable recovery of this unexplained long-lasting cholestatic syndrome could be likely explained by downregulation of an endogenous ovarian overproduction, although estrogen-regulated local intracellular transduction pathways cannot be excluded.

Intestinal failure-associated liver disease (IFALD) is characterized by either liver steatosis or cholestasis and may develop in patients on long-term home parenteral nutrition for chronic intestinal failure. The pathogenesis of IFALD is multifactorial and includes gastrointestinal disease-related, parenteral nutrition-related, and systemic-related factors. Alteration of bile acid enterohepatic circulation, gut microbiome, and intestinal permeability, seem to be the main mechanisms. Patients forced to a total oral fasting regimen are at greater risk. Parenteral nutrition overfeeding and/or of soybean-based lipid emulsion may be contributing factors. Prevention and treatment are based on avoiding and promptly treating all the risk factors.

Alagille syndrome (AGS) is an autosomal-dominant disorder characterized by various degrees of abnormalities in the liver, heart, eyes, vertebrae, kidneys, face, vasculature, skeleton, and pancreas. This case report describes a newborn child exhibiting a congenital neural tube defect and peculiar craniofacial appearance characterized by a prominent forehead, deep-set eyes, bulbous nasal tip, and subtle upper lip. Just a few hours after birth, congenital heart disease was suspected for cyanosis and confirmed by heart evaluation. In particular, echocardiography indicated pulmonary atresia with ventricular septal defect with severe hypoplasia of the pulmonary branches (1.5 mm), large patent ductus arteriosus and several major aortopulmonary collateral arteries. Due to the association of peculiar craniofacial appearance and congenital heart disease, a form of Alagille syndrome was suspected. In addition, on the fifth day after birth, the patient developed jaundice, had acholic stools, and high levels of conjugated bilirubin and gamma-glutamyltransferase (GGT) were detected in the blood. Genetic testing revealed the novel variant c.802del in a single copy of the JAG1 gene. No variants in the NOTCH2 gene were detected. To the best of our knowledge, this is the first clinical description of a congenital neural tube defect in a molecularly confirmed Alagille patient. This work demonstrates a novel pathogenic heterozygous JAG1 mutation is associated with an atypical form of Alagille syndrome, suggesting an increased risk for neural tube defects compared to other Alagille patients.

The preservation of a graft's aberrant left hepatic artery (LHA) during liver transplantation (LT) ensures optimal vascularization of the left liver but can also be considered a risk factor for hepatic artery thrombosis (HAT). In contrast, ligation of an aberrant LHA may lead to hepatic ischemia with the potential risk of graft dysfunction and biliary complications. The aim of this study was to prospectively analyze the impact on the surgical strategy for LT of 5 tests performed to establish whether an aberrant LHA was an accessory or a replaced artery, thus leading to the design of a decisional algorithm. From August 2005 to December 2016, 395 whole LTs were performed in 376 patients. Five parameters were evaluated to determine whether an aberrant LHA was an accessory or a replaced artery. On the basis of our decision algorithm, an aberrant LHA was ligated during surgery when assessed as accessory and preserved when assessed as replaced. A total of 138 anatomical variants of hepatic arterial vascularization occurred in 120/395 (30.4%) grafts. Overall, the incidence of an aberrant LHA was 63/395 (15.9%). The LHA was ligated in 33 (52.4%) patients and preserved in 30 (47.6%) patients. After a mean follow-up period of 50.9 ± 39.7 months, the incidence of HAT, primary nonfunction, early allograft dysfunction, biliary stricture or leaks, and overall survival was similar in the 2 groups. In conclusion, once shown to be an accessory, an LHA can be safely ligated without clinical consequences on the outcome of LT. Liver Transplantation 24 204-213 2018 AASLD.

Drug-induced liver injury (DILI) remains the most common cause of acute liver failure in the Western world. Chemotherapy is one of the major class of drugs most frequently associated with idiosyncratic DILI. For this reason, patients who receive chemotherapy require careful assessment of liver function prior to treatment to determine which drugs may not be appropriate and which drug doses should be modified. S-adenosylmethionine (SAMe) is an endogenous agent derived from methionine. Its supplementation is effective in the treatment of liver disease, in particular intrahepatic cholestasis (IHC). The target of this review is to analyze the mechanisms of hepatotoxicity of the principal anticancer agents and the role of SAMe in the prevention of this complication.

