Publications by authors named "Michael Trauner"

521 Publications

Prognosis of patients with hepatocellular carcinoma treated with immunotherapy - development and validation of the CRAFITY score.

J Hepatol 2021 Oct 11. Epub 2021 Oct 11.

Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Laboratory, Medical University of Vienna, Vienna, Austria; Christian-Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.

Background: Immunotherapy with atezolizumab plus bevacizumab represents the new standard of care in systemic front-line treatment of hepatocellular carcinoma (HCC). Prognostic biomarkers are an unmet need.

Methods: Patients with HCC put on PD-(L)1-based immunotherapy in 6 European centers (training set; n=190) and in 8 European centers (validation set; n=102) were included. We investigated the prognostic value of baseline variables on overall survival by using a Cox model in the training set and developed the easily applicable CRAFITY (CRP and AFP in ImmunoTherapY) score. The score was validated in the independent, external cohort, and evaluated in a cohort of patients treated with sorafenib (n=204).

Results: Baseline serum alpha-fetoprotein ≥100 ng/ml (HR, 1.7; p=0.007) and C-reactive protein ≥1 mg/dl (HR, 1.7; p=0.007) were identified as independent prognostic factors in multivariable analysis and were used to develop the CRAFITY score. Patients who fulfilled no criterion (0 points; CRAFITY-low) had the longest median overall survival (27.6 (95%CI, 19.5-35.8) months), followed by those fulfilling one criterion (1 point; CRAFITY-intermediate; 11.3 (95%CI, 8.0-14.6) months), and patients meeting both criteria (2 points; CRAFITY-high; 6.4 (95%CI, 4.8-8.1) months; p<0.001). Additionally, best radiological response (complete response/partial response/stable disease/progressive disease) was significantly better in patients with lower CRAFITY score (CRAFITY-low:9%/20%/52%/20% vs. CRAFITY-intermediate:3%/25%/36%/36% vs. CRAFITY-high:2%/15%/22%/61%; p=0.003). These results were confirmed in the independent validation set as well as in different subgroups including Child-Pugh A and B, performance status 0 and ≥1, and first-line and later lines. In the sorafenib cohort, CRAFITY was associated with survival, but not radiological response.

Conclusions: The CRAFITY score is associated with survival and radiological response. The score may help with patient counseling, but requires prospective validation.

Lay Summary: The immunotherapy based regimen of atezolizumab plus bevacizumab represents the new standard of care in systemic first-line therapy of hepatocellular carcinoma (HCC). Biomarkers to predict treatment outcome are an unmet need in patients undergoing immunotherapy for HCC. We developed and externally validated a score that predicts outcome in patients with HCC undergoing immunotherapy with immune checkpoint blockers.
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http://dx.doi.org/10.1016/j.jhep.2021.09.035DOI Listing
October 2021

Novel therapeutic targets for cholestatic and fatty liver disease.

Gut 2021 Oct 6. Epub 2021 Oct 6.

Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.

Cholestatic and non-alcoholic fatty liver disease (NAFLD) share several key pathophysiological mechanisms which can be targeted by novel therapeutic concepts that are currently developed for both areas. Nuclear receptors (NRs) are ligand-activated transcriptional regulators of key metabolic processes including hepatic lipid and glucose metabolism, energy expenditure and bile acid (BA) homoeostasis, as well as inflammation, fibrosis and cellular proliferation. Dysregulation of these processes contributes to the pathogenesis and progression of cholestatic as well as fatty liver disease, placing NRs at the forefront of novel therapeutic approaches. This includes BA and fatty acid activated NRs such as farnesoid-X receptor (FXR) and peroxisome proliferator-activated receptors, respectively, for which high affinity therapeutic ligands targeting specific or multiple isoforms have been developed. Moreover, novel liver-specific ligands for thyroid hormone receptor beta 1 complete the spectrum of currently available NR-targeted drugs. Apart from FXR ligands, BA signalling can be targeted by mimetics of FXR-activated fibroblast growth factor 19, modulation of their enterohepatic circulation through uptake inhibitors in hepatocytes and enterocytes, as well as novel BA derivatives undergoing cholehepatic shunting (instead of enterohepatic circulation). Other therapeutic approaches more directly target inflammation and/or fibrosis as critical events of disease progression. Combination strategies synergistically targeting metabolic disturbances, inflammation and fibrosis may be ultimately necessary for successful treatment of these complex and multifactorial disorders.
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http://dx.doi.org/10.1136/gutjnl-2021-324305DOI Listing
October 2021

Morphometric Analysis of Mast Cells in Tumor Predicts Recurrence of Hepatocellular Carcinoma After Liver Transplantation.

Hepatol Commun 2021 Aug 27. Epub 2021 Aug 27.

Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.

Tumor-infiltrating immune cells are relevant prognostic and immunotherapeutic targets in hepatocellular carcinoma (HCC). Mast cells play a key role in allergic response but may also be involved in anticancer immunity. Digital morphometric analysis of patient tissue sections has become increasingly available for clinical routine and provides unbiased quantitative data. Here, we apply morphometric analysis of mast cells to retrospectively evaluate their relevance for HCC recurrence in patients after orthotopic liver transplantation (OLT). A total of 173 patients underwent OLT for HCC at the Medical University of Vienna (21 women, 152 men; 55.2 ± 7.9 years; 74 beyond Milan criteria, 49 beyond up-to-7 criteria for liver transplantation). Tissue arrays from tumors and corresponding surrounding tissues were immunohistochemically stained for mast cell tryptase. Mast cells were quantified by digital tissue morphometric analysis and correlated with HCC recurrence. Mast cells were detected in 93% of HCC tumors and in all available surrounding liver tissues. Tumor tissues revealed lower mast cell density than corresponding surrounding tissues (P < 0.0001). Patients lacking intratumoral mast cells (iMCs) displayed larger tumors and higher tumor recurrence rates both in the whole cohort (hazard ratio [HR], 2.74; 95% confidence interval [CI], 1.09-6.93; P = 0.029) and in patients beyond transplant criteria (Milan HR, 2.81; 95% CI, 1.04-7.62; P = 0.01; up-to-7 HR, 3.58; 95% CI, 1.17-10.92; P = 0.02). Notably, high iMC identified additional patients at low risk classified outside the Milan and up-to-7 criteria, whereas low iMC identified additional patients at high risk classified within the alpha-fetoprotein French and Metroticket criteria. iMCs independently predicted tumor recurrence in a multivariate Cox regression analysis (Milan HR, 2.38; 95% CI, 1.16-4.91; P = 0.019; up-to-7 HR, 2.21; 95% CI, 1.05-4.62; P = 0.035). Conclusion: Hepatic mast cells might be implicated in antitumor immunity in HCC. Morphometric analysis of iMCs refines prognosis of HCC recurrence after liver transplantation.
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http://dx.doi.org/10.1002/hep4.1770DOI Listing
August 2021

Therapeutic aspects of bile acid signalling in the gut-liver axis.

Aliment Pharmacol Ther 2021 Sep 23. Epub 2021 Sep 23.

Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.

Background: Bile acids are important endocrine modulators of intestinal and hepatic signalling cascades orchestrating critical pathophysiological processes in various liver diseases. Increasing knowledge on bile acid signalling has stimulated the development of synthetic ligands of nuclear bile acid receptors and other bile acid analogues.

Aim: This review summarises important aspects of bile acid-mediated crosstalk between the gut and the liver ("gut-liver axis") as well as recent findings from experimental and clinical studies.

Methods: We performed a literature review on bile acid signalling, and therapeutic applications in chronic liver disease.

