Publications by authors named "Herbert Tilg"

281 Publications

Calprotectin: from biomarker to biological function.

Gut 2021 Jun 18. Epub 2021 Jun 18.

Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University of Innsbruck, Innsbruck, Austria

The incidence of inflammatory bowel diseases (IBD) emerged with Westernisation of dietary habits worldwide. Crohn's disease and ulcerative colitis are chronic debilitating conditions that afflict individuals with substantial morbidity and challenge healthcare systems across the globe. Since identification and characterisation of calprotectin (CP) in the 1980s, faecal CP emerged as significantly validated, non-invasive biomarker that allows evaluation of gut inflammation. Faecal CP discriminates between inflammatory and non-inflammatory diseases of the gut and portraits the disease course of human IBD. Recent studies revealed insights into biological functions of the CP subunits S100A8 and S100A9 during orchestration of an inflammatory response at mucosal surfaces across organ systems. In this review, we summarise longitudinal evidence for the evolution of CP from biomarker to rheostat of mucosal inflammation and suggest an algorithm for the interpretation of faecal CP in daily clinical practice. We propose that mechanistic insights into the biological function of CP in the gut and beyond may facilitate interpretation of current assays and guide patient-tailored medical therapy in IBD, a concept warranting controlled clinical trials.
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http://dx.doi.org/10.1136/gutjnl-2021-324855DOI Listing
June 2021

Discontinuation versus continuation of renin-angiotensin-system inhibitors in COVID-19 (ACEI-COVID): a prospective, parallel group, randomised, controlled, open-label trial.

Lancet Respir Med 2021 Jun 11. Epub 2021 Jun 11.

Department of Internal Medicine I (Cardiology), University Hospital Aachen, Aachen, Germany.

Background: SARS-CoV-2 entry in human cells depends on angiotensin-converting enzyme 2, which can be upregulated by inhibitors of the renin-angiotensin system (RAS). We aimed to test our hypothesis that discontinuation of chronic treatment with ACE-inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) mitigates the course o\f recent-onset COVID-19.

Methods: ACEI-COVID was a parallel group, randomised, controlled, open-label trial done at 35 centres in Austria and Germany. Patients aged 18 years and older were enrolled if they presented with recent symptomatic SARS-CoV-2 infection and were chronically treated with ACEIs or ARBs. Patients were randomly assigned 1:1 to discontinuation or continuation of RAS inhibition for 30 days. Primary outcome was the maximum sequential organ failure assessment (SOFA) score within 30 days, where death was scored with the maximum achievable SOFA score. Secondary endpoints were area under the death-adjusted SOFA score (AUC), mean SOFA score, admission to the intensive care unit, mechanical ventilation, and death. Analyses were done on a modified intention-to-treat basis. This trial is registered with ClinicalTrials.gov, NCT04353596.

Findings: Between April 20, 2020, and Jan 20, 2021, 204 patients (median age 75 years [IQR 66-80], 37% females) were randomly assigned to discontinue (n=104) or continue (n=100) RAS inhibition. Within 30 days, eight (8%) of 104 died in the discontinuation group and 12 (12%) of 100 patients died in the continuation group (p=0·42). There was no significant difference in the primary endpoint between the discontinuation and continuation group (median [IQR] maximum SOFA score 0·00 (0·00-2·00) vs 1·00 (0·00-3·00); p=0·12). Discontinuation was associated with a significantly lower AUC (0·00 [0·00-9·25] vs 3·50 [0·00-23·50]; p=0·040), mean SOFA score (0·00 [0·00-0·31] vs 0·12 [0·00-0·78]; p=0·040), and 30-day SOFA score (0·00 [10-90th percentile, 0·00-1·20] vs 0·00 [0·00-24·00]; p=0·023). At 30 days, 11 (11%) in the discontinuation group and 23 (23%) in the continuation group had signs of organ dysfunction (SOFA score ≥1) or were dead (p=0·017). There were no significant differences for mechanical ventilation (10 (10%) vs 8 (8%), p=0·87) and admission to intensive care unit (20 [19%] vs 18 [18%], p=0·96) between the discontinuation and continuation group.

Interpretation: Discontinuation of RAS-inhibition in COVID-19 had no significant effect on the maximum severity of COVID-19 but may lead to a faster and better recovery. The decision to continue or discontinue should be made on an individual basis, considering the risk profile, the indication for RAS inhibition, and the availability of alternative therapies and outpatient monitoring options.

Funding: Austrian Science Fund and German Center for Cardiovascular Research.
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http://dx.doi.org/10.1016/S2213-2600(21)00214-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195495PMC
June 2021

MRI-Based Iron Phenotyping and Patient Selection for Next-Generation Sequencing of Non-Homeostatic Iron Regulator Hemochromatosis Genes.

Hepatology 2021 May 28. Epub 2021 May 28.

Department of Medicine I and Christian Doppler Laboratory on Iron and Phosphate Biology, Medical University of Innsbruck, Innsbruck, Austria.

