Publications by authors named "Christian Jansen"

107 Publications

Extrahepatic Surgery in Cirrhosis Significantly Increases Portal Pressure in Preclinical Animal Models.

Front Physiol 2021 20;12:720898. Epub 2021 Aug 20.

Department of Internal Medicine 1, Center for Cirrhosis and Portal Hypertension Bonn (CCB), University Hospital Bonn, Bonn, Germany.

Liver cirrhosis is a relevant comorbidity with increasing prevalence. Postoperative decompensation and development of complications in patients with cirrhosis remains a frequent clinical problem. Surgery has been discussed as a precipitating event for decompensation and complications of cirrhosis, but the underlying pathomechanisms are still obscure. The aim of this study was to analyze the role of abdominal extrahepatic surgery in cirrhosis on portal pressure and fibrosis in a preclinical model. Compensated liver cirrhosis was induced using tetrachlormethane (CCL4) inhalation and bile duct ligation (BDL) models in rats, non-cirrhotic portal hypertension by partial portal vein ligation (PPVL). Intestinal manipulation (IM) as a model of extrahepatic abdominal surgery was performed. 2 and 7 days after IM, portal pressure was measured . Hydroxyproline measurements, Sirius Red staining and qPCR measurements of the liver were performed for evaluation of fibrosis development and hepatic inflammation. Laboratory parameters of liver function in serum were analyzed. Portal pressure was significantly elevated 2 and 7 days after IM in both models of cirrhosis. In the non-cirrhotic model the trend was the same, while not statistically significant. In both cirrhotic models, IM shows strong effects of decompensation, with significant weight loss, elevation of liver enzymes and hypoalbuminemia. 7 days after IM in the BDL group, Sirius red staining and hydroxyproline levels showed significant progression of fibrosis and significantly elevated mRNA levels of hepatic inflammation compared to the respective control group. A progression of fibrosis was not observed in the CCL4 model. In animal models of cirrhosis with continuous liver injury (BDL), IM increases portal pressure, and development of fibrosis. Perioperative portal pressure and hence inflammation processes may be therapeutic targets to prevent post-operative decompensation in cirrhosis.
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http://dx.doi.org/10.3389/fphys.2021.720898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8418541PMC
August 2021

Role of circulating angiogenin levels in portal hypertension and TIPS.

PLoS One 2021 25;16(8):e0256473. Epub 2021 Aug 25.

Department of Internal Medicine 1, University Hospital, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.

Background: Pathogenesis of portal hypertension is multifactorial and includes pathologic intrahepatic angiogenesis, whereby TIPS insertion is an effective therapy of portal hypertension associated complications. While angiogenin is a potent contributor to angiogenesis in general, little is known about its impact on TIPS function over time.

Methods: In a total of 118 samples from 47 patients, angiogenin concentrations were measured in portal and inferior caval vein plasma at TIPS insertion (each blood compartment n = 23) or angiographic intervention after TIPS (each blood compartment n = 36) and its relationship with patient outcome was investigated.

Results: Angiogenin levels in the inferior caval vein were significantly higher compared to the portal vein (P = 0.048). Ten to 14 days after TIPS, inferior caval vein angiogenin level correlated inversely with the portal systemic pressure gradient (P<0.001), measured invasively during control angiography. Moreover, patients with TIPS revision during this angiography, showed significantly lower angiogenin level in the inferior caval vein compared to patients without TIPS dysfunction (P = 0.01).

Conclusion: In cirrhosis patients with complications of severe portal hypertension, circulating levels of angiogenin are derived from the injured liver. Moreover, angiogenin levels in the inferior caval vein after TIPS may predict TIPS dysfunction.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0256473PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8386873PMC
August 2021

Elective Surgery but not Transjugular Intrahepatic Portosystemic Shunt Precipitates Acute-On-Chronic Liver Failure.

Hepatol Commun 2021 Jul 26;5(7):1265-1277. Epub 2021 Mar 26.

Department of Internal Medicine I University of Bonn Bonn Germany.

Acute-on-chronic liver failure (ACLF) is a syndrome associated with organ failure and high short-term mortality. Presence of ACLF at interventions, such as surgery or transjugular intrahepatic portosystemic shunt (TIPS), has been shown to determine outcome, but those interventions have also been attributed to precipitate ACLF in different studies. However, dedicated investigation for the risk of ACLF development in these interventions, especially in elective settings, has not been conducted. Patients with cirrhosis undergoing elective surgery were propensity score matched and compared to patients receiving TIPS. The primary endpoint was ACLF development within 28 days after the respective procedure. The secondary endpoint was 3-month and 1-year mortality. In total, 190 patients were included. Within 28 days, ACLF developed in 24% of the surgery and 3% of the TIPS cohorts, with the highest ACLF incidence between 3 and 8 days. By day 28 after the procedure, ACLF improved in the TIPS cohort. In both cohorts, patients developing ACLF within 28 days after surgery or TIPS placement showed significantly worse survival than patients without ACLF development at follow-up. After 12 months, mortality was significantly higher in the surgery cohort compared to the TIPS cohort (40% vs. 23%, respectively;  = 0.031). Regression analysis showed a European Foundation Chronic Liver Failure Consortium acute decompensation (CLIF-C AD) score ≥50 and surgical procedure as independent predictors of ACLF development. CLIF-C AD score ≥50, C-reactive protein, and ACLF development within 28 days independently predicted 1-year mortality. Elective surgical interventions in patients with cirrhosis precipitate ACLF development and ultimately death, but TIPS plays a negligible role in the development of ACLF. Elective surgery in patients with CLIF-C AD ≥50 should be avoided, while the window of opportunity would be CLIF-C AD <50.
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http://dx.doi.org/10.1002/hep4.1712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279462PMC
July 2021

Level of MFAP4 in ascites independently predicts 1-year transplant-free survival in patients with cirrhosis.

JHEP Rep 2021 Jun 29;3(3):100287. Epub 2021 Mar 29.

Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark.

Background & Aims: Prognostic models of cirrhosis underestimate disease severity for patients with cirrhosis and ascites. Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix protein linked to hepatic neoangiogenesis and fibrogenesis. We investigated ascites MFAP4 as a predictor of transplant-free survival in patients with cirrhosis and ascites.

Methods: A dual-centre observational study of patients with cirrhosis and ascites recruited consecutively in relation to a paracentesis was carried out. Patients were followed up for 1 year, until death or liver transplantation (LTx). Ascites MFAP4 was tested with the model for end-stage liver disease (MELD-Na), CLIF Consortium Acute Decompensation (CLIF-C AD), and Child-Pugh score in Cox regression models.

Results: Ninety-three patients requiring paracentesis were included. Median ascites MFAP4 was 29.7 U/L [22.3-41.3], and MELD-Na was 19 [16-23]. A low MELD-Na score (<20) was observed in 49 patients (53%). During follow-up, 20 patients died (22%), and 6 received LTx (6%). High ascites MFAP4 (>29.7 U/L) was associated with 1-year transplant-free survival ( = 0.002). In Cox regression, ascites MFAP4 and MELD-Na independently predicted 1-year transplant-free survival (hazard ratio [HR] = 0.97,  = 0.03, and HR = 1.08,  = 0.01, respectively). Ascites MFAP4 and CLIF-C AD also predicted survival independently (HR = 0.96,  = 0.02, and HR = 1.05,  = 0.03, respectively), whereas only ascites MFAP4 did, controlling for the Child-Pugh score (HR = 0.97,  = 0.03, and HR = 1.18,  = 0.16, respectively). For patients with MELD-Na <20, ascites MFAP4 but not ascites protein predicted 1-year transplant-free survival (HR 0.91,  = 0.02, and HR = 0.94,  = 0.17, respectively).