Results: Intestinal and hepatic bile acid signalling pathways maintain bile acid homeostasis. Perturbations of bile acid-mediated gut-liver crosstalk dysregulate transcriptional networks involved in inflammation, fibrosis and endothelial dysfunction. Bile acids induce enterohepatic feedback signalling by the release of intestinal hormones, and regulate enterohepatic circulation. Importantly, bile acid signalling plays a central role in maintaining intestinal barrier integrity and antibacterial defense, which is particularly relevant in cirrhosis, where bacterial translocation has a profound impact on disease progression. The nuclear bile acid farnesoid X receptor (FXR) is a central intersection in bile acid signalling and has emerged as a relevant therapeutic target.

Conclusions: Experimental evidence suggests that bile acid signalling improves the intestinal barrier and protects against bacterial translocation in cirrhosis. FXR agonists have displayed efficacy for the treatment of cholestatic and metabolic liver disease in randomised controlled clinical trials. However, similar effects remain to be shown in advanced liver disease, particularly in patients with decompensated cirrhosis.
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http://dx.doi.org/10.1111/apt.16602DOI Listing
September 2021

Impact of restrictions due to COVID-19 on a quality-assured screening colonoscopy program.

Endosc Int Open 2021 Sep 16;9(9):E1315-E1320. Epub 2021 Aug 16.

Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria.

On February 25, 2020, the first patient was diagnosed with COVID-19 in Austria. On March 16, 2020, the Austrian government imposed restrictions and subsequently the Austrian Medical Association recommended minimizing screening examinations in compliance with government restrictions. The aims of this study were to evaluate the impact of this recommendation on the number of colonoscopies performed weekly and detection of non-advanced adenomas, advanced adenomas (AA) and colorectal cancer (CRC) and to calculate how many undetected adenomas could have developed into CRC. We analyzed the number of colonoscopies and pathological findings within a quality assured national colorectal cancer screening program before the COVID-19 pandemic (March 1, 2019 to September 1, 2019, Period 1) and compared those rates to months during which access to colonoscopy was limited (March 1, 2020 and September 1, 2020, Period 2) with a Wilcoxon-rank-test and a chi-square test. A total of 29,199 screening colonoscopies were performed during Period 1 and 24,010 during Period 2. The mean rate of colonoscopies per week during Period 1 was significantly higher than during Period 2 (808,35 [SD = 163,75] versus 594,50 [SD = 282,24],  = 0.005). A total of 4,498 non-advanced adenomas were detected during Period 1 versus 3,562 during Period 2 (  < 0.001). In total 1,317 AAs and 140 CRCs were detected during Period 1 versus 919 AAs and 106 CRCs during Period 2. These rates did not differ significantly (  = 0.2 and  = 0.9). During the COVID-19 crisis, the number of colonoscopies performed per week was significantly lower compared to the year before, but there was no difference in the detection of CRCs and AAs.
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http://dx.doi.org/10.1055/a-1497-1123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8367447PMC
September 2021

COVID-19 pandemic: Impact on the management of patients with hepatocellular carcinoma at a tertiary care hospital.

PLoS One 2021 26;16(8):e0256544. Epub 2021 Aug 26.

Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.

Background: Patients with hepatocellular carcinoma (HCC) represent a vulnerable population potentially negatively affected by COVID-19-associated reallocation of healthcare resources. Here, we report the impact of COVID-19 on the management of HCC patients in a large tertiary care hospital.

Methods: We retrospectively analyzed clinical data of HCC patients who presented at the Vienna General Hospital, between 01/DEC/2019 and 30/JUN/2020. We compared patient care before (period 1) and after (period 2) implementation of COVID-19-associated healthcare restrictions on 16/MAR/2020.

Results: Of 126 patients, majority was male (n = 104, 83%) with a mean age of 66±11 years. Half of patients (n = 57, 45%) had impaired liver function (Child-Pugh stage B/C) and 91 (72%) had intermediate-advanced stage HCC (BCLC B-D). New treatment, was initiated in 68 (54%) patients. Number of new HCC diagnoses did not differ between the two periods (n = 14 vs. 14). While personal visits were reduced, an increase in teleconsultation was observed (period 2). Number of patients with visit delays (n = 31 (30%) vs. n = 10 (10%); p = 0.001) and imaging delays (n = 25 (25%) vs. n = 7 (7%); p = 0.001) was higher in period 2. Accordingly, a reduced number of patients was discussed in interdisciplinary tumor boards (lowest number in April (n = 24), compared to a median number of 57 patients during period 1). Median number of elective/non-elective admissions was not different between the periods. One patient contracted COVID-19 with lethal outcome.

Conclusions: Changes in patient care included reduced personal contacts but increased telephone visits, and delays in diagnostic procedures. The effects on long-term outcome need to be determined.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0256544PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8389415PMC
September 2021

Hepatocyte-specific deletion of adipose triglyceride lipase (ATGL/PNPLA2) ameliorates dietary induced steatohepatitis in mice.

Hepatology 2021 Aug 13. Epub 2021 Aug 13.

Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria.

Background And Aims: Increased FA flux from adipose tissue to the liver contributes to the development of NAFLD. Since free FAs are key lipotoxic triggers accelerating disease progression, inhibiting ATGL/PNPLA2, the main enzyme driving lipolysis, may attenuate steatohepatitis.

Approach And Results: Hepatocyte-specific ATGL knockout (ATGL LKO) mice were challenged with MCD or HFHC diet. Serum biochemistry, hepatic lipid content and liver histology were assessed. Mechanistically, hepatic gene and protein expression of lipid metabolism, inflammation, fibrosis, apoptosis and ER stress markers were investigated. DNA binding activity for PPARα and PPARδ was measured. After sh-RNA mediated ATGL-knockdown, HepG2 cells were treated with LPS or OP21 to explore the direct role of ATGL in inflammation in vitro. Upon MCD and HFHC challenge, ATGL LKO mice showed reduced PPARα and increased PPARδ DNA binding activity when compared to challenged WT mice. Despite histologically and biochemically pronounced hepatic steatosis, dietary challenged ATGL LKO mice showed lower hepatic inflammation, reflected by reduced number of MAC-2 and MPO positive cells and low mRNA expression levels of inflammatory markers (such as IL1β and F4/80) when compared to WT mice. In line, protein levels of ER stress markers PERK and IRE1α were reduced in ATGL LKO MCD fed mice. Accordingly, pretreatment of LPS treated HepG2 cells with the PPARδ agonist GW0742, suppressed mRNA expression of inflammatory markers. Additionally, ATGL-knockdown in HepG2 cells attenuated LPS/OP21-induced expression of pro-inflammatory cytokines and chemokines such as Cxcl5, Ccl2 and Ccl5.

Conclusions: Low hepatic lipolysis and increased PPARδ activity in ATGL/PNPLA2 deficiency may counteract hepatic inflammation and ER stress despite increased steatosis. Therefore, lowering hepatocyte lipolysis via ATGL inhibition represents a promising therapeutic strategy for the treatment of steatohepatitis.
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http://dx.doi.org/10.1002/hep.32112DOI Listing
August 2021

New risk stratification after colorectal polypectomy reduces burden of surveillance without increasing mortality.

United European Gastroenterol J 2021 Oct 3;9(8):947-954. Epub 2021 Aug 3.

Division for Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.

Background: The 2020 postpolypectomy surveillance guideline update of European Society for Gastrointestinal Endoscopy defines a more restrictive group of individuals in need for surveillance 3 years after colonoscopy.

Aim: The aim of this cohort study was to validate the new guideline recommendation.