Background And Aims: High serum ferritin is frequent among patients with chronic liver disease and commonly associated with hepatic iron overload. Genetic causes of high liver iron include homozygosity for the p.Cys282Tyr variant in homeostatic iron regulator (HFE) and rare variants in non-HFE genes. The aims of the present study were to describe the landscape and frequency of mutations in hemochromatosis genes and determine whether patient selection by noninvasive hepatic iron quantification using MRI improves the diagnostic yield of next-generation sequencing (NGS) in patients with hyperferritinemia.

Approach And Results: A cohort of 410 unselected liver clinic patients with high serum ferritin (defined as ≥200 μg/L for women and ≥300 μg/L for men) was investigated by HFE genotyping and abdominal MRI R2*. Forty-one (10%) patients were homozygous for the p.Cys282Tyr variant in HFE. Of the remaining 369 patients, 256 (69%) had high transferrin saturation (TSAT; ≥45%) and 199 (53%) had confirmed hepatic iron overload (liver R2* ≥70 s ). NGS of hemochromatosis genes was carried out in 180 patients with hepatic iron overload, and likely pathogenic variants were identified in 68 of 180 (38%) patients, mainly in HFE (79%), ceruloplasmin (25%), and transferrin receptor 2 (19%). Low spleen iron (R2* <50 s ), but not TSAT, was significantly associated with the presence of mutations. In 167 patients (93%), no monogenic cause of hepatic iron overload could be identified.

Conclusions: In patients without homozygosity for p.Cys282Tyr, coincident pathogenic variants in HFE and non-HFE genes could explain hyperferritinemia with hepatic iron overload in a subset of patients. Unlike HFE hemochromatosis, this type of polygenic hepatic iron overload presents with variable TSAT. High ferritin in blood is an indicator of the iron storage disease, hemochromatosis. A simple genetic test establishes this diagnosis in the majority of patients affected. MRI of the abdomen can guide further genetic testing.
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http://dx.doi.org/10.1002/hep.31982DOI Listing
May 2021

Non-alcoholic fatty liver disease: a multisystem disease requiring a multidisciplinary and holistic approach.

Lancet Gastroenterol Hepatol 2021 Jul 4;6(7):578-588. Epub 2021 May 4.

Department of Nutrition and Metabolism, Faculty of Medicine, University of Southampton, Southampton, UK; NIHR Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, UK.

Non-alcoholic fatty liver disease (NAFLD) is a public health problem worldwide. This narrative Review provides an overview of the current literature to support the notion that NAFLD is a multisystem disease. Convincing evidence shows a strong association between NAFLD and the risk of developing multiple extrahepatic complications such as type 2 diabetes, cardiovascular disease (ie, the predominant cause of mortality in people with NAFLD), chronic kidney disease, and some types of extrahepatic malignancies. The magnitude of this risk parallels the severity of NAFLD (especially the stage of liver fibrosis). There are probably multiple underlying mechanisms by which NAFLD might increase the risk of cardiovascular disease, type 2 diabetes, and extrahepatic complications. Addressing the growing burden of NAFLD will require setting up a multidisciplinary working group and framework to progress and embrace novel collaborative ways of working to deliver holistic, person-centred care and management of people with NAFLD.
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http://dx.doi.org/10.1016/S2468-1253(21)00020-0DOI Listing
July 2021

Dietary spermidine improves cognitive function.

Cell Rep 2021 Apr;35(2):108985

Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, 6020 Innsbruck, Austria.

Decreased cognitive performance is a hallmark of brain aging, but the underlying mechanisms and potential therapeutic avenues remain poorly understood. Recent studies have revealed health-protective and lifespan-extending effects of dietary spermidine, a natural autophagy-promoting polyamine. Here, we show that dietary spermidine passes the blood-brain barrier in mice and increases hippocampal eIF5A hypusination and mitochondrial function. Spermidine feeding in aged mice affects behavior in homecage environment tasks, improves spatial learning, and increases hippocampal respiratory competence. In a Drosophila aging model, spermidine boosts mitochondrial respiratory capacity, an effect that requires the autophagy regulator Atg7 and the mitophagy mediators Parkin and Pink1. Neuron-specific Pink1 knockdown abolishes spermidine-induced improvement of olfactory associative learning. This suggests that the maintenance of mitochondrial and autophagic function is essential for enhanced cognition by spermidine feeding. Finally, we show large-scale prospective data linking higher dietary spermidine intake with a reduced risk for cognitive impairment in humans.
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http://dx.doi.org/10.1016/j.celrep.2021.108985DOI Listing
April 2021

Validation of the "Inflammatory Bowel Disease - Distribution, Chronicity, Activity (IBD-DCA) Score" for Ulcerative Colitis and Crohn´s disease.

J Crohns Colitis 2021 Mar 27. Epub 2021 Mar 27.

Institute of Pathology, Klinikum Bayreuth GmbH, Bayreuth, Germany.