Conclusions: Ascites MFAP4 predicts 1-year transplant-free survival in patients with cirrhosis and ascites. In patients with low MELD-Na scores, ascites MFAP4, but not total ascites protein, significantly predicted 1-year transplant-free survival.

Lay Summary: Patients with cirrhosis who have fluid in the abdomen, ascites, are at an increased risk of death and in need for liver transplantation. Our study identified patients with ascites and a poor prognosis by measuring microfibrillar associated protein 4 (MFAP4), a protein present in the abdominal fluid. Patients with low levels of the MFAP4 protein are at particularly increased risk of death or liver transplantation, suggesting that clinical care should be intensified in this group of patients.
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http://dx.doi.org/10.1016/j.jhepr.2021.100287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141937PMC
June 2021

Glue Embolization of Gastroesophageal Varices during Transjugular Intrahepatic Portosystemic Shunt (TIPS) Improves Survival Compared to Coil-only Embolization-A Single-Center Retrospective Study.

Cardiovasc Intervent Radiol 2021 Aug 21;44(8):1240-1250. Epub 2021 May 21.

Department of Radiology, University Hospital Bonn, Bonn, Germany.

Purpose: To compare the safety and effectiveness of coil versus glue embolization of gastroesophageal varices during transjugular intrahepatic portosystemic shunt (TIPS) creation.

Materials And Methods: In this monocentric retrospective study 104 (males: 67 (64%)) patients receiving TIPS with concomitant embolization of GEV and a minimum follow-up of one year (2008-2017) were included. Primary outcome parameter was overall survival (6 week; 1 year). Six-week overall survival was assessed as a surrogate for treatment failure as proposed by the international Baveno working group. Secondary outcome parameters were development of acute-on-chronic liver failure (ACLF), variceal rebleeding and hepatic encephalopathy (HE). Survival analysis was performed using Kaplan-Meier with log-rank test and adjusted Cox regression analysis.

Results: Indications for TIPS were refractory ascites (n = 33) or variceal bleeding (n = 71). Embolization was performed using glue with or without coils (n = 40) (Group G) or coil-only (n = 64) (Group NG). Overall survival was significantly better in group G (p = 0.022; HR = -3.333). Six-week survival was significantly lower in group NG (p = 0.014; HR = 6.945). Rates of development of ACLF were significantly higher in group NG after 6 months (NG = 14; G = 6; p = 0.039; HR = 3.243). Rebleeding rates (NG = 6; G = 3; p = 0.74) and development of HE (NG = 22; G = 15; p = 0.75) did not differ significantly between groups.

Conclusion: Usage of glue in embolization of GEV may improve overall survival, reduce treatment failure and may be preferable over coil embolization alone.
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http://dx.doi.org/10.1007/s00270-021-02852-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249301PMC
August 2021

Controlled underdilation using novel VIATORR® controlled expansion stents improves survival after transjugular intrahepatic portosystemic shunt implantation.

JHEP Rep 2021 Jun 3;3(3):100264. Epub 2021 Mar 3.

Department of Internal Medicine I, University of Frankfurt, Frankfurt, Germany.

Background & Aims: Smaller 8-mm diameter transjugular intrahepatic portosystemic shunts (TIPS) appear to be more beneficial than larger 10-mm TIPS stent-grafts, but lack the ability for secondary dilation in cases of clinical ineffectiveness. Underdilated VIATORR® TIPS stent grafts (VTS) expand passively, whereas novel VIATORR Controlled Expansion (VCX) stent grafts do not. This study evaluated the impact on survival of underdilated VCX compared with VTS in patients with decompensated cirrhosis.

Methods: This was a prospective case-control study including patients with cirrhosis receiving TIPS using 10-mm VCX underdilated to 8 mm. Patients with cirrhosis receiving 10-mm VTS underdilated to 8 mm were matched for age, sex, indication for TIPS, and liver function.

Results: A total of 114 patients (47 VCX, 47 VTS, and 20 fully dilated VCX/VTS) were included. After TIPS implantation, underdilated VCX diameter was 8.0 (7.8-9.2) mm at a median time of 359 (87-450) days, compared with VTS at 9.9 (9.7-10.0) mm ( <0.001). The portosystemic pressure gradient immediately after TIPS procedure and after 7 days did not change significantly in VCX [mean 9.4 (± 0.8) 10.4 (± 0.7) mmHg,  = 0.115). Hospital readmission rates for hepatic encephalopathy were 23% (n = 11) 51% (n = 24) for VCX and VTS ( <0.001), respectively. Patients with VCX had significantly lower rates of large-volume paracentesis (n = 5 [11%] n = 10 [21%],  = 0.017) and heart failure (n = 1 [2%] n = 7 [15%],  = 0.015). One-year mortality for underdilated VCX and VTS was 15% (n = 7) and 30% (n = 14) and, for fully dilated VCX/VTS, was 45% (n = 9) (log-rank  = 0.008), respectively.

Conclusions: This study demonstrated that VCX stent grafts underdilated to 8 mm do not passively expand to nominal diameter and suggests reduced hospital readmissions because of hepatic encephalopathy, uncontrolled ascites, and heart failure, and improved 1-year survival compared with underdilated VTS.

Lay Summary: Transjugular intrahepatic portosystemic shunt (TIPS) improves survival in selected patients with liver cirrhosis and acute variceal bleeding or refractory ascites. Smaller 8-mm diameter TIPS stent grafts appear to improve patient outcome compared with larger 10-mm diameter stent grafts. Novel VIATORR® Controlled Expansion (VCX) stent grafts facilitate safe and stable underdilation to 8 mm of large 10-mm diameter stent grafts with improved patient outcome (survival, hepatic encephalopathy, ascites and heart failure) compared with legacy VIATORR TIPS stent graft (VTS). Thus, the use of underdilated VCX could preserve heart function.

Clinical Trials Registration: The study is registered at Clinicaltrials.govNCT03628807.
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http://dx.doi.org/10.1016/j.jhepr.2021.100264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113713PMC
June 2021

Cucurbituril-Encapsulating Metal-Organic Framework via Mechanochemistry: Adsorbents with Enhanced Performance.

Angew Chem Int Ed Engl 2021 Jul 9;60(28):15365-15370. Epub 2021 Jun 9.

Hoffmann Institute of Advanced Materials, Shenzhen Polytechnic, 7098 Liuxian Blvd, Nanshan District, Shenzhen, 518055, China.

The first examples of monolithic crystalline host-guest hybrid materials are described. The reaction of 1,3,5-benzenetricarboxylic acid (H BTC) and Fe(NO ) ⋅9 H O in the presence of decamethylcucurbit[5]uril ammonium chloride (MC5⋅2 NH Cl⋅4 H O) directly affords [email protected](Fe) hybrid monoliths featuring hierarchical micro-, meso- and macropores. Particularly, this "bottle-around-ship" synthesis and one-pot shaping are facilitated by a newly discovered Fe-MC5 flowing gel formed by mechanochemistry. The designed [email protected](Fe) hybrid material with MC5 as active domains shows enhanced CH and lead(II) uptake performance, and selective capture of lead(II) cations at low concentrations. This shows that host-guest hybrid materials can exhibit synergic properties that out-perform materials based on individual components.
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http://dx.doi.org/10.1002/anie.202100675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362037PMC
July 2021

Prognostic Value of the CLIF-C AD Score in Patients With Implantation of Transjugular Intrahepatic Portosystemic Shunt.

Hepatol Commun 2021 04 5;5(4):650-660. Epub 2021 Jan 5.

Department of Medicine II Medical Center University of Freiburg Faculty of Medicine University of Freiburg Freiburg Germany.