Methods: Based on a national quality assurance program, we compared the 2020 risk group definition with the previous 2013 recommendations for their strength of association with (1) colorectal cancer death, and (2) all-cause death.

Results: A total of 265,608 screening colonoscopies were included in the study. Mean age was 61.1 years (SD ±9.0), and 50.6% were women. During a mean follow-up of 59.3 months (SD ±35.0), 170 CRC deaths and 7723 deaths of any cause were identified. 62.4% of colonoscopies were negative and 4.9% were assigned to surveillance after 3 years according to the 2020 guidelines versus 10.4% following the 2013 guidelines, which corresponds to a relative reduction in colonoscopies by 47%. The strength of association with CRC mortality was markedly higher with the 2020 surveillance group as compared to the 2013 guidelines (HR 2.56, 95% CI 1.62-4.03 vs. HR 1.73, 95% CI 1.13-2.62), while the magnitude of association with CRC mortality for low risk individuals was lower (HR 1.17, 95% CI 0.83-1.63 vs. 1.25, 95% CI 0.88-1.76).

Conclusions: Adherence to the updated guidelines reduces the burden of surveillance colonoscopies by 47% while preserving the efficacy of surveillance in preventing CRC mortality.
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http://dx.doi.org/10.1002/ueg2.12119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8498405PMC
October 2021

Nuclear receptors in liver fibrosis.

Biochim Biophys Acta Mol Basis Dis 2021 Dec 31;1867(12):166235. Epub 2021 Jul 31.

Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Experimental Hepatic Hemodynamic Lab (HEPEX), Medical University of Vienna, Vienna, Austria; Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. Electronic address:

Nuclear receptors are ligand-activated transcription factors that regulate gene expression of a variety of key molecular signals involved in liver fibrosis. The primary cellular driver of liver fibrogenesis is activated hepatic stellate cells. Different nuclear receptors regulate the hepatic expression of pro-inflammatory and pro-fibrogenic cytokines that promote the transformation of hepatic stellate cells into fibrogenic myofibroblasts. Importantly, nuclear receptors regulate gene expression circuits that promote hepatic fibrogenesis and/or allow liver fibrosis regression. In this review, we highlight the direct and indirect influence of nuclear receptors on liver fibrosis, with a focus on hepatic stellate cells, and discuss potential therapeutic effects of nuclear receptor modulation in regard to anti-fibrotic and anti-inflammatory effects. Further research on nuclear receptors-related signaling may lead to the clinical development of effective anti-fibrotic therapies for patients with liver disease.
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http://dx.doi.org/10.1016/j.bbadis.2021.166235DOI Listing
December 2021

Characterization of endogenous bile acid composition in individuals with cold-activated brown adipose tissue.

Mol Cell Endocrinol 2021 10 28;536:111403. Epub 2021 Jul 28.

Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria. Electronic address:

Introduction: Bile acid signaling has been suggested to promote BAT activity in various experimental models. However, little is known if and how physiologic bile acid metabolism is linked to BAT function in humans. Here we investigated the association between BAT activity and circulating bile acid concentrations in lean and obese individuals.

Methods: BAT F-fluorodeoxyglucose uptake was measured after a standardized cooling protocol by positron emission tomography/computed tomography. Cold-induced thermogenesis was assessed by indirect calorimetry. Fasting bile acid concentrations were determined by high performance liquid chromatography-high-resolution mass spectrometry.

Results: In a cohort of 24 BAT-negative and 20 BAT-positive individuals matched by age, sex, and body mass index, circulating bile acid levels were similar between groups except for higher ursodeoxycholic acid and a trend towards a lower 12α-OH/non-12α-OH bile acid ratio in lean participants with active BAT compared to those without. Moreover, the 12α-OH/non-12α-OH ratio, a marker of CYP8B1 activity, correlated negatively with BAT volume and activity.

Conclusion: Fasting concentrations of major bile acids are not associated with cold-induced BAT activity in humans. However, the inverse association between BAT activity and 12α-OH/non-12α-OH ratio may suggest CYP8B1 as a potential new target in BAT function and warrants additional investigation.
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http://dx.doi.org/10.1016/j.mce.2021.111403DOI Listing
October 2021

Diet and exercise in NAFLD/NASH: Beyond the obvious.

Liver Int 2021 Oct 21;41(10):2249-2268. Epub 2021 Aug 21.

Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.

Lifestyle represents the most relevant factor for non-alcoholic fatty liver disease (NAFLD) as the hepatic manifestation of the metabolic syndrome. Although a tremendous body of clinical and preclinical data on the effectiveness of dietary and lifestyle interventions exist, the complexity of this topic makes firm and evidence-based clinical recommendations for nutrition and exercise in NAFLD difficult. The aim of this review is to guide readers through the labyrinth of recent scientific findings on diet and exercise in NAFLD and non-alcoholic steatohepatitis (NASH), summarizing "obvious" findings in a holistic manner and simultaneously highlighting stimulating aspects of clinical and translational research "beyond the obvious". Specifically, the importance of calorie restriction regardless of dietary composition and evidence from low-carbohydrate diets to target the incidence and severity of NAFLD are discussed. The aspect of ketogenesis-potentially achieved via intermittent calorie restriction-seems to be a central aspect of these diets warranting further investigation. Interactions of diet and exercise with the gut microbiota and the individual genetic background need to be comprehensively understood in order to develop personalized dietary concepts and exercise strategies for patients with NAFLD/NASH.
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http://dx.doi.org/10.1111/liv.15024DOI Listing
October 2021

Role of FXR in Bile Acid and Metabolic Homeostasis in NASH: Pathogenetic Concepts and Therapeutic Opportunities.

Semin Liver Dis 2021 Nov 21;41(4):461-475. Epub 2021 Jul 21.

Department of Internal Medicine III, Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Medical University of Vienna, Austria.

Nonalcoholic fatty liver disease (NAFLD) has become the most prevalent cause of liver disease, increasingly contributing to the burden of liver transplantation. In search for effective treatments, novel strategies addressing metabolic dysregulation, inflammation, and fibrosis are continuously emerging. Disturbed bile acid (BA) homeostasis and microcholestasis via hepatocellular retention of potentially toxic BAs may be an underappreciated factor in the pathogenesis of NAFLD and nonalcoholic steatohepatitis (NASH) as its progressive variant. In addition to their detergent properties, BAs act as signaling molecules regulating cellular homeostasis through interaction with BA receptors such as the Farnesoid X receptor (FXR). Apart from being a key regulator of BA metabolism and enterohepatic circulation, FXR regulates metabolic homeostasis and has immune-modulatory effects, making it an attractive therapeutic target in NAFLD/NASH. In this review, the molecular basis and therapeutic potential of targeting FXR with a specific focus on restoring BA and metabolic homeostasis in NASH is summarized.
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http://dx.doi.org/10.1055/s-0041-1731707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492195PMC
November 2021

Epidemiological trends of HBV and HDV coinfection among Viennese HIV+ patients.

Liver Int 2021 Jul 16. Epub 2021 Jul 16.

Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.

Background And Aims: Despite vaccination recommendations, hepatitis B (HBV) and D (HDV) coinfections are common in HIV+individuals.

Methods: HBV immunization status (anti-HBs) as well as HBV (HBsAg/HBV-DNA) and HDV (anti-HDV) coinfection rates were assessed in 1870 HIV+individuals at HIV diagnosis (baseline, BL) and last follow-up (FU).

