Christoph Jüngst

Background: Secondary sclerosing cholangitis (SSC) has emerged as a severe complication in critically ill COVID-19 patients. This study outlines the clinical course, prognostic markers, and liver transplantation (LT) outcomes of COVID-19-associated SSC. Methods: This retrospective multicenter study included 36 COVID-19-associated SSC patients from three Swiss tertiary centers. Clinical, laboratory, imaging, and histopathological data were analyzed with respect to outcomes defined as survival without LT versus LT or death. Post-transplant outcomes were assessed. Results: All 36 critically ill patients developed acute respiratory distress syndrome. SSC was diagnosed post-ICU in 80.6% of cases. After a median follow-up of 537 days, 12 patients died, six progressed to decompensation, 14 had compensated liver disease, and four underwent LT. Among 17 LT-evaluated patients, eight died during evaluation or on the waiting list. All four transplanted patients survived. Univariable analysis identified male sex and extent of elevated alkaline phosphatase (AP), bilirubin, aspartate aminotransferase, and alanine aminotransferase at SSC diagnosis, and at peak as predictors of poor outcomes. Histopathological features associated with adverse outcomes included portal edema and bile infarcts, whereas septal fibrosis, florid inflammation, and MRI-detected parenchymal signal changes correlated with transplant-free survival. In multivariable analysis, parenchymal signal changes (OR 0.03, 95%CI 0.00–0.83) and peak AP (OR 7.23, 95%CI 1.14–45.73) remained independently associated with outcome. Conclusions: COVID-19-associated SSC carries high morbidity and mortality. Clinical, biochemical, imaging, and histopathological parameters enable early risk stratification and predict outcome. Timely LT evaluation is recommended in severe cases, given favorable post-transplant outcomes.

Hepatitis E virus (HEV) is a leading cause of acute viral hepatitis worldwide. Whereas HEV infection is typically self‐limiting, rare cases of prolonged cholestasis have been reported. The underlying mechanisms remain unclear, though host genetic variation may contribute. This study aimed to investigate the role of genetic predisposition in HEV‐induced prolonged cholestasis by analysing variants in genes associated with hepatocanalicular transport. We performed a retrospective review of medical records from three university centres in Switzerland and Germany and identified five immunocompetent patients with prolonged cholestasis following acute HEV infections. Genetic analysis using next‐generation sequencing included a panel of five genes involved in cholestatic liver diseases ( ATP8B1, ABCB11 , ABCB4, ABCC2 and MYO5B ). Variant frequencies were evaluated using population reference databases and compared with a genetically characterised cohort of asymptomatic HEV‐infected blood donors. All five patients were male, with a median age of 59 years. The median duration of cholestasis exceeded 77 days. Two patients exhibited potentially pathogenic heterozygous variants: ATP8B1 p.N45T in one patient and MYO5B p.K429R in another. Additionally, common ABCB11 variants were detected in all patients, which might have contributed to cholestatic clinical presentation. In the asymptomatic HEV‐infected controls, the MYO5B p.K429R variant was absent, whereas the ATP8B1 p.N45T variant was detected in only one individual in a heterozygous state. These case series illustrate that host genetics might influence the severity of HEV infection, particularly prolonged cholestatic jaundice. Further research is needed to explore the interaction between viral infections and host genetics in liver disorders.

Immune checkpoint inhibitors have improved the treatment of many cancers. However, immune-related (IR) adverse events can limit their use. A rare but potentially severe IR adverse event is IR-cholangitis, which is mostly induced by anti-programmed cell death 1 (PD1) antibodies and is often corticosteroid-resistant. Consequently, immunosuppressive therapy is increased, which interferes with the antitumor response and bears the risk of infection. We report on 2 patients with BRAF V600E mutant melanoma, who presented with IR-sclerosing cholangitis under triplet therapy with atezolizumab [anti–programmed cell death ligand 1 (PD-L1) antibody], vemurafenib (BRAF inhibitor), and cobimetinib (MEK inhibitor). In both cases, the administration of corticosteroids initially resulted in a marginal improvement but was followed by a rebound of biliary enzymes and the subsequent emergence of pyogenic liver abscesses with bacteremia. Liver abscesses developed without preceding invasive procedures, which implies that a more restrictive approach to immunosuppressive therapy for IR-cholangitis should be considered. To our knowledge, we report the first 2 cases of IR-cholangitis and subsequent liver abscesses without prior invasive intervention, the first cases of IR-cholangitis induced by triplet therapy, and 2 of the few anti-PD-L1 induced cases contributing to the evidence that both anti-PD1 and anti-PD-L1 antibodies induce IR-cholangitis. Treatment strategies for IR-cholangitis need to be improved to prevent life-threatening infectious complications.