Introduction: Farnesoid X nuclear receptor is involved in the regulation of lipid and glucose metabolism, though mainly in the homeostasis of bile acids. Indeed, the agonists of farnesoid X nuclear receptor represent promising drugs. Areas covered: Obeticholic acid, a novel semisynthetic analogue of the naturally occurring bile acid, has led to encouraging preliminary results in both cholestatic and metabolic liver disease. In patients with primary biliary cholangitis, obeticholic acid determines a significant biochemical improvement although the effects on liver fibrosis are lacking. Obeticholic acid has been suggested for the treatment of nonalcoholic liver disease with good laboratory results. In cirrhotic animal models, the drug seems to reduce both portal hypertension and gut bacterial translocation. Expert commentary: The use of obeticholic acid for the treatment of primary biliary cholangitis shows satisfying results. However, some open questions remain unresolved. Herein, we provide an overview of the current knowledge about the use of obeticholic acid in the field of nonviral chronic liver diseases. We tried to give a global point of view using a translational approach.

The disease entity today widely called ‘primary biliary cirrhosis’ was first described by Addison and Gull in 18511 and Hanot in 1876.2 One hundred years after its first description, MacMahon and Thannhauser3 proposed the term ‘xanthomatous biliary cirrhosis’ for this disease based on the typical xanthoma formation with accumulation of cholesterol esters in the skin around the eyes in association with inflammatory destruction of small intrahepatic bile ductules leading to a biliary type cirrhosis. Xanthoma formation, however, is not a very common sign in this disorder. This may be the reason why the term ‘primary biliary cirrhosis’, proposed 1 year later for the same disorder by Ahrens et al ,4 gained wider acceptance when most patients were presenting with advanced liver disease. Dame Sheila Sherlock, already in 1959, opposed the term ‘primary biliary cirrhosis’ as many of her patients were free of cirrhosis at the time of diagnosis and the mean survival was 5 and a half years (3–11) even for the fatal cases, whereas many asymptomatic patients would survive more than 10 years.5 The term ‘primary biliary cirrhosis’ remained an issue of concern as reflected by the name change proposal of Rubin, Schaffner and Popper in 1965 with their paper ‘Primary biliary cirrhosis—Chronic non-suppurative destructive cholangitis’.6 Sherlock7 wisely commented on this new name: “…a better one, although it is unlikely that it will replace the more popular, although inaccurate, one of primary biliary cirrhosis”. She was right, again. And even 40 years later, the European8 and American9 Clinical Practice Guidelines still used the term ‘primary biliary cirrhosis’ even though it was an anachronism and did not accurately reflect the natural history of disease in the vast majority of patients as it is today. The early diagnosis of primary biliary cirrhosis has …

Bile acid receptors represent well-defined targets for the development of novel therapeutic approaches to metabolic and inflammatory diseases. In the present study, we report the generation of novel C-3 modified 6-ethylcholane. The pharmacological characterization and molecular docking studies for the structure-activity rationalization, allowed the identification of 3-azido-6α-ethyl-7α-hydroxy-5β-cholan-24-oic acid (compound 2), a potent and selective FXR agonist with a nanomolar potency in transactivation assay and high efficacy in the recruitment of SRC-1 co-activator peptide in Alfa Screen assay. In vitro, compound 2 was completely inactive towards common off-targets such as the nuclear receptors PPAR, PPAR, LXR, and LXRand the membrane G-coupled bile acid receptor, GPBAR1. This compound when administered in vivo exerts a robust FXR agonistic activity increasing the liver expression of FXR-target genes including SHP, BSEP, OST and FgF21, while represses the expression of genes that are negatively regulated by FXR (CYP7A1), and collectively these effects result in a significant reshaping of bile acid pool in mouse. In summary, compound 2 could represent a promising candidate for drug development in liver metabolic disorders.

