C Jüngst

Cholestatic Liver Disease

Cholestasis develops as a consequence of impaired bile formation and/or bile flow and can be classified as intra- or extrahepatic. Chronic cholestatic diseases are mostly intrahepatic with the exception of primary and secondary sclerosing cholangitis affecting intra- and extrahepatic bile ducts. Recent genome-wide association studies have confirmed major histocompatibility complex associations and discovered multiple susceptibility loci in primary biliary cirrhosis and primary sclerosing cholangitis, providing new insights into disease pathogenesis, which may translate into more precise therapeutic prevention and intervention in the future. Diagnostic steps in cholestatic conditions comprise a thorough patient history, abdominal imaging and distinct serological studies including antimitochondrial antibodies and IgG4 levels; if the diagnosis remains unclear, liver biopsy is warranted. Genetic testing should also be considered, as mutations in the hepatobiliary transporters ATP8B1, ABCB11 and ABCB4 are causative for three different forms of familial intrahepatic cholestasis. Disease severity is dependent on the genotypic variants of these transporters, ranging from mildly elevated liver enzymes in adults to cirrhosis in early childhood. Ligands of nuclear receptors, which represent important regulators of hepatobiliary transporters, and modified bile salts are new promising therapeutic options in cholestatic liver disease and are currently being investigated in clinical trials.

Intrahepatic cholestasis in common chronic liver diseases

Cholestasis represents the consequence of impaired bile formation and decrease in bile flow, generally classified as extra‐ and intrahepatic. Cholestasis is the pivotal hallmark of the so‐called primary cholestatic liver diseases but may also emerge in other forms of chronic liver injury. The aim now was to summarise the current state of knowledge on intrahepatic cholestasis related to chronic liver diseases.

Severe drug‐induced liver injury related to therapy with dimethyl fumarate

Dimethyl fumarate, a fumaric ester, has been used for the treatment of severe psoriasis for many years and only recently been licensed as first-line therapy for relapsing-remitting multiple sclerosis in the United States and Europe, turning dimethyl fumarate to one of the most prescribed disease-modifying agents. The safety profile is generally considered favorable, and only moderate elevations of liver enzymes have been reported in long-term safety assessments in patients with psoriasis. However, to date, dimethyl fumarate has not been linked to instances of clinically apparent liver injury with jaundice (http://livertox.nlm.nih.gov/DimethylFumarate. htm).

Phenotypic spectrum and diagnostic pitfalls of ABCB4 deficiency depending on age of onset

Genetic variants in the adenosine triphosphate‐binding cassette subfamily B member 4 (ABCB4) gene, which encodes hepatocanalicular phosphatidylcholine floppase, can lead to different phenotypes, such as progressive familial intrahepatic cholestasis (PFIC) type 3, low phospholipid‐associated cholelithiasis, and intrahepatic cholestasis of pregnancy. The aim of this multicenter project was to collect information on onset and progression of this entity in different age groups and to assess the relevance of this disease for the differential diagnosis of chronic liver disease. Clinical and laboratory data of 38 patients (17 males, 21 females, from 29 families) with homozygous or (compound) heterozygous ABCB4 mutations were retrospectively collected. For further analysis, patients were grouped according to the age at clinical diagnosis of ABCB4‐associated liver disease into younger age (<18 years) or adult age (≥18 years). All 26 patients diagnosed in childhood presented with pruritus (median age 1 year). Hepatomegaly and splenomegaly were present in 85% and 96% of these patients, respectively, followed by jaundice (62%) and portal hypertension (69%). Initial symptoms preceded diagnosis by 1 year, and 13 patients received a liver transplant (median age 6.9 years). Of note, 9 patients were misdiagnosed as biliary atresia, Alagille syndrome, or PFIC type 1. In the 12 patients with diagnosis in adulthood, the clinical phenotype was generally less severe, including intrahepatic cholestasis of pregnancy, low phospholipid‐associated cholelithiasis, or (non)cirrhotic PFIC3. Conclusion: ABCB4 deficiency with onset in younger patients caused a more severe PFIC type 3 phenotype with the need for liver transplantation in half the children. Patients with milder phenotypes are often not diagnosed before adulthood. One third of the children with PFIC type 3 were initially misdiagnosed, indicating the need for better diagnostic tools and medical education. (Hepatology Communications 2018;2:504‐514)