Results: Sixty-eight (3.6%) HIV patients were never tested for HBV. At BL, 89/1802 (4.9%) HIV patients were HBV coinfected. Four hundred and fifteen (23.0%) showed virological HBV clearance [HBsAg(-)/anti-HBc(+)/anti-HBs(+)] and 210 (11.7%) presented with anti-HBc(+) only. Seven hundred and ten (39.4%) were HBV naïve [HBsAg(-)/anti-HBs(-)/anti-HBc(-)/HBV-DNA(-)], but only 378 (21.0%) received vaccinations with detectable anti-HBs(+) titres. Among the 89 HBV/HIV-coinfected patients, only 52 (58.4%) were tested for HDV: 11/49 (22.4%) had anti-HDV(+) and 3/12 (25.0%) showed HDV-RNA viraemia. During a median FU of 6.5 (IQR 7.2) years, 44 (4.6%) of the 953 retested BL HBV-negative patients acquired new HBV infection (including 15/304, 4.9% of vaccinated patients). Of the 89 patients, 22 (24.7%) patients cleared their HBsAg, resulting in 60/1625 (3.7%) HIV/HBV individuals at FU: 34 (56.7%) showed HBV-DNA suppression and 15 (25.0%) were HBV viraemic, while 12/89 (13.5%) remained without a FU test. Vaccinations induced anti-HBs(+) in 137 of the retested 649 (21.1%) BL HBV-naïve patients.

Conclusion: HBV testing is well established among Viennese HIV+patients with HBV coinfection rates around 4%-5%. HBV vaccinations are insufficiently implemented since anti-HBs titres were detected in only 21.1% of HBV-naive HIV(+) patients and new HBV infections occurred in previously vaccinated patients. HDV testing is not systematically performed despite up to 25% of HIV/HBV patients may show HDV coinfection.
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http://dx.doi.org/10.1111/liv.15018DOI Listing
July 2021

Decreasing von Willebrand Factor Levels Upon Nonselective Beta Blocker Therapy Indicate a Decreased Risk of Further Decompensation, Acute-on-chronic Liver Failure, and Death.

Clin Gastroenterol Hepatol 2021 Jul 10. Epub 2021 Jul 10.

Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Laboratory, Vienna, Austria; Christian Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria.

Background & Aims: Nonselective beta blockers (NSBBs) exert beneficial effects beyond lowering hepatic venous pressure gradient (HVPG), which may be particularly relevant in patients with decompensated cirrhosis (DC), in whom bacterial translocation and bacterial-induced systemic inflammation drive the development of complications such as acute-on-chronic liver failure (ACLF). We evaluated whether NSBB-related changes in von Willebrand factor (VWF) may serve as a biomarker for these effects.

Methods: In this retrospective analysis, 159 prospectively characterized patients with clinically stable DC (ie, without acute decompensation) who underwent paired HVPG/VWF assessments before/on NSBB therapy were classified as 'VWF responders' (as defined by a ≥5% decrease in VWF) versus 'VWF nonresponders.'

Results: There were no major differences in baseline characteristics between VWF responders (61%) and VWF nonresponders. VWF responders showed more pronounced decreases in inflammation (procalcitonin), whereas rates of HVPG response were similar. In line, NSBB-related changes in VWF correlated with the dynamics of bacterial translocation/inflammation (lipopolysaccharide-binding protein, C-reactive protein, and procalcitonin), rather than those of HVPG. Interestingly, VWF responders also showed less pronounced NSBB-related decreases in mean arterial pressure, suggesting an amelioration of systemic vasodilatation. Finally, VWF response was associated with decreased risks of further decompensation (adjusted hazard ratio [aHR], 0.555; 95% confidence interval [CI], 0.337-0.912; P = .020), ACLF (aHR, 0.302; 95% CI, 0.126-0.721; P = .007), and liver-related death (aHR, 0.332; 95% CI, 0.179-0.616; P < .001) in Cox regression models adjusted for prognostic factors including changes in HVPG.

Conclusions: Decreases in VWF upon NSBB therapy reflect their anti-inflammatory activity, are accompanied by less pronounced adverse effects on systemic hemodynamics, and are independently associated with a decreased risk of further decompensation, ACLF, and death. VWF response may discriminate between decompensated patients who benefit from NSBB treatment and have a favorable prognosis versus patients with poor outcomes.
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http://dx.doi.org/10.1016/j.cgh.2021.07.012DOI Listing
July 2021

24-Norursodeoxycholic acid reshapes immunometabolism in CD8 T cells and alleviates hepatic inflammation.

J Hepatol 2021 Jul 7. Epub 2021 Jul 7.

Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria. Electronic address:

Background & Aims: 24-Norursodeoxycholic acid (NorUDCA) is a novel therapeutic bile acid used to treat immune-mediated cholestatic liver diseases, such as primary sclerosing cholangitis (PSC), where dysregulated T cells including CD8 T cells contribute to hepatobiliary immunopathology. We hypothesized that NorUDCA may directly modulate CD8 T cell function thus contributing to its therapeutic efficacy.

Methods: NorUDCA's immunomodulatory effects were first studied in Mdr2 mice, as a cholestatic model of PSC. To differentiate NorUDCA's immunomodulatory effects on CD8 T cell function from its anticholestatic actions, we also used a non-cholestatic model of hepatic injury induced by an excessive CD8 T cell immune response upon acute non-cytolytic lymphocytic choriomeningitis virus (LCMV) infection. Studies included molecular and biochemical approaches, flow cytometry and metabolic assays in murine CD8 T cells in vitro. Mass spectrometry was used to identify potential CD8 T cell targets modulated by NorUDCA. The signaling effects of NorUDCA observed in murine cells were validated in circulating T cells from patients with PSC.

Results: NorUDCA demonstrated immunomodulatory effects by reducing hepatic innate and adaptive immune cells, including CD8 T cells in the Mdr2 model. In the non-cholestatic model of CD8 T cell-driven immunopathology induced by acute LCMV infection, NorUDCA ameliorated hepatic injury and systemic inflammation. Mechanistically, NorUDCA demonstrated strong immunomodulatory efficacy in CD8 T cells affecting lymphoblastogenesis, expansion, glycolysis and mTORC1 signaling. Mass spectrometry identified that NorUDCA regulates CD8 T cells by targeting mTORC1. NorUDCA's impact on mTORC1 signaling was further confirmed in circulating PSC CD8 T cells.

Conclusions: NorUDCA has a direct modulatory impact on CD8 T cells and attenuates excessive CD8 T cell-driven hepatic immunopathology. These findings are relevant for treatment of immune-mediated liver diseases such as PSC.

Lay Summary: Elucidating the mechanisms by which 24-norursodeoxycholic acid (NorUDCA) works for the treatment of immune-mediated liver diseases, such as primary sclerosing cholangitis, is of considerable clinical interest. Herein, we uncovered an unrecognized property of NorUDCA in the immunometabolic regulation of CD8 T cells, which has therapeutic relevance for immune-mediated liver diseases, including PSC.
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http://dx.doi.org/10.1016/j.jhep.2021.06.036DOI Listing
July 2021

Modern imaging of cholangitis.

Br J Radiol 2021 Sep 20;94(1125):20210417. Epub 2021 Jul 20.

Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.