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BACKGROUND The purpose of this study was to investigate immunological risk factors associated with BS (Biliary Strictures) after LT (Liver Transplantation). MATERIAL AND METHODS The study included 192 patients out of 273 adult liver transplantations performed from August 2005 to December 2012, with a radiological or surgically proven biliary stricture. About 35 potential risk factors for biliary strictures were studied. Results A biliary stricture was diagnosed in 22.9% of transplants; the anastomotic type and the non-anastomotic type complicated the transplantation in 18.2% and 7.8% of cases, respectively. Six patients (3.1%) presented both of forms. Univariate analysis using logistic regression showed that preoperative serum bilirubin level >2 mg/dl (P=0.040), donor age >46 years old (P=0.007), positive crossmatch (P=0.007), product of donor age and preoperative Model for End Stage Liver Disease (DMELD) >710 (P=0.011), occurrence of acute or chronic rejection (P=0.004; P=0.003), and biliary leak (P=0.002) were all significantly associated with the development of biliary stricture. At the multivariate analysis, Primary Biliary Cirrhosis (PBC) (P=0.019), donor age >46 years (P=0.008), crossmatch positivity (P=0.001), and acute or chronic rejection (P=0.005; P=0.043) appeared to be the only variables independently associated with the development of a biliary stricture. Conclusions Immunological risk factors (PBC, crossmatch positivity, acute and chronic rejection) emerged as being the most important variables associated to the development of biliary strictures after LT.

Background: Long-term home parenteral nutrition (HPN) may induce liver disorders. Transient elastography (TE) has been proposed as a noninvasive alternative to liver biopsy analysis for assessment of the progression of hepatic fibrosis to cirrhosis. The goal of this study was to compare values from TE measurements to biopsy-determined stages of histologic fibrosis in patients receiving HPN. Methods: In this multicenter prospective study, patients receiving long-term HPN (‰6 months) who required a liver biopsy for clinical reasons were included. TE (FibroScan) values for each patient were compared with the degree of hepatic fibrosis measured from biopsy specimens based on the Brunt classification. TE values were also correlated to biochemical and histologic cholestasis. Two noninvasive indices for predicting liver fibrosis (APRI and FIB-4) were also evaluated. Results: Thirty patients were included in this study (mean age, 42.1 years; 63% male). The mean duration of HPN was 100.7 months; 25 patients had a short bowel and 13 had an intestinal stoma. Biochemical cholestasis was described in 22 patients. Liver histologic features varied among these patients. There was no correlation between the values of TE and the stages of histologic fibrosis, but TE values were significantly correlated to serum bilirubin level and the severity of histologic cholestasis as well as APRI and FIB-4 scores. Conclusions: In patients with long-term HPN, TE failed to assess the degree of hepatic fibrosis. This could be due to the heterogeneity of liver histologic features observed in these patients and the presence of chronic cholestasis.

[No abstract available]

BACKGROUND & AIMS: Approaches to risk stratification for patients with primary biliary cirrhosis (PBC) are limited, single-center based, and often dichotomous. We aimed to develop and validate a better model for determining prognoses of patients with PBC. METHODS: We performed an international, multicenter meta-analysis of 4119 patients with PBC treated with ursodeoxycholic acid at liver centers in 8 European and North American countries. Patients were randomly assigned to derivation (n = 2488 [60%]) and validation cohorts (n = 1631 [40%]). A risk score (GLOBE score) to predict transplantation-free survival was developed and validated with univariate and multivariable Cox regression analyses using clinical and biochemical variables obtained after 1 year of ursodeoxycholic acid therapy. Risk score outcomes were compared with the survival of age-, sex-, and calendar time-matched members of the general population. The prognostic ability of the GLOBE score was evaluated alongside those of the Barcelona, Paris-1, Rotterdam, Toronto, and Paris-2 criteria. RESULTS: Age (hazard ratio = 1.05; 95% confidence interval [CI]: 1.04-1.06; P 0.30 had significantly shorter times of transplant-free survival than matched healthy individuals (P