Prognostic assessment of patients with liver cirrhosis allocated for implantation of a transjugular intrahepatic portosystemic shunt (TIPS) is a challenging task in clinical practice. The aim of our study was to assess the prognostic value of the CLIF-C AD (Acute Decompensation) score in patients with TIPS implantation. Transplant-free survival (TFS) and 3-month mortality were reviewed in 880 patients who received TIPS implantation for the treatment of cirrhotic portal hypertension. The prognostic value of the CLIF-C AD score was compared with the Model for End-Stage Liver Disease (MELD) score, Child-Pugh score, and albumin-bilirubin (ALBI) score using Harrell's C concordance index. The median TFS after TIPS implantation was 40.0 (34.6-45.4) months. The CLIF-C AD score (c = 0.635 [0.609-0.661]) was superior in the prediction of TFS in comparison to MELD score (c = 0.597 [0.570-0.623],  = 0.006), Child-Pugh score (c = 0.579 [0.552-0.606],  < 0.001), and ALBI score (c = 0.573 [0.545-0.600],  < 0.001). However, the CLIF-C AD score did not perform significantly better than the MELD-Na score (c = 0.626 [0.599-0.653],  = 0.442). There were no profound differences in the scores' ranking with respect to indication for TIPS implantation, stent type, or underlying liver disease. Subgroup analyses revealed that a CLIF-C AD score >45 was a predictor of 3-month mortality in the supposed low-risk group of patients with a MELD score ≤12 (14.7% vs. 5.1%,  < 0.001). The CLIF-C AD score is suitable for prognostic assessment of patients with cirrhotic portal hypertension receiving TIPS implantation. In the prediction of TFS, the CLIF-C AD score is superior to MELD score, Child-Pugh score, and ALBI score but not the MELD-Na score.
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http://dx.doi.org/10.1002/hep4.1654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034565PMC
April 2021

Bacterial infections in patients with acute variceal bleeding in the era of antibiotic prophylaxis.

J Hepatol 2021 Aug 12;75(2):342-350. Epub 2021 Jun 12.

Gastroenterology Department, University Hospital of the Canary Islands, La Laguna, Tenerife, Spain.

Background & Aims: Antibiotic prophylaxis reduces the risk of infection and mortality in patients with cirrhosis and acute variceal bleeding (AVB). This study examines the incidence of, and risk factors for, bacterial infections during hospitalization in patients with AVB on antibiotic prophylaxis.

Methods: A post hoc analysis was performed using the database of an international, multicenter, observational study designed to examine the role of pre-emptive transjugular intrahepatic portosystemic shunts in patients with cirrhosis and AVB. Data were collected on patients with cirrhosis hospitalized for AVB (n = 2,138) from a prospective cohort (October 2013-May 2015) at 34 referral centers, and a retrospective cohort (October 2011-September 2013) at 19 of these centers. The primary outcome was incidence of bacterial infection during hospitalization.

Results: A total of 1,656 patients out of 1,770 (93.6%) received antibiotic prophylaxis; third-generation cephalosporins (76.2%) and quinolones (19.0%) were used most frequently. Of the patients on antibiotic prophylaxis, 320 patients developed bacterial infection during hospitalization. Respiratory infection accounted for 43.6% of infections and for 49.7% of infected patients, and occurred early after admission (median 3 days, IQR 1-6). On multivariate analysis, respiratory infection was independently associated with Child-Pugh C (odds ratio [OR] 3.1; 95% CI 1.4-6.7), grade III-IV encephalopathy (OR 2.8; 95% CI 1.8-4.4), orotracheal intubation for endoscopy (OR 2.6; 95% CI 1.8-3.8), nasogastric tube placement (OR 1.7; 95% CI 1.2-2.4) or esophageal balloon tamponade (OR 2.4; 95% CI 1.2-4.9).

Conclusion: Bacterial infections develop in almost one-fifth of patients with AVB despite antibiotic prophylaxis. Respiratory infection is the most frequent, is an early event after admission, and is associated with advanced liver failure, severe hepatic encephalopathy and use of nasogastric tube, orotracheal intubation for endoscopy or esophageal balloon tamponade.

Lay Summary: Bacterial infections develop during hospitalization in close to 20% of patients with acute variceal bleeding despite antibiotic prophylaxis. Respiratory bacterial infections are the most frequent and occur early after admission. Respiratory infection is associated with advanced liver disease, severe hepatic encephalopathy and a need for a nasogastric tube, orotracheal intubation for endoscopy or esophageal balloon tamponade.
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http://dx.doi.org/10.1016/j.jhep.2021.03.026DOI Listing
August 2021

Impact of transjugular intrahepatic portosystemic shunt creation on the central lymphatic system in liver cirrhosis.

Sci Rep 2021 03 29;11(1):7065. Epub 2021 Mar 29.

Department of Internal Medicine I, University Hospital of Bonn, Venusberg-Campus 1, 53105, Bonn, Germany.

The puropse of this study was to evaluate associations of cisterna chyli (CCh) diameter with portal hemodynamics and the influence of TIPS-creation in cirrhotic patients. 93 cirrhotic patients (57 male, mean age 59 years) received CT prior to TIPS-creation. 38/93 additionally underwent post-interventional CT. CCh-diameter was measured. After categorization into patients with and without large venous collaterals (i.e. > 6 mm), data were analyzed regarding associations between CCh-diameter, clinical and portal-hemodynamic parameters and diameter-changes after TIPS-creation. Patient survival post-TIPS was analyzed. Median portosystemic pressure-gradient decreased from 20 to 9 mmHg after TIPS-creation. Large venous collaterals were observed in 59 patients. In 69/93 patients (74.2%) the CCh was detectable. Mean pre-interventional diameter was 9.4 ± 2.7 mm (large collaterals: 8.7 ± 2.0 mm, no large collaterals: 10.7 ± 3.2 mm, p = 0.003). CCh-diameter correlated strongly with pre-TIPS portal-pressure (Rs = 0.685, p = 0.0001), moderately with portosystemic-gradient (Rs = 0.524, p = 0.006), liver shear-wave-elastography (Rs = 0.597, p = 0.004) and spleen size (Rs = 0.501, p = 0.01) in patients without large collaterals, but not in patients with large collaterals. Post-TIPS CCh-diameter decreased significantly from 10.2 ± 2.8 mm to 8.3 ± 3.0 mm (p < 0.001). Patients without a detectable CCh on CT survived significantly shorter. The diameter of the CCh is associated with portal-pressure and decreases after TIPS-creation in cirrhotic patients, reflecting a portal decompression mechanism via the lymphatic system. Lack of larger central lymphatics detectable on CT may be associated with shorter survival.
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http://dx.doi.org/10.1038/s41598-021-86006-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007746PMC
March 2021

Profiling circulating microRNAs in patients with cirrhosis and acute-on-chronic liver failure.

JHEP Rep 2021 Apr 19;3(2):100233. Epub 2021 Jan 19.

Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

Background & Aims: MicroRNAs (miRNAs) circulate in several body fluids and can be useful biomarkers. The aim of this study was to identify blood-circulating miRNAs associated with cirrhosis progression and acute-on-chronic liver failure (ACLF).

Methods: Using high-throughput screening of 754 miRNAs, serum samples from 45 patients with compensated cirrhosis, decompensated cirrhosis, or ACLF were compared with those from healthy individuals (n = 15). miRNA levels were correlated with clinical parameters, organ failure, and disease progression and outcome. Dysregulated miRNAs were evaluated in portal and hepatic vein samples (n = 33), liver tissues (n = 17), and peripheral blood mononuclear cells (PBMCs) (n = 16).

