Opportunities and barriers in omics-based biomarker discovery for steatotic liver diseases.

The rising prevalence of liver diseases related to obesity and excessive use of alcohol is fuelling an increasing demand for accurate biomarkers aimed at community screening, diagnosis of steatohepatitis and significant fibrosis, monitoring, prognostication and prediction of treatment efficacy. Breakthroughs in omics methodologies and the power of bioinformatics have created an excellent opportunity to apply technological advances to clinical needs, for instance in the development of precision biomarkers for personalised medicine. Via omics technologies, biological processes from the genes to circulating protein, as well as the microbiome - including bacteria, viruses and fungi, can be investigated on an axis. However, there are important barriers to omics-based biomarker discovery and validation, including the use of semi-quantitative measurements from untargeted platforms, which may exhibit high analytical, inter- and intra-individual variance. Standardising methods and the need to validate them across diverse populations presents a challenge, partly due to disease complexity and the dynamic nature of biomarker expression at different disease stages. Lack of validity causes lost opportunities when studies fail to provide the knowledge needed for regulatory approvals, all of which contributes to a delayed translation of these discoveries into clinical practice. While no omics-based biomarkers have matured to clinical implementation, the extent of data generated has enabled the hypothesis-free discovery of a plethora of candidate biomarkers that warrant further validation. To explore the many opportunities of omics technologies, hepatologists need detailed knowledge of commonalities and differences between the various omics layers, and both the barriers to and advantages of these approaches.

Targeted decrease of portal hepatic pressure gradient improves ascites control after TIPS.

BACKGROUND: Ascites is a definitive sign of decompensated liver cirrhosis driven by portal hypertension. Although transjugular intrahepatic portosystemic shunt insertion (TIPS) is indicated for therapy of recurrent and refractory ascites, there is no evidence-based recommendation for a specific target of portal hepatic pressure gradient (PPG) decrease. METHODS: In this single-center, retrospective trial, we investigated the decrease of PPG in 341 patients undergoing TIPS insertion for therapy of refractory or recurrent ascites until 2015. During each procedure, portal and inferior vena cava pressures were invasively measured and correlated with patients' outcome and ascites progression over time, according to the prespecified Noninvasive Evaluation Program for TIPS and Follow-Up Network protocol (NCT03628807). RESULTS: Patients without ascites at 6 weeks after TIPS had significantly greater PPG reduction immediately after TIPS, compared to the patients with refractory ascites (median reduction 65% vs. 55% of pre-TIPS PPG; p = 0.001). Survival was significantly better if ascites was controlled, compared to patients with need for paracentesis 6 weeks after TIPS (median survival: 185 vs. 41 weeks; HR 2.0 [1.3-2.9]; p < 0.001). Therefore, higher PPG reduction by TIPS ( p = 0.005) and lower PPG after TIPS ( p = 0.02) correlated with resolution of severe ascites 6 weeks after TIPS. Multivariable analyses demonstrated that higher Child-Pugh score before TIPS (OR 1.3 [1.0-1.7]; p = 0.03) and lower serum sodium levels (OR 0.9 [0.9-1.0]; p = 0.004) were independently associated with ascites persistence 6 weeks after TIPS, whereas PPG reduction (OR 0.98 [0.97-1.00]; p = 0.02) was associated with resolution of ascites 6 weeks after TIPS. CONCLUSION: Extent of PPG reduction and/or lowering of target PPG immediately after TIPS placement is associated with improved ascites control in the short term and with survival in the long term. A structured follow-up visit for patients should assess persistence of ascites at 6 weeks after TIPS.

Janus kinase 2 inhibition by pacritinib as potential therapeutic target for liver fibrosis.