Cholangitis refers to inflammation of the bile ducts with or without accompanying infection. When intermittent or persistent inflammation lasts 6 months or more, the condition is classified as chronic cholangitis. Otherwise, it is considered an acute cholangitis. Cholangitis can also be classified according to the inciting agent, complete mechanical obstruction, which is the leading cause of acute cholangitis, longstanding partial mechanical blockage, or immune-mediated bile duct damage that results in chronic cholangitis.The work-up for cholangitis is based upon medical history, clinical presentation, and initial laboratory tests. Whereas ultrasound is the first-line imaging modality used to identify bile duct dilatation in patients with colicky abdominal pain, cross-sectional imaging is preferable when symptoms cannot be primarily localised to the hepatobiliary system. CT is very useful in oncologic, trauma, or postoperative patients. Otherwise, magnetic resonance cholangiopancreatography is the method of choice to diagnose acute and chronic biliary disorders, providing an excellent anatomic overview and, if gadoxetic acid is injected, simultaneously delivering morphological and functional information about the hepatobiliary system. If brush cytology, biopsy, assessment of the prepapillary common bile duct, stricture dilatation, or stenting is necessary, then endoscopic ultrasound and/or retrograde cholangiography are performed. Finally, when the pathologic duct is inaccessible from the duodenum or stomach, percutaneous transhepatic cholangiography is an option. The pace of the work-up depends upon the severity of cholestasis on presentation. Whereas sepsis, hypotension, and/or Charcot's triad warrant immediate investigation and management, chronic cholestasis can be electively evaluated.This overview article will cover the common cholangitides, emphasising our clinical experience with the chronic cholestatic liver diseases.
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http://dx.doi.org/10.1259/bjr.20210417DOI Listing
September 2021

COVID-19-Related Downscaling of In-Hospital Liver Care Decreased Patient Satisfaction and Increased Liver-Related Mortality.

Hepatol Commun 2021 10 1;5(10):1660-1675. Epub 2021 Jul 1.

Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.

The coronavirus disease 2019 (COVID-19) pandemic necessitated down-scaling of in-hospital care to prohibit the spread of severe acute respiratory syndrome-coronavirus-2. We (1) assessed patient perceptions on quality of care by telesurvey (cohort 1) and written questionnaire (cohort 2), and (2) analyzed trends in elective and nonelective admissions before (December 2019 to February 2020) and during (March to May 2020) the COVID-19 pandemic in Austria. A total of 279 outpatients were recruited into cohort 1 and 138 patients into cohort 2. All admissions from December 2019 to May 2020 to the Division of Gastroenterology/Hepatology at the Vienna General Hospital were analyzed. A total of 32.6% (n = 91 of 279) of cohort 1 and 72.5% (n = 95 of 131) of cohort 2 had telemedical contact, whereas 59.5% (n = 166 of 279) and 68.2% (n = 90 of 132) had face-to-face visits. A total of 24.1% (n = 32 of 133) needed acute medical help during health care restrictions; however, 57.3% (n = 51 of 89) reported that contacting their physician during COVID-19 was difficult or impossible. Patient-reported satisfaction with treatment decreased significantly during restrictions in cohort 1 (visual analog scale [VAS] 0-10: 9.0 ± 1.6 to 8.6 ± 2.2; P < 0.001) and insignificantly in cohort 2 (VAS 0-10: 8.9 ± 1.6 to 8.7 ± 2.1; P = 0.182). Despite fewer hospital admissions during COVID-19, the proportion of nonelective admissions (+6.3%) and intensive care unit admissions (+6.7%) increased. Patients with cirrhosis with nonelective admissions during COVID-19 had significantly higher Model for End-Stage Liver Disease (MELD) (25.5 [14.2] vs. 17.0 [interquartile range: 8.8]; P = 0.003) and ΔMELD (difference from last MELD: 3.9 ± 6.3 vs. 8.7 ± 6.4; P = 0.008), required immediate intensive care more frequently (26.7% vs. 5.6%; P = 0.034), and had significantly increased 30-day liver-related mortality (30.0% vs. 8.3%; P = 0.028). Conclusion: The COVID-19 pandemic's effects on quality of liver care is evident from decreased patient satisfaction, hospitalization of sicker patients with advanced chronic liver disease, and increased liver-related mortality. Strategies for improved telemedical liver care and preemptive treatment of cirrhosis-related complications are needed to counteract the COVID-19-associated restrictions of in-hospital care.
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http://dx.doi.org/10.1002/hep4.1758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239672PMC
October 2021

Concentration of Gallbladder Phosphatidylcholine in Cholangiopathies: A Phosphorus-31 Magnetic Resonance Spectroscopy Pilot Study.

J Magn Reson Imaging 2021 Jul 5. Epub 2021 Jul 5.

Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.

Background: Biliary phosphatidylcholine (PtdC) concentration plays a role in the pathogenesis of bile duct diseases. In vivo phosphorus-31 magnetic resonance spectroscopy ( P-MRS) at 7 T offers the possibility to assess this concentration noninvasively with high spectral resolution and signal intensity.

Purpose: Comparison of PtdC levels of cholangiopathic patient groups to a control group using a measured T relaxation time of PtdC in healthy subjects.

Study Type: Case control.

Subjects: Two patient groups with primary sclerosing cholangitis (PSC, 2f/3 m; age: 43 ± 7 years) and primary biliary cholangitis (PBC, 4f/2 m; age: 57 ± 6 years), and a healthy control group (CON, 2f/3 m; age: 38 ± 7 years). Ten healthy subjects for the assessment of the T relaxation time of PtdC.

Field Strength/sequence: A 3D phase-encoded pulse-acquire P-MRSI sequence for PtdC quantification and a 1D image-selected in vivo P spectroscopy for T estimation at 7 T, and a T2-weighted half-Fourier single-shot turbo spin echo MRI sequence for volumetry at 3 T.

Assessment: Calculation of gallbladder volumes and PtdC concentration in groups using hepatic gamma-adenosine triphosphate signal as an internal reference and correction for insufficient relaxation of PtdC with a T value assessed in healthy subjects.

Statistical Tests: Group comparison of PtdC content and gallbladder volumes of the PSC/PBC and CON group using Student's t-tests with a significance level of 5%.

Results: PtdC T value of 357 ± 85 msec in the gallbladder. Significant lower PtdC content for the PSC group, and for the female subgroup of the PBC group compared to the CON group (PSC/CON: 5.74 ± 0.73 mM vs. 9.64 ± 0.97 mM, PBC(f)/CON: 5.77 ± 1.44 mM vs. 9.64 ± 0.97 mM). Significant higher gallbladder volumes of the patient groups compared to the CON group (PSC/CON: 66.3 ± 15.8 mL vs. 20.9 ± 2.2 mL, PBC/CON: 49.8 ± 18.2 mL vs. 20.9 ± 2.2 mL).

Data Conclusion: This study demonstrated the application of a P-MRSI protocol for the quantification of PtdC in the human gallbladder at 7 T. Observed differences in PtdC concentration suggest that this metabolite could serve as a biomarker for specific hepatobiliary disorders.

Level Of Evidence: 2 TECHNICAL EFFICACY STAGE: 3.
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http://dx.doi.org/10.1002/jmri.27817DOI Listing
July 2021

On the Mechanisms of Biliary Flux.

Hepatology 2021 Jun 23. Epub 2021 Jun 23.

Leibniz Research Centre for Working Environment and Human Factors, Dortmund, Germany.

Since the late 1950s, transport of bile in the liver has been described by the "osmotic concept," according to which bile flows into the canaliculi toward the ducts, countercurrent to the blood flow in the sinusoids. However, because of the small size of canaliculi, it was so far impossible to observe, let alone to quantify this process. Still, "osmotic canalicular flow" was a sufficient and plausible explanation for the clearance characteristics of a wide variety of choleretic compounds excreted in bile. Imaging techniques have now been established that allow direct flux analysis in bile canaliculi of the intact liver in living organisms. In contrast to the prevailing osmotic concept these analyses strongly suggest that the transport of small molecules in canalicular bile is diffusion dominated, while canalicular flow is negligibly small. In contrast, with the same experimental approach, it could be shown that in the interlobular ducts, diffusion is augmented by flow. Thus, bile canaliculi can be compared to a standing water zone that is connected to a river. The seemingly subtle difference between diffusion and flow is of relevance for therapy of a wide range of liver diseases including cholestasis and NAFLD. Here, we incorporated the latest findings on canalicular solute transport, and align them with extant knowledge to present an integrated and explanatory framework of bile flux that will undoubtedly be refined further in the future.
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http://dx.doi.org/10.1002/hep.32027DOI Listing
June 2021

Safety of direct oral anticoagulants in patients with advanced liver disease.