Results: miRNA screening analysis revealed that circulating miRNAs are dysregulated in cirrhosis progression, with 51 miRNAs being differentially expressed among all groups of patients. Unsupervised clustering and principal component analysis indicated that the main differences in miRNA expression occurred at decompensation, showing similar levels in patients with decompensated cirrhosis and those with ACLF. Of 43 selected miRNAs examined for differences among groups, 10 were differentially expressed according to disease progression. Moreover, 20 circulating miRNAs were correlated with model for end-stage liver disease and Child-Pugh scores. Notably, 11 dysregulated miRNAs were associated with kidney or liver failure, encephalopathy, bacterial infection, and poor outcomes. The most severely dysregulated miRNAs ( miR-146a-5p, miR-26a-5p, and miR-191-5p) were further evaluated in portal and hepatic vein blood and liver tissue, but showed no differences. However, PBMCs from patients with cirrhosis showed significant downregulation of miR-26 and miR-146a, suggesting a extrahepatic origin of some circulating miRNAs.

Conclusions: This study is a repository of circulating miRNA data following cirrhosis progression and ACLF. Circulating miRNAs were profoundly dysregulated during the progression of chronic liver disease, were associated with failure of several organs and could have prognostic utility.

Lay Summary: Circulating miRNAs are small molecules in the blood that can be used to identify or predict a clinical condition. Our study aimed to identify miRNAs for use as biomarkers in patients with cirrhosis or acute-on-chronic liver failure. Several miRNAs were found to be dysregulated during the progression of disease, and some were also related to organ failure and disease-related outcomes.
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http://dx.doi.org/10.1016/j.jhepr.2021.100233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902550PMC
April 2021

Balance between macrophage migration inhibitory factor and sCD74 predicts outcome in patients with acute decompensation of cirrhosis.

JHEP Rep 2021 Apr 17;3(2):100221. Epub 2020 Dec 17.

Department of Internal Medicine III, RWTH Aachen University Hospital, Aachen, Germany.

Background & Aims: Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine and an important regulator of innate immune responses. We hypothesised that serum concentrations of MIF are associated with disease severity and outcome in patients with decompensated cirrhosis and acute-on-chronic liver failure (ACLF).

Methods: Circulating concentrations of MIF and its soluble receptor CD74 (sCD74) were determined in sera from 292 patients with acute decompensation of cirrhosis defined as new onset or worsening of ascites requiring hospitalisation. Of those, 78 (27%) had ACLF. Short-term mortality was assessed 90 days after inclusion.

Results: Although serum concentrations of MIF and sCD74 did not correlate with liver function parameters or ACLF, higher MIF (optimum cut-off >2.3 ng/ml) and lower concentrations of sCD74 (optimum cut-off <66.5 ng/ml) both indicated poorer 90-day transplant-free survival in univariate analyses (unadjusted hazard ratio [HR] 2.01 [1.26-3.22];  = 0.004 for MIF; HR 0.59 [0.38-0.92];  = 0.02 for sCD74) and after adjustment in multivariable models. Higher MIF concentrations correlated with surrogates of systemic inflammation (white blood cells,  = 0.005; C-reactive protein,  = 0.05) and were independent of genetic MIF promoter polymorphisms. Assessment of MIF plasma concentrations in portal venous blood and matched blood samples from the right atrium in a second cohort of patients undergoing transjugular intrahepatic portosystemic shunt insertion revealed a transhepatic MIF gradient with higher concentrations in the right atrial blood.

Conclusions: Serum concentrations of MIF and its soluble receptor CD74 predict 90-day transplant-free survival in patients with acute decompensation of cirrhosis. This effect was independent of liver function and genetic predispositions, but rather reflected systemic inflammation. Therefore, MIF and sCD74 represent promising prognostic markers beyond classical scoring systems in patients at risk of ACLF.

Lay Summary: Inflammatory processes contribute to the increased risk of death in patients with cirrhosis and ascites. We show that patients with high serum levels of the inflammatory cytokine macrophage migration inhibitory factor (MIF) alongside low levels of its binding receptor sCD74 in blood indicate an increased mortality risk in patients with ascites. The cirrhotic liver is a relevant source of elevated circulating MIF levels.
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http://dx.doi.org/10.1016/j.jhepr.2020.100221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890204PMC
April 2021

Refining prediction of survival after TIPS with the novel Freiburg index of post-TIPS survival.

J Hepatol 2021 Jun 26;74(6):1362-1372. Epub 2021 Jan 26.

Department of Medicine II, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany; PraxisZentrum für Gastroenterologie und Endokrinologie, Freiburg, Germany.

Background & Aims: Transjugular intrahepatic portosystemic shunt (TIPS) implantation is an effective and safe treatment for complications of portal hypertension. Survival prediction is important in these patients as they constitute a high-risk population. Therefore, the aim of our study was to develop an alternative prognostic model for accurate survival prediction after planned TIPS implantation.

Methods: A total of 1,871 patients with de novo TIPS implantation for ascites or secondary prophylaxis of variceal bleeding were recruited retrospectively. The study cohort was divided into a training set (80% of study patients; n = 1,496) and a validation set (20% of study patients; n = 375). Further, patients with early (preemptive) TIPS implantation due to variceal bleeding were included as another validation cohort (n = 290). Medical data and overall survival (OS) were assessed. A Cox regression model was used to create an alternative prediction model, which includes significant prognostic factors.

Results: Age, bilirubin, albumin and creatinine were the most important prognostic factors. These parameters were included in a new score named the Freiburg index of post-TIPS survival (FIPS). The FIPS score was able to identify high-risk patients with a significantly reduced median survival of 5.0 (3.1-6.9) months after TIPS implantation in the training set. These results were confirmed in the validation set (median survival of 3.1 [0.9-5.3] months). The FIPS score showed better prognostic discrimination compared to the Child-Pugh, MELD, MELD-Na score and the bilirubin-platelet model. However, the FIPS score showed insufficient prognostic discrimination in patients with early TIPS implantation.

Conclusions: The FIPS score is superior to established scoring systems for the identification of high-risk patients with a worse prognosis following elective TIPS implantation.

Lay Summary: Implantation of a transjugular intrahepatic portosystemic shunt (TIPS) is a safe and effective treatment for patients with cirrhosis and clinically significant portal hypertension. However, risk stratification is a major challenge in these patients as currently available scoring systems have major drawbacks. Age, bilirubin, albumin and creatinine were included in a new risk score which was named the Freiburg index of post-TIPS survival (FIPS). The FIPS score can identify patients at high risk and may guide clinical decision making.
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http://dx.doi.org/10.1016/j.jhep.2021.01.023DOI Listing
June 2021

Regulation of uridine diphosphate-glucuronosyltransferase 1A expression by miRNA-214-5p and miRNA-486-3p.

Epigenomics 2021 Feb 12;13(4):271-283. Epub 2021 Jan 12.

Department of Internal Medicine I, University Hospital Bonn, Bonn 53127, Germany.

This study aimed to identify novel miRNAs (miRs) as regulators of gene expression and to evaluate them as potential risk factors for the development of liver fibrosis/cirrhosis. miRNA target sites in UDP-glucuronosyltransferase 1A (UGT1A) 3'-UTR were predicted and confirmed by luciferase assays, quantitative real-time PCR and western blot using HEK293, HepG2 and Huh7 cells. and miRNA expression were analyzed in cirrhotic patients and a mouse model of alcoholic liver fibrosis. miR-214-5p and miR-486-3p overexpression reduced UGT1A mRNA, protein levels and enzyme activity in HepG2 and Huh7 cells. miR-486-3p was upregulated in cirrhotic patients and fibrotic mice livers, whereas UGT1A mRNA levels were reduced. In conclusion, we identified two novel miRNAs capable to repress UGT1A expression and . Furthermore, miR-486-3p may represent a potential risk factor for the development or progression of liver fibrosis/cirrhosis by means of a reduced UGT1A-mediated detoxification activity.
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http://dx.doi.org/10.2217/epi-2020-0244DOI Listing
February 2021

Evaluation of impact of elective invasive examinations in patients with transjugular intrahepatic portosystemic shunt in the long-term follow up.