Background And Aims: Histological scoring plays a key role in the assessment of disease activity in ulcerative colitis (UC) and is also important in Crohn´s disease (CD). Currently, there is no common scoring available for UC and CD. We aimed to validate the Inflammatory Bowel Disease (IBD) - Distribution (D), Chronicity (C), Activity (A) score (IBD-DCA score) for histological disease activity assessment in IBD.

Methods: Inter- and intra-rater reliability were assessed by 16 observers on biopsy specimen from 59 patients with UC and 25 patients with CD. Construct validity and responsiveness to treatment were retrospectively evaluated on a second cohort of 30 patients.

Results: Inter-rater reliability was moderate to good for the UC cohort (intraclass correlation coefficients (ICCs) = 0.645, 0.623, 0.767 for D, C and A, respectively) and at best moderate for the CD cohort (ICC = 0.690, 0.303, 0.733 for D, C and A, respectively). Intra-rater agreement ranged from good to excellent in both cohorts. Correlation with the Nancy Histological Index (NHI) was moderate and strong with the Simplified Geboes Score (SGS) and a Visual Analog Scale (VAS). Large effect sizes (ES) were obtained for all three parameters. External responsiveness analysis revealed correlated changes between IBD-DCA score and NHI, SGS and VAS.

Conclusions: The IBD-DCA score is a simple histological activity score for UC and CD, agreed and validated by a large group of IBD specialists. It provides reliable information on treatment response. Therefore, it has potential value for use in routine diagnostics as well as clinical studies.
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http://dx.doi.org/10.1093/ecco-jcc/jjab055DOI Listing
March 2021

Auto-aggressive CXCR6 CD8 T cells cause liver immune pathology in NASH.

Nature 2021 Apr 24;592(7854):444-449. Epub 2021 Mar 24.

Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University Innsbruck, Innsbruck, Austria.

Nonalcoholic steatohepatitis (NASH) is a manifestation of systemic metabolic disease related to obesity, and causes liver disease and cancer. The accumulation of metabolites leads to cell stress and inflammation in the liver, but mechanistic understandings of liver damage in NASH are incomplete. Here, using a preclinical mouse model that displays key features of human NASH (hereafter, NASH mice), we found an indispensable role for T cells in liver immunopathology. We detected the hepatic accumulation of CD8 T cells with phenotypes that combined tissue residency (CXCR6) with effector (granzyme) and exhaustion (PD1) characteristics. Liver CXCR6 CD8 T cells were characterized by low activity of the FOXO1 transcription factor, and were abundant in NASH mice and in patients with NASH. Mechanistically, IL-15 induced FOXO1 downregulation and CXCR6 upregulation, which together rendered liver-resident CXCR6 CD8 T cells susceptible to metabolic stimuli (including acetate and extracellular ATP) and collectively triggered auto-aggression. CXCR6 CD8 T cells from the livers of NASH mice or of patients with NASH had similar transcriptional signatures, and showed auto-aggressive killing of cells in an MHC-class-I-independent fashion after signalling through P2X7 purinergic receptors. This killing by auto-aggressive CD8 T cells fundamentally differed from that by antigen-specific cells, which mechanistically distinguishes auto-aggressive and protective T cell immunity.
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http://dx.doi.org/10.1038/s41586-021-03233-8DOI Listing
April 2021

Modulation of Liver Inflammation and Fibrosis by Interleukin-37.

Front Immunol 2021 4;12:603649. Epub 2021 Mar 4.

Department of Pediatric Gastroenterology, Nephrology and Metabolic Diseases, Charité Universitätsmedizin Berlin, Berlin, Germany.

Chronic inflammation induces liver fibrosis, cirrhosis and potentially liver cancer. Kupffer cells modulate hepatic stellate cells by secreting immunologically active proteins as TGF-β. TGF-β promotes liver fibrosis the activation of Sma- and Mad-related protein 3. IL-37 broadly suppresses innate and adaptive immune responses. Intracellular IL-37 interacts with Smad3. We hypothesize that IL-37 downregulates the activation of hepatic Kupffer and stellate cells and interferes with the TGF-β signaling cascade to modulate liver fibrogenesis. The role of IL-37 on liver inflammation and fibrogenesis was assessed in three mouse models as well as isolated Kupffer- and stellate cells. Serum IL-37 was tested by ELISA in a clinical cohort and correlated with liver disease severity. Transgene expression of IL-37 in mice extends survival, reduces hepatic damage, expression of early markers of fibrosis and histologically assessed liver fibrosis after bile duct ligation. IL-37tg mice were protected against CCl-induced liver inflammation. Colitis-associated liver inflammation and fibrosis was less severe in IL-10 knockout IL-37tg mice. Spontaneous and LPS/TGF-β-induced cytokine release and profibrogenic gene expression was lower in HSC and KC isolated from IL-37tg mice and IL-37 overexpressing, IL-1β stimulated human LX-2 stellate cells. However, administration of recombinant human IL-37 did not modulate fibrosis pathways after BDL in mice, LX2 cells or murine HSCs. In a large clinical cohort, we observed a positive correlation of serum IL-37 levels with disease severity in liver cirrhosis. Predominantly intracellular IL-37 downregulates liver inflammation and fibrosis. The correlation of serum IL-37 with disease severity in cirrhosis suggests its potential as a novel target modulating the course of liver fibrosis.
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http://dx.doi.org/10.3389/fimmu.2021.603649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970756PMC
June 2021

Non-alcoholic fatty liver disease and increased risk of incident extrahepatic cancers: a meta-analysis of observational cohort studies.