Liver Int 2021 09 10;41(9):2159-2170. Epub 2021 Jul 10.

Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.

Background & Aims: While direct oral anticoagulants (DOACs) are increasingly used in patients with liver disease, safety data especially in advanced chronic liver disease (ACLD) are limited.

Methods: Liver disease patients receiving DOAC treatment (ACLD: n = 104; vascular liver disease: n = 29) or vitamin K antagonists (VKA)/low-molecular-weight heparin (LMWH; ACLD: n = 45; vascular: n = 13) between January 2010 and September 2020 were retrospectively included. Invasive procedures and bleeding events were recorded. Calibrated anti-Xa peak levels and thrombomodulin-modified thrombin generation assays (TM-TGAs) were measured in a subgroup of 35/28 DOAC patients.

Results: Among patients receiving DOAC, 55 (41.3%) had advanced liver dysfunction (Child-Pugh-stage [CPS] B/C) and 66 (49.6%) had experienced decompensation. Overall, 205 procedures were performed in 60 patients and procedure-related bleedings occurred in 7 (11.7%) patients. Additionally, 38 (28.6%) patients experienced spontaneous (15 minor, 23 major) bleedings during a median follow-up of 10.5 (IQR: 4.0-27.8) months. Spontaneous bleedings in ACLD patients were more common in CPS-B/C (at 12 months: 36.9% vs CPS-A: 15.9%, subdistribution hazard ratio [SHR]: 3.23 [95% CI: 1.59-6.58], P < .001), as were major bleedings (at 12 months: 22.0% vs 5.0%, SHR: 5.82 [95% CI: 2.00-16.90], P < .001). Importantly, CPS (adjusted SHR: 4.12 [91% CI: 1.82-9.37], P < .001), but not the presence of hepatocellular carcinoma or varices, was independently associated with major bleeding during DOAC treatment. Additionally, ACLD patients experiencing bleeding had worse overall survival (at 12 months: 88.9% vs 95.0% without bleeding; P < .001). Edoxaban anti-Xa peak levels were higher in patients with CPS-B/C (345 [95% CI: 169-395] vs CPS-A: 137 [95% CI: 96-248] ng/mL, P = .048) and were associated with lower TM-TGA. Importantly, spontaneous bleeding rates were comparable to VKA/LMWH patients.

Conclusions: Anticoagulants including DOACs should be used with caution in patients with advanced liver disease due to a significant rate of spontaneous bleeding events.
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http://dx.doi.org/10.1111/liv.14992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8456813PMC
September 2021

Recent advances in the understanding and management of hepatorenal syndrome.

Fac Rev 2021 21;10:48. Epub 2021 May 21.

Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.

Renal dysfunction occurs frequently in hospitalized patients with advanced chronic liver disease (ACLD)/cirrhosis and has profound prognostic implications. In ACLD patients with ascites, hepatorenal syndrome (HRS) may result from circulatory dysfunction that leads to reduced kidney perfusion and glomerular filtration rate (in the absence of structural kidney damage). The traditional subclassification of HRS has recently been replaced by acute kidney injury (AKI) type of HRS (HRS-AKI) and non-AKI type of HRS (HRS-NAKI), replacing the terms "HRS type 1" and "HRS type 2", respectively. Importantly, the concept of absolute serum creatinine (sCr) cutoffs for diagnosing HRS was partly abandoned and short term sCr dynamics now may suffice for AKI diagnosis, which facilitates early treatment initiation that may prevent the progression to HRS-AKI or increase the chances of AKI/HRS-AKI reversal. Recent randomized controlled trials have established (a) the efficacy of (long-term) albumin in the prevention of complications of ascites (including HRS-AKI), (b) the benefits of transjugular intrahepatic portosystemic shunt placement in patients with recurrent ascites, and (c) the superiority of terlipressin over noradrenaline for the treatment of HRS-AKI in the context of acute-on-chronic liver failure. This review article aims to summarize recent advances in the understanding and management of HRS.
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http://dx.doi.org/10.12703/r/10-48DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170686PMC
May 2021

Correction: Identification of a novel Wilson disease gene mutation frequent in Upper Austria: a genetic and clinical study.

J Hum Genet 2021 Jun 16. Epub 2021 Jun 16.

Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.

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http://dx.doi.org/10.1038/s10038-021-00918-wDOI Listing
June 2021

Combined effects of PNPLA3, TM6SF2 and HSD17B13 variants on severity of biopsy-proven non-alcoholic fatty liver disease.

Hepatol Int 2021 Aug 2;15(4):922-933. Epub 2021 Jun 2.

Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.

Objective: Several single-nucleotide polymorphisms have been identified to be disadvantageous or protective in regard to disease severity in patients with non-alcoholic fatty liver disease (NAFLD). However, it is unclear, whether including genetic risk factor(s) either alone or combined into risk stratification algorithms for NAFLD actually provides incremental benefit over clinical risk factors.

Design: Patients with biopsy-proven NAFLD were genotyped for the PNPLA3-rs738409(minor allele:G), TM6SF2-rs58542926(minor allele:T) and HSD17B13- rs72613567 (minor allele:TA) variants. The NAFLD activity score (NAS) and fibrosis stage (F0-F4) were used to grade and stage all liver biopsy samples. Patients from seven centers throughout Central Europe were considered for the study.

Results: 703 patients were included: NAS ≥ 5:173(24.6%); Fibrosis: F3-4:81(11.5%). PNPLA3 G/G genotype was associated with a NAS ≥ 5(aOR 2.23, p = 0.007) and advanced fibrosis (aOR-3.48, p < 0.001).TM6SF2 T/- was associated with advanced fibrosis (aOR 1.99, p = 0.023). HSD17B13 TA/- was associated with a lower probability of NAS ≥ 5(TA/T: aOR 0.65, p = 0.041, TA/TA: aOR 0.40, p = 0.033). Regarding the predictive capability for NAS ≥ 5, well-known risk factors (age, sex, BMI, diabetes, and ALT; baseline model) had an AUC of 0.758, Addition of PNPLA3(AUC 0.766), HSB17B13(AUC 0.766), and their combination(AUC 0.775), but not of TM6SF2(AUC 0.762), resulted in a higher diagnostic accuracy of the model. Addition of genetic markers for the prediction of advanced fibrosis (baseline model: age, sex, BMI, diabetes: AUC 0.777) resulted in a higher AUC if PNPLA3(AUC 0.789), and TM6SF2(AUC 0.786) but not if HSD17B13(0.777) were added.

Conclusion: In biopsy-proven NAFLD, PNPLA3 G/-, TM6SF2 T/- and HSD17B13 TA/- carriage are associated with severity of NAFLD. Incorporating these genetic risk factors into risk stratification models might improve their predictive accuracy for severity of NAFLD and/or advanced fibrosis on liver biopsy.
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http://dx.doi.org/10.1007/s12072-021-10200-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8382644PMC
August 2021

Patterns of acute decompensation in hospitalized patients with cirrhosis and course of acute-on-chronic liver failure.

United European Gastroenterol J 2021 May;9(4):427-437

Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria.