Z Gastroenterol 2021 Jan 11;59(1):24-34. Epub 2021 Jan 11.

Medical Clinic B, Department of Gastroenterology, Hepatology, Endocrinology, Clinical Infectiology, University Hospital Muenster, Muenster, Germany.

Introduction:  In the management of patients with decompensated liver cirrhosis, transjugular intrahepatic portosystemic shunt (TIPS) insertion is well-established but common recommendations in the follow up management are inconsistent. Doppler sonography is commonly used for detection for TIPS dysfunction whilst data on the impact of elective invasive examinations are scarce.

Aim:  The aim of this retrospective analysis is to evaluate potential benefits of elective invasive examinations in the follow up management of patients after TIPS insertion METHODS:  Data of all patients receiving TIPS at the university hospitals of Muenster and Bonn between 2013 and 2018 (n = 534) were collected. The impact of performance of elective invasive examinations at 12 months after TIPS insertion on the occurrence of liver related events (LREs) and frequency of TIPS revisions within 24 months after TIPS insertion was analyzed.

Results:  No significant differences were found concerning occurrence of liver related events after 24 months depending on whether an elective invasive examination was performed. Occurrence of hepatic encephalopathy, relapse of initial indication for TIPS, as well as death or liver transplantation all did not differ. These findings were verified by a subgroup analysis including only patients who did not experience a LRE or TIPS revision within the first 12 months after TIPS procedure.

Conclusion:  The analyzed data suggest no evidence for a beneficial impact due to implementation of an elective invasive examination program after TIPS insertion. Invasive examinations should remain reserved to patients with suspected TIPS dysfunction.
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http://dx.doi.org/10.1055/a-1330-9867DOI Listing
January 2021

PREDICT identifies precipitating events associated with the clinical course of acutely decompensated cirrhosis.

J Hepatol 2021 05 20;74(5):1097-1108. Epub 2020 Nov 20.

Medical University of Innsbruck, Innsbruck, Austria.

Background & Aims: Acute decompensation (AD) of cirrhosis may present without acute-on-chronic liver failure (ACLF) (AD-No ACLF), or with ACLF (AD-ACLF), defined by organ failure(s). Herein, we aimed to analyze and characterize the precipitants leading to both of these AD phenotypes.

Methods: The multicenter, prospective, observational PREDICT study (NCT03056612) included 1,273 non-electively hospitalized patients with AD (No ACLF = 1,071; ACLF = 202). Medical history, clinical data and laboratory data were collected at enrolment and during 90-day follow-up, with particular attention given to the following characteristics of precipitants: induction of organ dysfunction or failure, systemic inflammation, chronology, intensity, and relationship to outcome.

Results: Among various clinical events, 4 distinct events were precipitants consistently related to AD: proven bacterial infections, severe alcoholic hepatitis, gastrointestinal bleeding with shock and toxic encephalopathy. Among patients with precipitants in the AD-No ACLF cohort and the AD-ACLF cohort (38% and 71%, respectively), almost all (96% and 97%, respectively) showed proven bacterial infection and severe alcoholic hepatitis, either alone or in combination with other events. Survival was similar in patients with proven bacterial infections or severe alcoholic hepatitis in both AD phenotypes. The number of precipitants was associated with significantly increased 90-day mortality and was paralleled by increasing levels of surrogates for systemic inflammation. Importantly, adequate first-line antibiotic treatment of proven bacterial infections was associated with a lower ACLF development rate and lower 90-day mortality.

Conclusions: This study identified precipitants that are significantly associated with a distinct clinical course and prognosis in patients with AD. Specific preventive and therapeutic strategies targeting these events may improve outcomes in patients with decompensated cirrhosis.

Lay Summary: Acute decompensation (AD) of cirrhosis is characterized by a rapid deterioration in patient health. Herein, we aimed to analyze the precipitating events that cause AD in patients with cirrhosis. Proven bacterial infections and severe alcoholic hepatitis, either alone or in combination, accounted for almost all (96-97%) cases of AD and acute-on-chronic liver failure. Whilst the type of precipitant was not associated with mortality, the number of precipitant(s) was. This study identified precipitants that are significantly associated with a distinct clinical course and prognosis of patients with AD. Specific preventive and therapeutic strategies targeting these events may improve patient outcomes.
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http://dx.doi.org/10.1016/j.jhep.2020.11.019DOI Listing
May 2021

Variceal bleeding has increased mortality compared to nonvariceal bleeding only in males.

Eur J Gastroenterol Hepatol 2020 Oct 16. Epub 2020 Oct 16.

Department of Medicine I, University of Bonn, Bonn, Germany.

Background: Gastrointestinal bleedings (GIBs) are frequent in cirrhotic patients and lead to high morbidity and mortality. Lately, there have been conflicting reports on the role of and bleeding type [variceal bleeding and nonvariceal bleeding (NVB)]. This study investigated the predictors of mortality in patients with variceal bleeding and NVB with relationship to sex differences.

Materials And Methods: A total of 271 patients with suspected upper GIB who underwent endoscopy were included. Patients were followed up at 1 week, 6 months and 1 year after admission. Univariate and multivariate logistic or Cox regression analyses investigated correlations of predictive factors and clinical outcomes. Propensity score matching was performed to control for severity of disease and compare groups for sex and bleeding type.

Results: A total of 42 patients were excluded (cirrhosis or bleeding not confirmed). The remaining patients were classified by bleeding type into patients with variceal bleeding (n = 115) or NVB (n = 156). Males (n = 155) had higher mortality in variceal bleeding than in NVB, while in females (n = 116) mortality was similar in the two bleeding types. This was confirmed after matching in males (n = 116) and females (n = 82). Further independent predictors of mortality in males were model for end-stage liver disease (MELD) at baseline, blood urea nitrogen, alanine aminotransferase, while in females age, leukocytes, MELD, history of ascites and hepatic encephalopathy.

Conclusion: This study shows that variceal bleeding has higher mortality in males compared to NVB, while in females the type of GIB does not impact the outcome. This highlights that sex-specific clinical management should be based on bleeding type after endoscopy.
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http://dx.doi.org/10.1097/MEG.0000000000001964DOI Listing
October 2020

Myocardial Fibrosis and Inflammation in Liver Cirrhosis: MRI Study of the Liver-Heart Axis.

Radiology 2020 Oct 18;297(1):51-61. Epub 2020 Aug 18.

From the Departments of Radiology (A.I., A.F., A.M.S., C.C.P., C.M., D.D., D.T., U.A., D.K., J.A.L.) and Internal Medicine I (M.P., C.J., J.C.), University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany; Quantitative Imaging Laboratory Bonn (QILaB), Bonn, Germany (A.I., A.F., A.M.S., D.D., D.T., D.K., J.A.L.); Institute for Medical Biometry, Informatics and Epidemiology (IMBIE), University of Bonn, Bonn, Germany (R.F.); Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt am Main, Germany (J.T.).