Gut 2021 Mar 8. Epub 2021 Mar 8.

Endocrinology and Metabolism, Department of Medicine, University of Verona, Verona, Italy

Objective: We performed a meta-analysis of observational studies to quantify the magnitude of the association between non-alcoholic fatty liver disease (NAFLD) and risk of extrahepatic cancers.

Design: We systematically searched PubMed, Scopus and Web of Science databases from the inception date to 30 December 2020 using predefined keywords to identify observational cohort studies conducted in individuals, in which NAFLD was diagnosed by imaging techniques or International Classification of Diseases codes. No studies with biopsy-proven NAFLD were available for the analysis. Meta-analysis was performed using random-effects modelling.

Results: We included 10 cohort studies with 182 202 middle-aged individuals (24.8% with NAFLD) and 8485 incident cases of extrahepatic cancers at different sites over a median follow-up of 5.8 years. NAFLD was significantly associated with a nearly 1.5-fold to twofold increased risk of developing GI cancers (oesophagus, stomach, pancreas or colorectal cancers). Furthermore, NAFLD was associated with an approximately 1.2-fold to 1.5-fold increased risk of developing lung, breast, gynaecological or urinary system cancers. All risks were independent of age, sex, smoking, obesity, diabetes or other potential confounders. The overall heterogeneity for most of the primary pooled analyses was relatively low. Sensitivity analyses did not alter these findings. Funnel plots did not reveal any significant publication bias.

Conclusion: This large meta-analysis suggests that NAFLD is associated with a moderately increased long-term risk of developing extrahepatic cancers over a median of nearly 6 years (especially GI cancers, breast cancer and gynaecological cancers). Further research is required to decipher the complex link between NAFLD and cancer development.
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http://dx.doi.org/10.1136/gutjnl-2021-324191DOI Listing
March 2021

Induction and Long-term Follow-up With ABX464 for Moderate-to-severe Ulcerative Colitis: Results of Phase IIa Trial.

Gastroenterology 2021 Jun 2;160(7):2595-2598.e3. Epub 2021 Mar 2.

Department of Pathology, University Hospitals Leuven, Leuven, Belgium; Abivax, Paris, France.

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http://dx.doi.org/10.1053/j.gastro.2021.02.054DOI Listing
June 2021

Apolipoprotein A5 controls fructose-induced metabolic dysregulation in mice.

Nutr Metab Cardiovasc Dis 2021 03 17;31(3):972-978. Epub 2020 Nov 17.

Department of Medicine I, Medical University of Innsbruck, Innsbruck, Austria; Christan Doppler Laboratory for Metabolic Crosstalk, Department of Medicine I, Medical University of Innsbruck, Innsbruck, Austria. Electronic address:

Background And Aims: Western dietary habits are partially characterized by increased uptake of fructose, which contributes to metabolic dysregulation and associated liver diseases. For example, a diet enriched with fructose drives insulin resistance and non-alcoholic fatty liver disease (NAFLD). The molecular hubs that control fructose-induced metabolic dysregulation are poorly understood. Apolipoprotein A5 (apoA5) controls triglyceride metabolism with a putative role in hepatic lipid deposition. We explored apoA5 as a rheostat for fructose-induced hepatic and metabolic disease in mammals.

Methods And Results: ApoA5 knock out (-/-) and wildtype (wt) mice were fed with high fructose diet or standard diet for 10 weeks. Afterwards, we conducted a metabolic characterization by insulin tolerance test as well as oral glucose tolerance test. Additionally, hepatic lipid content as well as transcription patterns of key enzymes and transcription factors in glucose and lipid metabolism were evaluated. Despite comparable body weight, insulin sensitivity was significantly improved in high fructose diet fed apoA5 (-/-) when compared to wildtype mice on the same diet. In parallel, hepatic triglyceride content was significantly lower in apoA5 (-/-) mice than in wt mice. No difference was seen between apoA5 (-/-) and wt mice on a standard diet.

Conclusion: ApoA5 is involved in fructose-induced metabolic dysregulation and associated hepatic steatosis suggesting that apoA5 may be a novel target to treat metabolic diseases.
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http://dx.doi.org/10.1016/j.numecd.2020.11.008DOI Listing
March 2021

Increased Fecal Neopterin Parallels Gastrointestinal Symptoms in COVID-19.

Clin Transl Gastroenterol 2021 01 12;12(1):e00293. Epub 2021 Jan 12.

Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University of Innsbruck, Innsbruck, Austria.