Introduction: Recently, based on data from the PREDICT study, the European Foundation for the Study of Chronic Liver Failure (EF-CLIF) consortium proposed pathophysiological/prognostic groups in hospitalized patients with cirrhosis: stable decompensated cirrhosis (SDC), unstable decompensated cirrhosis (UDC), pre-acute-on-chronic liver failure (pre-ACLF), and ACLF. We evaluated the outcomes of these subgroups in a real-life cohort of hospitalized patients with cirrhosis.

Methods: Patients with cirrhosis developing first AD between 09/2010 and 12/2017 at the Vienna General Hospital were evaluated for this retrospective analysis.

Results: Two hundred and ten patients with cirrhosis (aged 57.6 ± 11.8 years) including n = 45 (21.4%) SDC, n = 100 (47.6%) UDC, n = 28 (13.3%) pre-ACLF, and n = 37 (17.6%) with ACLF were considered. The proposed AD subgroups discriminated between patients with favorable (1-year mortality: SDC: 6.7% and UDC: 19.6%) and dismal prognosis (90-day mortality: pre-ACLF: 42.9%). Interestingly, systemic inflammation gradually increased (e.g., C-reactive protein, SDC: 0.9 mg/dl, vs. UDC: 2.0 mg/dl vs. pre-ACLF: 3.2 mg/dl, p < 0.001) while renal function was progressively deteriorating (creatinine levels, SDC: 0.8 mg/dl vs. UDC: 0.9 mg/dl vs. pre-ACLF: 1.2 mg/dl, p < 0.001) across prognostic subgroups in patients with cirrhosis.

Discussion: The recently proposed pathophysiological/prognostic EF-CLIF subgroups are also reproduceable in a real-life cohort of cirrhotic patients. As ACLF is a common and important complication, patients at risk of pre-ACLF at index AD should be evaluated and if disease proceeds, been treated early and aggressively to avoid excessive mortality.
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http://dx.doi.org/10.1002/ueg2.12089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259248PMC
May 2021

The differential activation of cardiovascular hormones across distinct stages of portal hypertension predicts clinical outcomes.

Hepatol Int 2021 Oct 21;15(5):1160-1173. Epub 2021 May 21.

Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.

Background And Aims: The cardiovascular hormones renin/angiotensin/aldosterone (RAA), brain-type natriuretic peptide (BNP)and arginine-vasopressin (AVP) are key regulators of systemic circulatory homeostasis in portal hypertension (PH). We assessed (i) the activation of renin, BNP and AVP across distinct stages of PH and (ii) whether activation of these hormones correlates with clinical outcomes.

Methods: Plasma levels of renin, proBNP and copeptin (AVP biomarker) were determined in 663 patients with advanced chronic liver disease (ACLD) undergoing hepatic venous pressure gradient (HVPG) measurement at the Vienna General Hospital between 11/2011 and 02/2019. We stratified for Child stage (A-C), HVPG (6-9 mmHg, 10-15 mmHg, ≥ 16 mmHg) and compensated vs. decompensated ACLD.

Results: With increasing PH, hyperdynamic state was indicated by higher heart rates (6-9 mmHg: median 71.0 [IQR 18.0] bpm, 10-15 mmHg: 76.0 [19.0] bpm, ≥ 16 mmHg: 80.0 [22.0] bpm; p < 0.001), lower mean arterial pressure (6-9 mmHg: 103.0 [13.5] mmHg, 10-15 mmHg: 101.0 [19.5] mmHg, ≥ 16 mmHg: 99.0 [21.0] mmHg; p = 0.032) and lower serum sodium (6-9 mmHg: 139.0 [3.0] mmol/L, 10-15 mmHg: 138.0 [4.0] mmol/L, ≥ 16 mmHg: 138.0 [5.0] mmol/L; p < 0.001). Across HVPG strata (6-9 mmHg vs. 10-15 mmHg vs ≥ 16 mmHg), median plasma levels of renin (21.0 [50.5] vs. 25.1 [70.9] vs. 65.4 [219.6] µIU/mL; p < 0.001), proBNP (86.1 [134.0] vs. 63.6 [118.0], vs. 132.2 [208.9] pg/mL; p = 0.002) and copeptin (7.8 [7.7] vs. 5.6 [8.0] vs. 10.7 [18.6] pmol/L; p = 0.024) increased with severity of PH. Elevated renin levels independently predicted first hepatic decompensation (adjusted hazard ratio [aHR]: 1.69; 95% confidence interval [95% CI] 1.07-2.68; p = 0.025) and mortality in compensated patients (aHR: 3.15; 95% CI 1.70-5.84; p < 0.001) and the overall cohort aHR: 1.42; 95% CI 1.01-2.01; p = 0.046). Elevated copeptin levels predicted mortality in decompensated patients (aHR: 5.77; 95% CI 1.27-26.33; p = 0.024) and in the overall cohort (aHR: 3.29; 95% CI 1.36-7.95; p = 0.008). ProBNP levels did not predict clinical outcomes.

Conclusions: The cardiovascular hormones renin, proBNP and AVP are activated with progression of ACLD and PH. Renin activation is a risk factor for hepatic decompensation and mortality, especially in compensated patients. Increased plasma copeptin is a risk factor for mortality, in particular in decompensated patients.
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http://dx.doi.org/10.1007/s12072-021-10203-9DOI Listing
October 2021

Intraperitoneal Activation of Coagulation and Fibrinolysis in Patients with Cirrhosis and Ascites.

Thromb Haemost 2021 May 21. Epub 2021 May 21.

Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.

Development of ascites is the most common form of decompensation of cirrhosis. We aimed to investigate the coagulation system in ascitic fluid and plasma of patients with cirrhosis. We determined coagulation parameters and performed clotting and fibrinolysis experiments in ascitic fluid and plasma of thoroughly characterized patients with cirrhosis and ascites ( = 25) and in plasma of patients with cirrhosis but without ascites ( = 25), matched for severity of portal hypertension. We also investigated plasma D-dimer levels in an independent cohort of patients ( = 317) with clinically significant portal hypertension (HVPG ≥ 10 mmHg), grouped according to ascites severity. Ascitic fluid was procoagulant in a clotting assay. The procoagulant potential of ascitic fluid was abolished by depletion of extracellular vesicles from ascitic fluid by filtration or by addition of a tissue factor-neutralizing antibody. Compared with plasma, extracellular vesicle-associated tissue factor activity was high in ascitic fluid, while activities of other coagulation factors were low. The extracellular vesicle-depleted fraction of ascitic fluid induced fibrinolysis, which was prevented by aprotinin, indicating the presence of plasmin in ascitic fluid. Plasma peak thrombin generation and parameters reflecting fibrinolysis were independently associated with the presence of ascites. Finally, plasma D-dimer levels were independently linked to ascites severity in our second cohort comprising 317 patients. In conclusion, coagulation and fibrinolysis become activated in ascites of patients with cirrhosis. While tissue factor-exposing extracellular vesicles in ascitic fluid seem unable to pass the peritoneal membrane, fibrinolytic enzymes get activated in ascitic fluid and may re-enter the systemic circulation and induce systemic fibrinolysis.
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http://dx.doi.org/10.1055/a-1515-9529DOI Listing
May 2021

Diagnostic accuracy of non-invasive tests for advanced fibrosis in patients with NAFLD: an individual patient data meta-analysis.

Gut 2021 May 17. Epub 2021 May 17.

Department of Internal Medicine I, University Medical Centre of the Johannes Gutenberg-University Mainz, Mainz, Rhineland-Palatinate, Germany.