Background Cardiac involvement in liver cirrhosis in the absence of underlying cardiac disease is termed . The pathophysiology of this condition is still poorly understood. Purpose To investigate the extent of subclinical imaging changes in terms of fibrosis and inflammation and to explore the relationship between the severity of liver disease and the degree of myocardial involvement. Materials and Methods In this prospective study from November 2018 to December 2019, participants with liver cirrhosis and healthy control participants underwent hepatic and cardiac MRI. The multiparametric scan protocol assessed hepatic (T1 and T2 relaxation times, extracellular volume [ECV], and MR elastography-based liver stiffness) and cardiac (T1 and T2 relaxation times, ECV, myocardial edema, late gadolinium enhancement [LGE], and myocardial strain) parameters. Student tests, one-way analysis of variance, Pearson correlation, and multivariable binary regression analysis were used for statistical analyses. Results A total of 42 participants with liver cirrhosis (mean age ± standard deviation, 57 years ± 11; 23 men) and 18 control participants (mean age, 54 years ± 19; 11 men) were evaluated. Compared with control participants, the participants with liver cirrhosis displayed reduced longitudinal strain and elevated markers of myocardial disease (T1 and T2 relaxation times, ECV, and qualitative and quantitative LGE). Myocardial T1 (978 msec ± 23 vs 1006 msec ± 29 vs 1044 msec ± 14; < .001) and T2 relaxation times (56 msec ± 4 vs 59 msec ± 3 vs 62 msec ± 8; = .04) and ECV (30% ± 5 vs 33% ± 5 vs 38% ± 7; = .009) were higher depending on Child-Pugh class (A vs B vs C). Positive LGE lesions (three of 11 [27%] vs 10 of 19 [53%] vs nine of 11 [82%]; = .04) were more prevalent in advanced Child-Pugh classes. MR elastography-based liver stiffness was an independent predictor for LGE (odds ratio, 1.6; 95% confidence interval: 1.2%, 2.1%; = .004) and correlated with quantitative LGE ( = 0.67; < .001), myocardial T1 relaxation times ( = 0.55; < .001), and ECV ( = 0.39; = .01). Conclusion In participants with liver cirrhosis, systolic dysfunction and elevated parameters of myocardial edema and fibrosis were observed at MRI, which were more abnormal with greater severity of liver disease. © RSNA, 2020 See also the editorial by de Roos and Lamb in this issue.
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http://dx.doi.org/10.1148/radiol.2020201057DOI Listing
October 2020

Magnetic resonance parametric mapping of the spleen for non-invasive assessment of portal hypertension.

Eur Radiol 2021 Jan 4;31(1):85-93. Epub 2020 Aug 4.

Department of Diagnostic and Interventional Radiology and Quantitative Imaging Lab Bonn (QILaB), University Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, Germany.

Objectives: In patients with advanced liver disease, portal hypertension is an important risk factor, leading to complications such as esophageal variceal bleeding, ascites, and hepatic encephalopathy. This study aimed to determine the diagnostic value of T1 and T2 mapping and extracellular volume fraction (ECV) for the non-invasive assessment of portal hypertension.

Methods: In this prospective study, 50 participants (33 patients with indication for trans-jugular intrahepatic portosystemic shunt (TIPS) and 17 healthy volunteers) underwent MRI. The derivation and validation cohorts included 40 and 10 participants, respectively. T1 and T2 relaxation times and ECV of the liver and the spleen were assessed using quantitative mapping techniques. Direct hepatic venous pressure gradient (HVPG) and portal pressure measurements were performed during TIPS procedure. ROC analysis was performed to compare diagnostic performance.

Results: Splenic ECV correlated with portal pressure (r = 0.72; p < 0.001) and direct HVPG (r = 0.50; p = 0.003). No significant correlations were found between native splenic T1 and T2 relaxation times with portal pressure measurements (p > 0.05, respectively). In the derivation cohort, splenic ECV revealed a perfect diagnostic performance with an AUC of 1.000 for the identification of clinically significant portal hypertension (direct HVPG ≥ 10 mmHg) and outperformed other parameters: hepatic T2 (AUC, 0.731), splenic T2 (AUC, 0.736), and splenic native T1 (AUC, 0.806) (p < 0.05, respectively). The diagnostic performance of mapping parameters was comparable in the validation cohort.

Conclusion: Splenic ECV was associated with portal pressure measurements in patients with advanced liver disease. Future studies should explore the diagnostic value of parametric mapping accross a broader range of pressure values.

Key Points: • Non-invasive assessment and monitoring of portal hypertension is an area of unmet interest. • Splenic extracellular volume fraction is strongly associated with portal pressure in patients with end-stage liver disease. • Quantitative splenic and hepatic MRI-derived parameters have a potential to become a new non-invasive diagnostic parameter to assess and monitor portal pressure.
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http://dx.doi.org/10.1007/s00330-020-07080-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755629PMC
January 2021

The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology.

J Hepatol 2020 10 13;73(4):842-854. Epub 2020 Jul 13.

CHTMAD Vila Real, Vila Real, Portugal.

Background & Aims: Acute decompensation (AD) of cirrhosis is defined as the acute development of ascites, gastrointestinal hemorrhage, hepatic encephalopathy, infection or any combination thereof, requiring hospitalization. The presence of organ failure(s) in patients with AD defines acute-on-chronic liver failure (ACLF). The PREDICT study is a European, prospective, observational study, designed to characterize the clinical course of AD and to identify predictors of ACLF.

Methods: A total of 1,071 patients with AD were enrolled. We collected detailed pre-specified information on the 3-month period prior to enrollment, and clinical and laboratory data at enrollment. Patients were then closely followed up for 3 months. Outcomes (liver transplantation and death) at 1 year were also recorded.

Results: Three groups of patients were identified. Pre-ACLF patients (n = 218) developed ACLF and had 3-month and 1-year mortality rates of 53.7% and 67.4%, respectively. Unstable decompensated cirrhosis (UDC) patients (n = 233) required ≥1 readmission but did not develop ACLF and had mortality rates of 21.0% and 35.6%, respectively. Stable decompensated cirrhosis (SDC) patients (n = 620) were not readmitted, did not develop ACLF and had a 1-year mortality rate of only 9.5%. The 3 groups differed significantly regarding the grade and course of systemic inflammation (high-grade at enrollment with aggravation during follow-up in pre-ACLF; low-grade at enrollment with subsequent steady-course in UDC; and low-grade at enrollment with subsequent improvement in SDC) and the prevalence of surrogates of severe portal hypertension throughout the study (high in UDC vs. low in pre-ACLF and SDC).

Conclusions: Acute decompensation without ACLF is a heterogeneous condition with 3 different clinical courses and 2 major pathophysiological mechanisms: systemic inflammation and portal hypertension. Predicting the development of ACLF remains a major future challenge. CLINICALTRIALS.

Gov Number: NCT03056612.

Lay Summary: Herein, we describe, for the first time, 3 different clinical courses of acute decompensation (AD) of cirrhosis after hospital admission. The first clinical course includes patients who develop acute-on-chronic liver failure (ACLF) and have a high short-term risk of death - termed pre-ACLF. The second clinical course (unstable decompensated cirrhosis) includes patients requiring frequent hospitalizations unrelated to ACLF and is associated with a lower mortality risk than pre-ACLF. Finally, the third clinical course (stable decompensated cirrhosis), includes two-thirds of all patients admitted to hospital with AD - patients in this group rarely require hospital admission and have a much lower 1-year mortality risk.
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http://dx.doi.org/10.1016/j.jhep.2020.06.013DOI Listing
October 2020

Rebleeding and mortality risk are increased by ACLF but reduced by pre-emptive TIPS.

J Hepatol 2020 11 24;73(5):1082-1091. Epub 2020 Apr 24.

Unit of Gastroenterology and Digestive Endoscopy, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy.

Background & Aims: The relationship between acute-on-chronic liver failure (ACLF) and acute variceal bleeding (AVB) is poorly understood. Specifically, the prevalence and prognosis of ACLF in the context of AVB is unclear, while the role of transjugular intrahepatic portosystemic shunt (TIPS) in the management in patients with ACLF has not been described to date.