Background: Staging of liver fibrosis traditionally relied on liver histology; however, transient elastography (TE) and more recently two‐dimensional shear wave elastography (2D‐SWE) evolved to noninvasive alternatives. Hence, we evaluated the diagnostic accuracy of 2D‐SWE assessed by the Canon Aplio i800 ultrasound system using liver biopsy as reference and compared the performance to TE.Methods: In total, 108 adult patients with chronic liver disease undergoing liver biopsy, 2D‐SWE and TE were enrolled prospectively at the University Hospital Zurich. Diagnostic accuracies were evaluated using the area under the receiver operating characteristic (AUROC) analysis, and optimal cut‐off values by Youden's index.Results: Diagnostic accuracy of 2D‐SWE was good for significant (≥F2; AUROC 85.2%, 95% confidence interval (95%CI):76.2–91.2%) as well as severe fibrosis (≥F3; AUROC 86.8%, 95%CI: 78.1–92.4%) and excellent for cirrhosis (AUROC 95.6%, 95%CI: 89.9–98.1%), compared to histology. TE performed equally well (significant fibrosis: 87.5%, 95%CI: 77.7–93.3%; severe fibrosis: 89.7%, 95%CI: 82.0–94.3%; cirrhosis: 96%, 95%CI: 90.4–98.4%), and accuracy was not statistically different to 2D‐SWE. 2D‐SWE optimal cut‐off values were 6.5, 9.8 and 13.1 kPa for significant fibrosis, severe fibrosis and cirrhosis, respectively.Conclusions: Performance of 2D‐SWE was good to excellent and well comparable with TE, supporting the application of this 2D‐SWE system in the diagnostic workup of chronic liver disease.

Introduction: Pathogenic mutations in genes encoding the hepatocanalicular transporters ATP8B1, ABCB11 and ABCB4 are causative for progressive cholestatic liver disease in children. In adults, less severe variants such as the common ABCB4 c.711A>T polymorphism have been associated with intrahepatic cholestasis in pregnancy and elevated liver enzymes. Hence, our aim was to study the role of common polymorphisms in adult patients with chronic unexplained cholestasis. Methods: Screening of outpatients of two university hospitals identified a cohort of 94 patients with chronic cholestasis of unknown origin after thorough exclusion of other causes. Genotyping was performed using TaqMan assays, and frequencies for the ABCB4 rs2109505 (c.711A>T), rs1202283 (c.504T>C), ABCB11 rs2287622 (p.A444V) and rs497692 (c.3084A>G) variants of the study cohort were compared to a cohort of 254 healthy controls. Results: The dominating symptoms of the patients were pruritus and jaundice, though the majority of them did not report symptoms at inclusion. Advanced fibrosis or cirrhosis was present in 11 patients (11.7%) only. Genotyping revealed the presence of the ABCB4 c.711A>T risk variant in 79 patients (84%), a frequency that is significantly (p = 0.037) higher than that in controls (71%). The ABCB11 p.A444V variant was also more frequent in cholestatic patients (p = 0.042). Conclusion: The common ABCB4 c.711A>T and ABCB11 p.A444V polymorphisms are more prevalent in adult patients with idiopathic cholestasis than in healthy controls and may therefore represent risk factors for the development of chronic cholestatic liver disease.

Background & Aims: Little is known about cholestasis, including its most severe variant secondary sclerosing cholangitis (SSC), in critically ill patients with coronavirus disease 19 (COVID‐19). In this study, we analysed the occurrence of cholestatic liver injury and SSC, including clinical, serological, radiological and histopathological findings.Methods: We conducted a retrospective single‐centre analysis of all consecutive patients admitted to the intensive care unit (ICU) as a result of severe COVID‐19 at the University Hospital Zurich to describe cholestatic injury in these patients. The findings were compared to a retrospective cohort of patients with severe influenza A.Results: A total of 34 patients with severe COVID‐19 admitted to the ICU were included. Of these, 14 patients (41%) had no cholestasis (group 0), 11 patients (32%, group 1) developed mild and 9 patients (27%, group 2) severe cholestasis. Patients in group 2 had a more complicated disease course indicated by significantly longer ICU stay (median 51 days, IQR 25‐86.5) than the other groups (group 0: median 9.5 days, IQR 3.8‐18.3, P = .001; and group 1: median 16 days, IQR 8‐30, P < .05 respectively). Four patients in group 2 developed SSC compared to none in the influenza A cohort. The available histopathological findings suggest an ischaemic damage to the perihilar bile ducts.Conclusions: The development of SSC represents an important complication of critically ill COVID‐19 patients and needs to be considered in the diagnostic work up in prolonged cholestasis. The occurrence of SSC is of interest in the ongoing pandemic since it is associated with considerable morbidity and mortality.