Introduction: Coronavirus disease (COVID-19) has spread from Wuhan, China, and become a worldwide pandemic. Most patients display respiratory symptoms but up to 50% report gastrointestinal symptoms. Neopterin is a surrogate marker for viral inflammation, and its production by macrophages is driven by interferon-γ.

Methods: We measured fecal neopterin in 37 hospitalized COVID-19 patients not requiring intensive care measures and 22 healthy controls.

Results: Fecal neopterin was elevated in stool samples from COVID-19 patients compared with that in samples from healthy controls. Especially, patients reporting gastrointestinal symptoms exhibited increased fecal neopterin values.

Discussion: COVID-19 is associated with an inflammatory immune response in the gastrointestinal tract.
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http://dx.doi.org/10.14309/ctg.0000000000000293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806232PMC
January 2021

Multiple cerebral lesions in a patient with refractory celiac disease: A case report.

World J Gastroenterol 2020 Dec;26(47):7584-7592

Department of Neurology, Medical University Innsbruck, Innsbruck 6020, Austria.

Background: Enteropathy-associated T cell lymphoma (EATL) is an aggressive intestinal T cell lymphoma derived from intraepithelial lymphocytes, which occurs in individuals with celiac disease (CD). Cerebral involvement is an extremely rare condition and as described so far, lymphoma lesions may present as parenchymal predo-minantly supratentorial or leptomeningeal involvement. We describe a case of EATL with multifocal supra- and infratentorial brain involvement in a patient with refractory celiac disease (RCD).

Case Summary: A 58-years old man with known CD developed ulcerative jejunitis and was diagnosed with RCD type II. Six months later he presented with subacute cerebellar symptoms (gait ataxia, double vision, dizziness). Cranial magnetic resonance imaging (MRI) revealed multifocal T2 hyperintense supra- and infratentorial lesions. Laboratory studies of blood and cerebrospinal fluid were inconspicuous for infectious, inflammatory or autoimmune diseases. F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) scan showed a suspect hypermetabolic lesion in the left upper abdomen and consequent surgical jejunal resection revealed the diagnosis of EATL. During the diagnostic work-up, neurological symptoms aggravated and evolved refractory to high-dosage cortisone. Recurrent MRI scans showed progressive cerebral lesions, highly suspicious for lymphoma and methotrexate chemotherapy was initiated. Unfortunately, clinically the patient responded only transiently. Finally, cerebral biopsy confirmed the diagnosis of cerebral involvement of EATL. Considering the poor prognosis and deterioration of the performance status, best supportive care was started. The patient passed away three weeks after diagnosis.

Conclusion: EATL with cerebral involvement must be considered as a possible differential diagnosis in patients with known RCD presenting with neurological symptoms.
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http://dx.doi.org/10.3748/wjg.v26.i47.7584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754549PMC
December 2020

The role of gut vascular barrier in experimental alcoholic liver disease and A. muciniphila supplementation.

Gut Microbes 2020 11;12(1):1851986

Department of Internal Medicine I, Gastroenterology, Hepatology and Endocrinology, Medical University Innsbruck , Innsbruck, Austria.

The translocation of bacterial components from the intestinal lumen into the portal circulation is crucial in the pathogenesis of alcoholic liver disease (ALD). Recently the important role of the gut vascular barrier (GVB) was elucidated in alcoholic liver disease. Here we report about the influence of supplementation in experimental ALD on the GVB. Ethanol feeding was associated with increased Pv-1, indicating altered endothelial barrier function, whereas administration tended to restore GVB. To further investigate GVB in experimental ALD, β-catenin gain-of-function mice, which display an enhanced GVB, were ethanol-fed. β-catenin gain-of-function mice were not protected from ethanol-induced liver injury, suggest an alternative mechanism of ethanol-induced GVB disruption. The description of the GVB in ALD could pave the way for new therapeutic options in the future.
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http://dx.doi.org/10.1080/19490976.2020.1851986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714498PMC
November 2020

Gut microbiome, liver immunology, and liver diseases.

Cell Mol Immunol 2021 01 14;18(1):4-17. Epub 2020 Dec 14.

Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria.

The gut microbiota is a complex and plastic consortium of microorganisms that are intricately connected with human physiology. The liver is a central immunological organ that is particularly enriched in innate immune cells and constantly exposed to circulating nutrients and endotoxins derived from the gut microbiota. The delicate interaction between the gut and liver prevents accidental immune activation against otherwise harmless antigens. Work on the interplay between the gut microbiota and liver has assisted in understanding the pathophysiology of various liver diseases. Of immense importance is the step from high-throughput sequencing (correlation) to mechanistic studies (causality) and therapeutic intervention. Here, we review the gut microbiota, liver immunology, and the interaction between the gut and liver. In addition, the impairment in the gut-liver axis found in various liver diseases is reviewed here, with an emphasis on alcohol-associated liver disease (ALD), nonalcoholic fatty liver disease (NAFLD), and autoimmune liver disease (AILD). On the basis of growing evidence from these preclinical studies, we propose that the gut-liver axis paves the way for targeted therapeutic modalities for liver diseases.
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http://dx.doi.org/10.1038/s41423-020-00592-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852541PMC
January 2021

Neurodegeneration in Hepatic and Neurologic Wilson's Disease.