Methods: A multicenter, international, observational study was conducted in 2,138 patients from 34 centers between 2011 and 2015. ACLF was defined and graded according to the EASL-CLIF consortium definition. Placement of pre-emptive TIPS (pTIPS) was based on individual center policy. Patients were followed-up for 1 year, until death or liver transplantation. Cox regression and competing risk models (Gray's test) were used to identify independent predictors of rebleeding or mortality.

Results: At admission, 380/2,138 (17.8%) patients had ACLF according to EASL-CLIF criteria (grade 1: 38.7%; grade 2: 39.2%; grade 3: 22.1%). The 42-day rebleeding (19% vs. 10%; p <0.001) and mortality (47% vs. 10%; p <0.001) rates were higher in patients with ACLF and increased with ACLF grades. Of note, the presence of ACLF was independently associated with rebleeding and mortality. pTIPS placement improved survival in patients with ACLF at 42 days and 1 year. This effect was also observed in propensity score matching analysis of 66 patients with ACLF, of whom 44 received pTIPs and 22 did not.

Conclusions: This large multicenter international real-life study identified ACLF at admission as an independent predictor of rebleeding and mortality in patients with AVB. Moreover, pTIPS was associated with improved survival in patients with ACLF and AVB.

Lay Summary: Acute variceal bleeding is a deadly complication of liver cirrhosis that results from severe portal hypertension. This study demonstrates that the presence of acute-on-chronic liver failure (ACLF) is the strongest predictor of mortality in patients with acute variceal bleeding. Importantly, patients with ACLF and acute variceal (re)bleeding benefit from pre-emptive (early) placement of a transjugular intrahepatic portosystemic shunt.
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http://dx.doi.org/10.1016/j.jhep.2020.04.024DOI Listing
November 2020

Serum levels of bone sialoprotein correlate with portal pressure in patients with liver cirrhosis.

PLoS One 2020 17;15(4):e0231701. Epub 2020 Apr 17.

Department of Gastroenterology/Hepatology, Charité University Medicine Berlin, Berlin, Germany.

Liver cirrhosis represents the common end-stage of chronic liver diseases regardless of its etiology. Patients with compensated disease are mostly asymptomatic, however, progression to a decompensated disease stage is common. The available stratification strategies are often unsuitable to identify patients with a higher risk for disease progression and a limited prognosis. SIBLINGs, soluble glycophosphoproteins, are secreted into the blood by immune-cells. While osteopontin, the most prominent member of the SIBLINGs family, has been repeatedly associated with liver cirrhosis, data on the diagnostic and/or prognostic value of bone sialoprotein (BSP) are scarce and partly inconclusive. In this study, we analyzed the diagnostic and prognostic potential of circulating BSP in comparison to other standard laboratory markers in a large cohort of patients with liver cirrhosis receiving transjugular intrahepatic portosystemic shunt (TIPS). Serum levels of BSP were similar in patients with different disease stages and were not indicative for prognosis. Interestingly, BSP serum levels did correlate inversely with portal pressure, as well as its surrogates such as platelet count, the portal vein cross-sectional area and correlated positively with the portal venous velocity. In summary, our data highlight that BSP might represent a previously unrecognized marker for portal hypertension in patients with liver cirrhosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0231701PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164617PMC
July 2020

Differential inflammasome activation predisposes to acute-on-chronic liver failure in human and experimental cirrhosis with and without previous decompensation.

Gut 2021 02 2;70(2):379-387. Epub 2020 Apr 2.

Department of Internal Medicine 1, University of Frankfurt, Frankfurt am Main, Germany

Objective: Systemic inflammation predisposes acutely decompensated (AD) cirrhosis to the development of acute-on-chronic liver failure (ACLF). Supportive treatment can improve AD patients, becoming recompensated. Little is known about the outcome of patients recompensated after AD. We hypothesise that different inflammasome activation is involved in ACLF development in compensated and recompensated patients.

Design: 249 patients with cirrhosis, divided into compensated and recompensated (previous AD), were followed prospectively for fatal ACLF development. Two external cohorts (n=327) (recompensation, AD and ACLF) were included. Inflammasome-driving interleukins (ILs), IL-1α (caspase-4/11-dependent) and IL-1β (caspase-1-dependent), were measured. In rats, bile duct ligation-induced cirrhosis and lipopolysaccharide exposition were used to induce AD and subsequent recompensation. IL-1α and IL-1β levels and upstream/downstream gene expression were measured.

Results: Patients developing ACLF showed higher baseline levels of ILs. Recompensated patients and patients with detectable ILs had higher rates of ACLF development than compensated patients. Baseline CLIF-C (European Foundation for the study of chronic liver failure consortium) AD, albumin and IL-1α were independent predictors of ACLF development in compensated and CLIF-C AD and IL-1β in recompensated patients. Compensated rats showed higher IL-1α gene expression and recompensated rats higher IL-1β levels with higher hepatic gene expression. Higher IL-1β detection rates in recompensated patients developing ACLF and higher IL-1α and IL-1β detection rates in patients with ACLF were confirmed in the two external cohorts.

Conclusion: Previous AD is an important risk factor for fatal ACLF development and possibly linked with inflammasome activation. Animal models confirmed the results showing a link between ACLF development and IL-1α in compensated cirrhosis and IL-1β in recompensated cirrhosis.
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http://dx.doi.org/10.1136/gutjnl-2019-320170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815638PMC
February 2021

Systemic MCP-1 Levels Derive Mainly From Injured Liver and Are Associated With Complications in Cirrhosis.

Front Immunol 2020 11;11:354. Epub 2020 Mar 11.

Department of Internal Medicine 1, University Hospital, University Bonn, Bonn, Germany.

Monocyte chemotactic protein-1 (MCP-1) is a potent chemoattractant for monocytes. It is involved in pathogenesis of several inflammatory diseases. Hepatic MCP-1 is a readout of macrophage activation. While inflammation is a major driver of liver disease progression, the origin and role of circulating MCP-1 as a biomarker remains unclear. Hepatic CC-chemokine ligand 2 () expression and F4/80 staining for Kupffer cells were measured and correlated in a mouse model of chronic liver disease (inhalative CCl for 7 weeks). Next, hepatic RNA levels of were measured in explanted livers of 39 patients after transplantation and correlated with severity of disease. Changes in MCP-1 were further evaluated in a rat model of experimental cirrhosis and acute-on-chronic liver failure (ACLF). Finally, we analyzed portal and hepatic vein levels of MCP-1 in patients receiving transjugular intrahepatic portosystemic shunt insertion for complications of portal hypertension. In this mouse model of fibrotic hepatitis, hepatic expression of ( = 0.009) and the amount of F4/80 positive cells in the liver ( < 0.001) significantly increased after induction of hepatitis by CCl compared to control animals. Moreover, strong correlation of hepatic expression and F4/80 positive cells were seen ( = 0.023). Furthermore, in human liver explants, hepatic transcription levels of correlated with the MELD score of the patients, and thus disease severity ( = 0.007). The experimental model of ACLF in rats revealed significantly higher levels of MCP-1 plasma ( = 0.028) and correlation of hepatic expression ( = 0.69, = 0.003). Particularly, plasma MCP-1 levels did not correlate with peripheral blood monocyte expression. Finally, higher levels of MCP-1 were observed in the hepatic compared to the portal vein ( = 0.01) in patients receiving TIPS. Similarly, a positive correlation of MCP-1 with Child-Pugh score was observed ( = 0.018). Further, in the presence of ACLF, portal and hepatic vein levels of MCP-1 were significantly higher compared to patients without ACLF (both = 0.039). Circulating levels of MCP-1 mainly derive from the injured liver and are associated with severity of liver disease. Therefore, liver macrophages contribute significantly to disease progression. Circulating MCP-1 may reflect the extent of hepatic macrophage activation.
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http://dx.doi.org/10.3389/fimmu.2020.00354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078155PMC
March 2021

2D shear wave liver elastography by Aixplorer to detect portal hypertension in cirrhosis: An individual patient data meta-analysis.