NOD2 gene variants confer risk for secondary sclerosing cholangitis in critically ill patients

Sclerosing cholangitis in critically ill patients (SC-CIP) is a progressive cholestatic disease of unknown aetiology characterized by chronic biliary infections. Hence we hypothesized that common NOD2 (nucleotide-binding oligomerisation domain containing 2) gene variants, known risk factors for Crohn’s disease and bacterial translocation in liver cirrhosis, increase the odds of developing SC-CIP. Screening of 4,641 endoscopic retrograde cholangiography procedures identified 17 patients with SC-CIP, who were then genotyped for the three common NOD2 mutations (Cohort 1, discovery cohort). To validate the association, we subsequently tested these NOD2 variants in 29 patients from SC-CIP cohorts of three additional medical centers (Cohort 2, replication cohort). In Cohort 1, the NOD2 variants were present in 5 of 17 SC-CIP patients (29.4%), which is twice the frequency of the general population. These results were replicated in Cohort 2 with 8 patients (27.6%) showing NOD2 mutations. In contrast, polymorphisms of hepatocanalicular transporter genes did not have major impact on SC-CIP risk. This first study on genetic susceptibility in SC-CIP patients shows an extraordinary high frequency of NOD2 variation, pointing to a critical role of inherited impaired anti-bacterial defense in the development of this devastating biliary disease.

Secondary sclerosing cholangitis rapidly leading to liver cirrhosis: a possible post-ICU treatment sequel

Learning points for clinicians Secondary sclerosing cholangitis in critically ill patients (SSC-CIP) should be suspected in patients who present with cholestasis after treatment on intensive care unit, regardless of the duration of the intensive care therapy. Increased awareness of this condition is necessary, because it may rapidly lead to liver cirrhosis. ERCP, ursodeoxycholic acid and transplantation represent currently available therapeutic options. A 64-year-old man was admitted to our department with increasing jaundice (bilirubin 9.1 mg/dl, gamma-GT 1492 U/l, AP 1745 U/L). He had a negative history of viral and non-viral liver diseases (including primary sclerosing cholangitis) and displayed no signs of inflammatory bowel disease in colonoscopy. Twenty-five days prior to …

P1142 : Next generation sequencing analysis of cholestatic patients reveals high impact variation in common and rare candidate genes: Dissecting the genetic architecture of cholestasis

(Mdr2-KO, bile duct ligation, treatment with dehydrocollidine – DDC). However, PC-2-gene expression was not reduced, suggesting that the decrease in PC2 protein content was due to increased degradation. To understand if factors involved in biliary damage influence PC2 protein expression, mouse cholangiocytes were treated with pro-inflammatory cytokines (IL-1b, IFNg, TNFa), nitric oxide (NO) donors (DETAnonoate) and ER stressors (thapsigargin). Expression of PC2 protein was again significantly reduced, but not its gene expression. Noteworthy, downregulation of PC-2 was associated to increased ERK1/2 phosphorylation, HIF1a transcription activity, secretion of VEGF and phosphorylation of VEGFR2. Expression of Herp and NEK, ubiquitin-like proteins that promote PC2 degradation by increasing the retrotranslocation from the ER to the proteasome complex was also increased. Pre-treatment with the proteasome inhibitor MG-132 restored the expression of PC2 in cells treated with cytokines but not in cells treated with NO donors or with ER stressors. In the latter conditions, PC2 degradation was inhibited by LY294002, an inhibitor of PI3K that blocks the autophagosome formation and by blockade of lysosomes with chloroquine, suggesting a role for autophagy. Finally, treatment of DDC-treated mice with the proteasome inhibitor bortezomib, significantly reduced the extent of the liver damage and restored PC2 expression. Conclusions: PC2 protein is modulated post-translationally by proinflammatory cytokines, ER-stressors and NO-donors and is reduced in mice with biliary damage. Down regulation of PC2 protein expression in cholangiocytes increases the ERK1/2/HIF1a pathway and VEGF secretion, thereby playing a pivotal role in the regulation of cholangiocyte response to biliary damage. Treatments able to restore PC2 expression (i.e. proteasome inhibitors) may represent a new therapeutic approach in biliary diseases.