Hepatology 2020 Dec 14. Epub 2020 Dec 14.

Department of Neurology, Medical University and University Hospital of Innsbruck, Innsbruck, Austria.

Clinical presentation of Wilson disease (WD) includes hepatic and neurologic manifestations. This study compares subcortical brain regions by magnetic resonance imaging in patients with WD and without neurological symptoms. Distinct atrophy affecting the basal ganglia, accumbens, and hippocampus was present in neurological WD. Cerebellar atrophy was observed in hepatic WD without neurological symptoms.
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http://dx.doi.org/10.1002/hep.31681DOI Listing
December 2020

Non-alcoholic fatty liver disease and risk of incident chronic kidney disease: an updated meta-analysis.

Gut 2020 Dec 10. Epub 2020 Dec 10.

Endocrinology and Metabolism, University of Verona Department of Medicine, Verona, Veneto, Italy

Objective: Studies reported a significant association between non-alcoholic fatty liver disease (NAFLD) and increased risk of chronic kidney disease (CKD). However, whether this risk changes with increasing severity of NAFLD remains uncertain. We performed a meta-analysis of observational studies to quantify the magnitude of the association between NAFLD and risk of incident CKD.

Design: We systematically searched PubMed, Web of Science and Scopus from January 2000 to August 2020 using predefined keywords to identify observational studies with a follow-up duration of ≥1 year, in which NAFLD was diagnosed by blood biomarkers/scores, International Classification of Diseases codes, imaging techniques or biopsy. Data from selected studies were extracted, and meta-analysis was performed using random-effects modelling.

Results: 13 studies with 1 222 032 individuals (28.1% with NAFLD) and 33 840 cases of incident CKD stage ≥3 (defined as estimated glomerular filtration rate <60 mL/min/1.73 m, with or without accompanying overt proteinuria) over a median follow-up of 9.7 years were included. NAFLD was associated with a moderately increased risk of incident CKD (n=10 studies; random-effects HR 1.43, 95% CI 1.33 to 1.54; =60.7%). All risks were independent of age, sex, obesity, hypertension, diabetes and other conventional CKD risk factors. Sensitivity analyses did not alter these findings. Funnel plot did not reveal any significant publication bias.

Conclusion: This large and updated meta-analysis indicates that NAFLD is significantly associated with a~1.45-fold increased long-term risk of incident CKD stage ≥3. Further studies are needed to examine the association between the severity of NAFLD and risk of incident CKD.
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http://dx.doi.org/10.1136/gutjnl-2020-323082DOI Listing
December 2020

Live Confocal Imaging as a Novel Tool to Assess Liver Quality: Insights From a Murine Model.

Transplantation 2020 12;104(12):2528-2537

Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria.

Background: In an experimental murine liver clamping model, we aimed to investigate the efficacy of real-time confocal microscopy (RCM) in assessing viability of steatotic livers in comparison to standard assessment tools, including histopathological evaluation.

Methods: C57Bl/6 mice were subjected to a methionine-choline-deficient diet causing nonalcoholic fatty liver disease or to Lieber DeCarli diet causing ethanol-induced liver injury. Untreated animals served as controls. Liver biopsies were analyzed following challenge with 45 min of warm ischemia time and either 4 h of reperfusion or 24 h of cold storage. Organ quality assessment was performed at defined time points by RCM, histological staining, measurement of serum alanine aminotransferase activity, and expression analyses of proinflammatory cytokines. Additionally, survival analysis was performed.

Results: Cold as well as warm ischemia time resulted in a significant decrease in cell viability when compared with naive livers as well as nonischemic-challenged steatotic livers (P < 0.05) as assessed by RCM. Furthermore, RCM revealed the actual cellular damage at early time points, while established methods including H&E-staining and serum transaminase profile failed.

Conclusions: In a translational attempt, we demonstrate that RCM is a suitable diagnostic tool to obtain information about functional damage of the liver apart from standard approaches.
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http://dx.doi.org/10.1097/TP.0000000000003405DOI Listing
December 2020

Hypophosphataemia after treatment of iron deficiency with intravenous ferric carboxymaltose or iron isomaltoside-a systematic review and meta-analysis.

Br J Clin Pharmacol 2021 May 7;87(5):2256-2273. Epub 2020 Dec 7.

Department of Medicine I, Gastroenterology, Hepatology and Endocrinology, Medical University of Innsbruck, Innsbruck, Austria.

Aims: Hypophosphataemia is an increasingly recognized side-effect of ferric carboxymaltose (FCM) and possibly iron isomaltoside/ferric derisomaltose (IIM), which are used to treat iron deficiency. The aim of this study was to determine frequency, severity, duration and risk factors of incident hypophosphataemia after treatment with FCM and IIM.