Objective: Liver biopsy is still needed for fibrosis staging in many patients with non-alcoholic fatty liver disease. The aims of this study were to evaluate the individual diagnostic performance of liver stiffness measurement by vibration controlled transient elastography (LSM-VCTE), Fibrosis-4 Index (FIB-4) and NAFLD (non-alcoholic fatty liver disease) Fibrosis Score (NFS) and to derive diagnostic strategies that could reduce the need for liver biopsies.

Design: Individual patient data meta-analysis of studies evaluating LSM-VCTE against liver histology was conducted. FIB-4 and NFS were computed where possible. Sensitivity, specificity and area under the receiver operating curve (AUROC) were calculated. Biomarkers were assessed individually and in sequential combinations.

Results: Data were included from 37 primary studies (n=5735; 45% women; median age: 54 years; median body mass index: 30 kg/m; 33% had type 2 diabetes; 30% had advanced fibrosis). AUROCs of individual LSM-VCTE, FIB-4 and NFS for advanced fibrosis were 0.85, 0.76 and 0.73. Sequential combination of FIB-4 cut-offs (<1.3; ≥2.67) followed by LSM-VCTE cut-offs (<8.0; ≥10.0 kPa) to rule-in or rule-out advanced fibrosis had sensitivity and specificity (95% CI) of 66% (63-68) and 86% (84-87) with 33% needing a biopsy to establish a final diagnosis. FIB-4 cut-offs (<1.3; ≥3.48) followed by LSM cut-offs (<8.0; ≥20.0 kPa) to rule out advanced fibrosis or rule in cirrhosis had a sensitivity of 38% (37-39) and specificity of 90% (89-91) with 19% needing biopsy.

Conclusion: Sequential combinations of markers with a lower cut-off to rule-out advanced fibrosis and a higher cut-off to rule-in cirrhosis can reduce the need for liver biopsies.
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http://dx.doi.org/10.1136/gutjnl-2021-324243DOI Listing
May 2021

The Role of Lipid Sensing Nuclear Receptors (PPARs and LXR) and Metabolic Lipases in Obesity, Diabetes and NAFLD.

Genes (Basel) 2021 04 26;12(5). Epub 2021 Apr 26.

Hans Popper Laboratory of Molecular Hepatology, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, 1090 Wien, Austria.

Obesity and type 2 diabetes mellitus (T2DM) are metabolic disorders characterized by metabolic inflexibility with multiple pathological organ manifestations, including non-alcoholic fatty liver disease (NAFLD). Nuclear receptors are ligand-dependent transcription factors with a multifaceted role in controlling many metabolic activities, such as regulation of genes involved in lipid and glucose metabolism and modulation of inflammatory genes. The activity of nuclear receptors is key in maintaining metabolic flexibility. Their activity depends on the availability of endogenous ligands, like fatty acids or oxysterols, and their derivatives produced by the catabolic action of metabolic lipases, most of which are under the control of nuclear receptors. For example, adipose triglyceride lipase (ATGL) is activated by peroxisome proliferator-activated receptor γ (PPARγ) and conversely releases fatty acids as ligands for PPARα, therefore, demonstrating the interdependency of nuclear receptors and lipases. The diverse biological functions and importance of nuclear receptors in metabolic syndrome and NAFLD has led to substantial effort to target them therapeutically. This review summarizes recent findings on the roles of lipases and selected nuclear receptors, PPARs, and liver X receptor (LXR) in obesity, diabetes, and NAFLD.
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http://dx.doi.org/10.3390/genes12050645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145571PMC
April 2021

Influence of Genetic Variants on Disease Regression and Outcomes in HCV-Related Advanced Chronic Liver Disease after SVR.

J Pers Med 2021 Apr 7;11(4). Epub 2021 Apr 7.

Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, Austria.

Genetic variants including and have been shown to influence progression to advanced chronic liver disease (ACLD) in patients with chronic hepatitis C (CHC). We aimed to investigate their impact on disease regression (i.e., changes in hepatic venous pressure gradient [HVPG] and non-invasive surrogates [liver stiffness measurement (LSM), von Willebrand factor (VWF), and VWF/platelet count ratio (VITRO)]) and clinical outcomes after CHC cure in 346 patients with pre-treatment ACLD. Patients carrying the minor allele had more advanced liver disease prior to antiviral therapy, confirming its impact on liver disease progression. In a subgroup of 88 patients who underwent paired HVPG-measurements and were genotyped for all SNP/indels, genotypes were not associated with changes in HVPG. In line, changes in non-invasive surrogates of portal hypertension (LSM/VWF/VITRO) were comparable between carriers and non-carriers of the -allele in the overall cohort. Finally, carriage of -allele was not associated with the development of hepatic decompensation, de-novo hepatocellular carcinoma, or transplant-free mortality during a median follow-up of 42 months after the end of antiviral treatment. Therefore, genetic variants in do not impact the regression of portal hypertension and clinical outcomes in patients with pre-treatment ACLD after CHC cure.
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http://dx.doi.org/10.3390/jpm11040281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067986PMC
April 2021

Association of Adenoma Detection Rate and Adenoma Characteristics With Colorectal Cancer Mortality After Screening Colonoscopy.

Clin Gastroenterol Hepatol 2021 09 18;19(9):1890-1898. Epub 2021 Apr 18.

Division of Gastroenterology and Hepatology, Department of Internal Medicine ///, Medical University of Vienna, Vienna, Austria; Quality Assurance Working Group, Austrian Society for Gastroenterology and Hepatology, Vienna, Austria. Electronic address:

Background & Aims: The adenoma detection rate (ADR) and characteristics of previously resected adenomas are associated with colorectal cancer (CRC) incidence and mortality. However, the combined effect of both factors on CRC mortality is unknown.

Patients And Methods: Using data of the Austrian quality assurance program for screening colonoscopy, we evaluated the combined effect of ADR and lesion characteristics on subsequent risk for CRC mortality. We analyzed mortality rates for individuals with low-risk adenomas (1-2 adenomas <10 mm), individuals with high-risk adenomas (advanced adenomas or ≥3 adenomas), and after negative colonoscopy (negative colonoscopy or small hyperplastic polyps) performed by endoscopists with an ADR <25% compared with ≥25%. Cox regression was used to determine the association of combined risk groups with CRC mortality, adjusted for age and sex.

Results: We evaluated 259,885 colonoscopies performed by 361 endoscopists. A total of 165 CRC-related deaths occurred during the follow-up period, up to 12.2 years. In all risk groups, CRC mortality was higher when colonoscopy was performed by an endoscopist with an ADR <25%. Compared with negative colonoscopy with an ADR ≥25%, CRC mortality was similar for individuals with low-risk adenomas irrespective of ADR (for ADR ≥25%: adjusted hazard ratio [HR], 1.22; 95% confidence interval [CI], 0.59-2.49; for ADR <25%: adjusted HR, 1.25; 95% CI, 0.64-2.43) and after negative colonoscopy with ADR <25% (adjusted HR, 1.27; 95% CI, 0.81-2.00). Individuals with high-risk adenomas were at significantly higher risk for CRC death if colonoscopy was performed by an endoscopist with an ADR <25% (adjusted HR, 2.25; 95% CI, 1.18-4.31) but not if performed by an endoscopist with an ADR ≥25% (adjusted HR, 1.35; 95% CI, 0.61-3.02).

Conclusions: Our study adds important evidence for mandatory assessment and monitoring of performance quality in screening colonoscopy. High-quality colonoscopy was associated with a lower risk for CRC death, and the impact of ADR was strongest for individuals with high-risk adenomas.
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http://dx.doi.org/10.1016/j.cgh.2021.04.023DOI Listing
September 2021
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