Secondary sclerosing cholangitis in critically ill patients (SC-CIP) occurs after long-term intensive care treatment. This study aimed to assess the gut–liver axis in SC-CIP. Stool microbiome composition, gut permeability, bacterial translocation and serum bile acid profiles of 18 SC-CIP patients compared to 11 patients after critical illness without liver disease (CIP controls), 21 patients with cirrhosis and 21 healthy controls were studied. 16S rDNA was isolated from stool and sequenced using the Illumina technique. Diamine oxidase, zonulin, soluble CD14 (sCD14) and lipopolysaccharide binding protein were measured in serum and calprotectin in stool. Serum bile acids were analyzed by high-performance liquid chromatography-mass spectrometry (HPLC-MS). Reduced microbiome alpha diversity and altered beta diversity were seen in SC-CIP, CIP controls and cirrhosis compared to healthy controls. SC-CIP patients showed a shift towards pathogenic taxa and an oralization. SC-CIP, CIP controls and cirrhotic patients presented with impaired gut permeability, and biomarkers of bacterial translocation were increased in SC-CIP and cirrhosis. Total serum bile acids were elevated in SC-CIP and cirrhosis and the bile acid profile was altered in SC-CIP, CIP controls and cirrhosis. In conclusions, observed alterations of the gut–liver axis in SC-CIP cannot solely be attributed to liver disease, but may also be secondary to long-term intensive care treatment.

Background: Poor adherence to medication leads to worsening of the disease, increased mortality and substantial rise in health care costs.Aim: It was our aim to evaluate drug adherence and influencing factors in a cohort of non-selected adult pharmacy customers with various chronic diseases and following long-term treatment.Design and Methods: We conducted an 8 week anonymized survey in 152 German pharmacies using the Morisky Medication Adherence Scale to measure medication adherence and a questionnaire comprising questions on multiple factors with potential impact on adherence. Depression was assessed applying the Patient Health Questionnaire-9.Results: In total, 1192 patients were included showing an overall adherence rate of 59.1%. A positive association to drug adherence was found in univariate analysis for non-smoking status, retirement, less disease related complaints, positive belief in drug effects, comprehensive knowledge about the disease and high quality of care by the physician and pharmacist. Multivariate regression analysis revealed that no or minimal depression (odds ratio (OR) 2.3, 95% confidence interval (CI) 1.7–3.0), higher patient age (>63 years) (OR 2.2, CI 1.7–2.8), high perceived importance of the medication (OR 2.0, CI 1.5–2.6), good tolerability of the medication (OR 2.0, CI 1.2–3.5) and drug effect as expected or better (OR 1.6, CI 1.1–2.3) were positively correlated with adherence.Conclusions: Suboptimal adherence to medication is common in pharmacy customers with chronic diseases. The determined factors influencing adherence may help to identify patients at risk for nonadherence and support the need of improvement in physicians’ communication with patients to achieve adequate adherence rates.

BACKGROUND: Colonic diverticulosis is one of the most common gastroenterological disorders. Although diverticulosis is typically benign, many individuals develop diverticulitis or other aspects of diverticular disease. Diverticulosis is thought to stem from a complex interaction of environmental, dietary, and genetic factors; however, the contributing genetic factors remain unknown.OBJECTIVE: The aim of our present study was to determine the role of genetic variants within genes encoding for collagens of the connective tissue in diverticulosis.DESIGN: This was a transsectional genetic association study.SETTINGS: This study was conducted at three tertiary referral centers in Germany and Lithuania.PATIENTS: Single-nucleotide polymorphisms inCOL3A1(rs3134646,rs1800255) andCOL1A1(rs1800012) were genotyped in 422 patients with diverticulosis and 285 controls of white descent by using TaqMan assays.MAIN OUTCOME MEASURES: The association of colonoscopy-proven diverticulosis with genetic polymorphisms with herniations was assessed in multivariate models.RESULTS: Thers3134646,rs1800255, andrs1800012variants were significantly associated with the risk of developing diverticulosis in the univariate model; however, these associations were not significant in the multivariate logistic regression analysis including additional nongenetic variables. When selectively analyzing sexes, the genotype AA (AA) inrs3134646remained significantly associated with diverticulosis in men (OR, 1.82; 95% CI, 1.04–3.20;p= 0.04).LIMITATIONS: Because a candidate approach was used, additional relevant variants could be missed. Within our cohort of patients with diverticulosis, only a small proportion had diverticular disease and thus, we could not examine the variants in these subgroups. Functional studies, including the analysis of the involved collagens, are also warranted.CONCLUSIONS: Our study shows that a variant ofCOL3A1(rs3134646) is associated with the risk of developing colonic diverticulosis in white men, whereasrs1800255(COL3A1) andrs1800012(COL1A1) were not associated with this condition after adjusting for confounding factors. Our data provide novel valuable insights in the genetic susceptibility to diverticulosis. SeeVideo Abstractat http://links.lww.com/DCR/A504.

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 (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)