Methods: A systematic literature search for articles indexed in EMBASE, PubMed and Web of Science in years 2005-2020 was carried out using the search terms 'ferric carboxymaltose' OR 'iron isomaltoside'. Prospective clinical trials reporting outcomes on hypophosphataemia rate, mean nadir serum phosphate and/or change in mean serum phosphate from baseline were selected. Hypophosphataemia rate and severity were compared for studies on IIM vs. FCM after stratification for chronic kidney disease. Meta-regression analysis was used to investigate risk factors for hypophosphataemia.

Results: Across the 42 clinical trials included in the meta-analysis, FCM induced a significantly higher incidence of hypophosphataemia than IIM (47%, 95% CI 36-58% vs. 4%, 95% CI 2-5%), and significantly greater mean decreases in serum phosphate (0.40 vs. 0.06 mmol/L). Hypophosphataemia persisted at the end of the study periods (maximum 3 months) in up to 45% of patients treated with FCM. Meta-regression analysis identified low baseline serum ferritin and transferrin saturation, and normal kidney function as significant predictors of hypophosphataemia.

Conclusion: FCM is associated with a high risk of hypophosphataemia, which does not resolve for at least 3 months in a large proportion of affected patients. More severe iron deficiency and normal kidney function are risk factors for hypophosphataemia.
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http://dx.doi.org/10.1111/bcp.14643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247006PMC
May 2021

Cardioprotective effects of short-term empagliflozin treatment in db/db mice.

Sci Rep 2020 11 12;10(1):19686. Epub 2020 Nov 12.

Department of Internal Medicine I, Christian Doppler Laboratory for Metabolic Crosstalk, Medical University Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria.

Sodium glucose transporter (SGLT)-2 inhibitors have consistently shown cardioprotective effects independent of the glycemic status of treated patients. In this study we aimed to investigate underlying mechanisms of short-term empagliflozin treatment in a mouse model of type II diabetes. Male db/db mice were fed a western type diet with or without enrichment with empagliflozin for 7 days. While glucose tolerance was significantly improved in empagliflozin treated mice, body weight and fasting insulin levels were comparable in both groups. Cardiac insulin signaling activity indicated by reduced proteinkinase B (AKT) phosphorylation was significantly decreased in the empagliflozin treated group. Remarkably, mitochondrial mass estimated by citrate synthase activity was significantly elevated in empagliflozin treated mice. Accordingly, mitochondrial morphology was significantly altered upon treatment with empagliflozin as analysed by transmission electron microscopy. Additionally, short-term empagliflozin therapy was associated with a changed cardiac tissue cytokine expression in favor of an anti-inflammatory pattern. Our data suggest that early cardioprotection in empagliflozin treated mice is independent of a reduction in body weight or hyperinsulinemia. Ameliorated mitochondrial ultrastructure, attenuated cardiac insulin signaling and diminished cardiac inflammation might contribute to the cardioprotective effects of empagliflozin.
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http://dx.doi.org/10.1038/s41598-020-76698-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665199PMC
November 2020

Commentary: Nonalcoholic or metabolic dysfunction-associated fatty liver disease? The epidemic of the 21st century in search of the most appropriate name.

Metabolism 2020 12 22;113:154413. Epub 2020 Oct 22.

Section of Endocrinology, Boston VA Healthcare System, Harvard Medical School, Boston, MA, USA; Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. Electronic address:

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http://dx.doi.org/10.1016/j.metabol.2020.154413DOI Listing
December 2020

A standardised model for stool banking for faecal microbiota transplantation: a consensus report from a multidisciplinary UEG working group.

United European Gastroenterol J 2021 Mar 9;9(2):229-247. Epub 2021 Mar 9.

Department of Internal Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands.

Background: Faecal microbiota transplantation is an emerging therapeutic option, particularly for the treatment of recurrent Clostridioides difficile infection. Stool banks that organise recruitment and screening of faeces donors are being embedded within the regulatory frameworks described in the European Union Tissue and Cells Directive and the technical guide to the quality and safety of tissue and cells for human application, published by the European Council.

Objective: Several European and international consensus statements concerning faecal microbiota transplantation have been issued. While these documents provide overall guidance, we aim to provide a detailed description of all processes that relate to the collection, handling and clinical application of human donor stool in this document.

Methods: Collaborative subgroups of experts on stool banking drafted concepts for all domains pertaining to stool banking. During a working group meeting in the United European Gastroenterology Week 2019 in Barcelona, these concepts were discussed and finalised to be included in our overall guidance document about faecal microbiota transplantation.

Results: A guidance document for all domains pertaining to stool banking was created. This document includes standard operating manuals for several processes involved with stool banking, such as handling of donor material, storage and donor screening.

Conclusion: The implementation of faecal microbiota transplantation by stool banks in concordance with our guidance document will enable quality assurance and guarantee the availability of donor faeces preparations for patients.
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http://dx.doi.org/10.1177/2050640620967898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259288PMC
March 2021

Metabolic recovery after weight loss surgery is reflected in serum microRNAs.