Liver Int 2020 06 8;40(6):1435-1446. Epub 2020 Apr 8.

Department of Gastroenterology and Hepatology and OPEN Patient Data Explorative Network, Odense University Hospital, Odense, Denmark.

Background & Aims: Liver stiffness measured with 2-dimensional shear wave elastography by Supersonic Imagine (2DSWE-SSI) is well-established for fibrosis diagnostics, but non-conclusive for portal hypertension.

Methods: We performed an individual patient data meta-analysis of 2DSWE-SSI to identify clinically significant portal hypertension (CSPH), severe portal hypertension and large varices in cirrhosis patients, using hepatic venous pressure gradient and upper endoscopy as reference. We used meta-analytical integration of diagnostic accuracies with optimized rule-out (sensitivity-90%) and rule-in (specificity-90%) cut-offs.

Results: Five studies from seven centres shared data on 519 patients. After exclusion, we included 328 patients. Eighty-nine (27%) were compensated and 286 (87%) had CSPH. 2DSWE-SSI < 14 kPa ruled out CSPH with a summary AUROC (sROC), sensitivity and specificity of 0.88, 91% and 37%, and correctly classified 85% of patients, with minimal between-study heterogeneity. The false negative rate was 60%, of which decompensated patients accounted for 78%. 2DSWE-SSI ≥ 32 kPa ruled in CSPH with sROC, sensitivity, specificity and correct classifications of 0.83, 47%, 89% and 55%. In a subgroup analysis, the 14 kPa cut-off showed consistent sensitivity and higher specificity for patients with compensated cirrhosis, without ascites, viral aetiology or BMI < 25 kg/m . 2DSWE-SSI ruled out severe portal hypertension and large varices with fewer correctly classified and lower sROC, and with minimal benefit for ruling in.

Conclusion: Liver stiffness using 2-dimensional shear wave elastography below 14 kPa may be used to rule out clinically significant portal hypertension in cirrhosis patients, but this would need validation in populations of compensated liver disease. 2DSWE-SSI cannot predict varices needing treatment.
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http://dx.doi.org/10.1111/liv.14439DOI Listing
June 2020

Total area of spontaneous portosystemic shunts independently predicts hepatic encephalopathy and mortality in liver cirrhosis.

J Hepatol 2020 06 15;72(6):1140-1150. Epub 2020 Jan 15.

Department of Radiology, University of Bonn, Bonn, Germany.

Background & Aims: Spontaneous portosystemic shunts (SPSS) frequently develop in liver cirrhosis. Recent data suggested that the presence of a single large SPSS is associated with complications, especially overt hepatic encephalopathy (oHE). However, the presence of >1 SPSS is common. This study evaluates the impact of total cross-sectional SPSS area (TSA) on outcomes in patients with liver cirrhosis.

Methods: In this retrospective international multicentric study, CT scans of 908 cirrhotic patients with SPSS were evaluated for TSA. Clinical and laboratory data were recorded. Each detected SPSS radius was measured and TSA calculated. One-year survival was the primary endpoint and acute decompensation (oHE, variceal bleeding, ascites) was the secondary endpoint.

Results: A total of 301 patients (169 male) were included in the training cohort. Thirty percent of all patients presented with >1 SPSS. A TSA cut-off of 83 mm was used to classify patients with small or large TSA (S-/L-TSA). Patients with L-TSA presented with higher model for end-stage liver disease score (11 vs. 14) and more commonly had a history of oHE (12% vs. 21%, p <0.05). During follow-up, patients with L-TSA experienced more oHE episodes (33% vs. 47%, p <0.05) and had lower 1-year survival than those with S-TSA (84% vs. 69%, p <0.001). Multivariate analysis identified L-TSA (hazard ratio 1.66; 95% CI 1.02-2.70, p <0.05) as an independent predictor of mortality. An independent multicentric validation cohort of 607 patients confirmed that patients with L-TSA had lower 1-year survival (77% vs. 64%, p <0.001) and more oHE development (35% vs. 49%, p <0.001) than those with S-TSA.

Conclusion: This study suggests that TSA >83 mm increases the risk for oHE and mortality in patients with cirrhosis. Our results support the clinical use of TSA/SPSS for risk stratification and decision-making in the management of patients with cirrhosis.

Lay Summary: The prevalence of spontaneous portosystemic shunts (SPSS) is higher in patients with more advanced chronic liver disease. The presence of more than 1 SPSS is common in advanced chronic liver disease and is associated with the development of hepatic encephalopathy. This study shows that total cross-sectional SPSS area (rather than diameter of the single largest SPSS) predicts survival in patients with advanced chronic liver disease. Our results support the clinical use of total cross-sectional SPSS area for risk stratification and decision-making in the management of SPSS.
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http://dx.doi.org/10.1016/j.jhep.2019.12.021DOI Listing
June 2020

Blood metabolomics uncovers inflammation-associated mitochondrial dysfunction as a potential mechanism underlying ACLF.

J Hepatol 2020 04 25;72(4):688-701. Epub 2019 Nov 25.

Service de Pharmacologie et Immuno-Analyse (SPI), Laboratoire d'Etude du Métabolisme des Médicaments, CEA, INRA, Université Paris Saclay, MetaboHUB, F-91191 Gif-sur-Yvette, France.

Background & Aims: Acute-on-chronic liver failure (ACLF), which develops in patients with cirrhosis, is characterized by intense systemic inflammation and organ failure(s). Because systemic inflammation is energetically expensive, its metabolic costs may result in organ dysfunction/failure. Therefore, we aimed to analyze the blood metabolome in patients with cirrhosis, with and without ACLF.

Methods: We performed untargeted metabolomics using liquid chromatography coupled to high-resolution mass spectrometry in serum from 650 patients with AD (acute decompensation of cirrhosis, without ACLF), 181 with ACLF, 43 with compensated cirrhosis, and 29 healthy individuals.

Results: Of the 137 annotated metabolites identified, 100 were increased in patients with ACLF of any grade, relative to those with AD, and 38 comprised a distinctive blood metabolite fingerprint for ACLF. Among patients with ACLF, the intensity of the fingerprint increased across ACLF grades, and was similar in patients with kidney failure and in those without, indicating that the fingerprint reflected not only decreased kidney excretion but also altered cell metabolism. The higher the ACLF-associated fingerprint intensity, the higher the plasma levels of inflammatory markers, tumor necrosis factor α, soluble CD206, and soluble CD163. ACLF was characterized by intense proteolysis and lipolysis; amino acid catabolism; extra-mitochondrial glucose metabolism through glycolysis, pentose phosphate, and D-glucuronate pathways; depressed mitochondrial ATP-producing fatty acid β-oxidation; and extra-mitochondrial amino acid metabolism giving rise to metabotoxins.

Conclusions: In ACLF, intense systemic inflammation is associated with blood metabolite accumulation and profound alterations in major metabolic pathways, in particular inhibition of mitochondrial energy production, which may contribute to the development of organ failures.

Lay Summary: Acute-on-chronic liver failure (ACLF), which develops in patients with cirrhosis, is characterized by intense systemic inflammation and organ failure(s). Because systemic inflammation is energetically expensive, its metabolic costs may result in organ dysfunction/failure. We identified a 38-metabolite blood fingerprint specific for ACLF that revealed mitochondrial dysfunction in peripheral organs. This may contribute to organ failures.
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http://dx.doi.org/10.1016/j.jhep.2019.11.009DOI Listing
April 2020
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