BMJ Open Diabetes Res Care 2020 10;8(2)

King's British Heart Foundation Centre, School of Cardiovascular Medicine and Sciences, King's College London, London, UK

Introduction: Bariatric surgery offers the most effective treatment for obesity, ameliorating or even reverting associated metabolic disorders, such as type 2 diabetes. We sought to determine the effects of bariatric surgery on circulating microRNAs (miRNAs) that have been implicated in the metabolic cross talk between the liver and adipose tissue.

Research Design And Methods: We measured 30 miRNAs in 155 morbidly obese patients and 47 controls and defined associations between miRNAs and metabolic parameters. Patients were followed up for 12 months after bariatric surgery. Key findings were replicated in a separate cohort of bariatric surgery patients with up to 18 months of follow-up.

Results: Higher circulating levels of liver-related miRNAs, such as miR-122, miR-885-5 p or miR-192 were observed in morbidly obese patients. The levels of these miRNAs were positively correlated with body mass index, percentage fat mass, blood glucose levels and liver transaminases. Elevated levels of circulating liver-derived miRNAs were reversed to levels of non-obese controls within 3 months after bariatric surgery. In contrast, putative adipose tissue-derived miRNAs remained unchanged (miR-99b) or increased (miR-221, miR-222) after bariatric surgery, suggesting a minor contribution of white adipose tissue to circulating miRNA levels. Circulating levels of liver-derived miRNAs normalized along with the endocrine and metabolic recovery of bariatric surgery, independent of the fat percentage reduction.

Conclusions: Since liver miRNAs play a crucial role in the regulation of hepatic biochemical processes, future studies are warranted to assess whether they may serve as determinants or mediators of metabolic risk in morbidly obese patients.
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http://dx.doi.org/10.1136/bmjdrc-2020-001441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594349PMC
October 2020

NAFLD-related mortality: simple hepatic steatosis is not as 'benign' as thought.

Gut 2021 Jul 19;70(7):1212-1213. Epub 2020 Oct 19.

Endocrinology and Metabolism, University of Verona, Ospedale Civile Maggiore, Verona, Italy.

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http://dx.doi.org/10.1136/gutjnl-2020-323188DOI Listing
July 2021

Letter of Thanks for UEG Week 2020 Reviewers.

Authors:
Herbert Tilg

United European Gastroenterol J 2020 Oct;8(8_suppl)

Chair of the UEG Scientifc Committee.

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http://dx.doi.org/10.1177/2050640620927330DOI Listing
October 2020

Livedo Racemosa - The Pathophysiology of Decompression-Associated Cutis Marmorata and Right/Left Shunt.

Front Physiol 2020 3;11:994. Epub 2020 Sep 3.

Department of Internal Medicine, University Clinic Innsbruck, Innsbruck, Austria.

Decompression sickness and arterial gas embolism, collectively known as decompression illness (DCI), are serious medical conditions that can result from compressed gas diving. DCI can present with a wide range of physiologic and neurologic symptoms. In diving medicine, skin manifestations are usually described in general as cutis marmorata (CM). Mainly in the Anglo-American literature the terms cutis marmorata, livedo reticularis (LR), and livedo racemosa (LRC) are used interchangeably but actually describe pathophysiologically different phenomena. CM is a synonym for LR, which is a physiological and benign, livid circular discoloration with a net-like, symmetric, reversible, and uniform pattern. The decompression-associated skin discolorations, however, correspond to the pathological, irregular, broken netlike pattern of LRC. Unlike in diving medicine, in clinical medicine/dermatology the pathology of livedo racemosa is well described as a thrombotic/embolic occlusion of arteries. This concept of arterial occlusion suggests that the decompression-associated livedo racemosa may be also caused by arterial gas embolism. Recent studies have shown a high correlation of cardiac right/left (R/L) shunts with arterial gas embolism and skin bends in divers with unexplained DCI. To further investigate this hypothesis, a retrospective analysis was undertaken in a population of Austrian, Swiss, and German divers. The R/L shunt screening results of 18 divers who suffered from an unexplained decompression illness (DCI) and presented with livedo racemosa were retrospectively analyzed. All of the divers were diagnosed with a R/L shunt, 83% with a cardiac shunt [patent foramen ovale (PFO)/atrium septum defect (ASD)], and 17% with a non-cardiac shunt. We therefore not only confirm this hypothesis but when using appropriate echocardiographic techniques even found a 100% match between skin lesions and R/L shunt. In conclusion, in diving medicine the term cutis marmorata/livedo reticularis is used incorrectly for describing the actual pathology of livedo racemosa. Moreover, this pathology could be a good explanation for the high correlation of livedo racemosa with cardiac and non-cardiac right/left shunts in divers without omission of decompression procedures.
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http://dx.doi.org/10.3389/fphys.2020.00994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497564PMC
September 2020
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