BACKGROUND AND AIMS: Janus kinase 2 (JAK2) signaling is increased in human and experimental liver fibrosis with portal hypertension. JAK2 inhibitors, such as pacritinib, are already in advanced clinical development for other indications and might also be effective in liver fibrosis. Here, we investigated the antifibrotic role of the JAK2 inhibitor pacritinib on activated hepatic stellate cells (HSCs) in vitro and in two animal models of liver fibrosis in vivo . APPROACH AND RESULTS: Transcriptome analyses of JAK2 in human livers and other targets of pacritinib have been shown to correlate with profibrotic factors. Although transcription of JAK2 correlated significantly with type I collagen expression and other profibrotic genes, no correlation was observed for interleukin-1 receptor-associated kinase and colony-stimulating factor 1 receptor. Pacritinib decreased gene expression of fibrosis markers in mouse primary and human-derived HSCs in vitro . Moreover, pacritinib decreased the proliferation, contraction, and migration of HSCs. C 57 BL/6J mice received ethanol in drinking water (16%) or Western diet in combination with carbon tetrachloride intoxication for 7 weeks to induce alcoholic or nonalcoholic fatty liver disease. Pacritinib significantly reduced liver fibrosis assessed by gene expression and Sirius red staining, as well as HSC activation assessed by alpha-smooth muscle actin immunostaining in fibrotic mice. Furthermore, pacritinib decreased the gene expression of hepatic steatosis markers in experimental alcoholic liver disease. Additionally, pacritinib protected against liver injury as assessed by aminotransferase levels. CONCLUSIONS: This study demonstrates that the JAK2 inhibitor pacritinib may be promising for the treatment of alcoholic and nonalcoholic liver fibrosis and may be therefore relevant for human pathology.

Pulmonary impairment independently determines mortality in critically ill patients with acute-on-chronic liver failure.

BACKGROUND & AIMS: In ACLF patients, an adequate risk stratification is essential, especially for liver transplant allocation, since ACLF is associated with high short-term mortality. The CLIF-C ACLF score is the best prognostic model to predict outcome in ACLF patients. While lung failure is generally regarded as signum malum in ICU care, this study aims to evaluate and quantify the role of pulmonary impairment on outcome in ACLF patients. METHODS: In this retrospective study, 498 patients with liver cirrhosis and admission to IMC/ICU were included. ACLF was defined according to EASL-CLIF criteria. Pulmonary impairment was classified into three groups: unimpaired ventilation, need for mechanical ventilation and defined pulmonary failure. These factors were analysed in different cohorts, including a propensity score-matched ACLF cohort. RESULTS: Mechanical ventilation and pulmonary failure were identified as independent risk factors for increased short-term mortality. In matched ACLF patients, the presence of pulmonary failure showed the highest 28-day mortality (83.7%), whereas mortality rates in ACLF with mechanical ventilation (67.3%) and ACLF without pulmonary impairment (38.8%) were considerably lower (p < .001). Especially in patients with pulmonary impairment, the CLIF-C ACLF score showed poor predictive accuracy. Adjusting the CLIF-C ACLF score for the grade of pulmonary impairment improved the prediction significantly. CONCLUSIONS: This study highlights that not only pulmonary failure but also mechanical ventilation is associated with worse prognosis in ACLF patients. The grade of pulmonary impairment should be considered in the risk assessment in ACLF patients. The new score may be useful in the selection of patients for liver transplantation.

Health-related quality of life outcomes following Roux-en-Y gastric bypass versus one anastomosis gastric bypass.

PURPOSE: Roux-en-Y gastric bypass (RYGB) and one anastomosis gastric bypass (OAGB) are effective standard bariatric surgeries with comparable weight loss and remission of obesity-related comorbidities. As procedure-specific health-related quality of life (HrQoL) outcomes have not been directly compared thus far, we conducted this questionnaire-based study. METHODS: Two hundred forty patients after undergoing either RYGB or OAGB between 2011 and 2016 were contacted and asked to fill out SF36 and BAROS questionnaires. All statistical analysis was performed with Microsoft Excel and GraphPad Prism. Primary objectives were procedure-dependent differences in HrQoL. Secondary objectives were weight loss and remission of comorbidities. RESULTS: One hundred nineteen of 240 contacted patients (49.6%) replied, 58 after RYGB (48.7%) and 61 after OAGB (51.3%). Follow-up period was < 24 months in 52 and > 24 months in 64 evaluable patients. The mean age was 46 years (range 23 to 71). Regarding the < 24 months groups, both physical and psychological SF36 sum scales were comparably high. Only the subcategory "general health perception" was significantly better after RYGB. Significantly higher excess weight loss (EWL) after RYGB (88.81%) compared to OAGB (66.25%) caused significantly better global < 24 months BAROS outcomes, whereas remission of comorbidities and HrQoL was similar. Both > 24 months groups showed high SF36-HrQoL sum scales. Global mean BAROS results after > 24 months were "very good" in both procedures. EWL in RYGB (80.81%) and in OAGB (81.36%) were comparably excellent. CONCLUSION: Concerning SF36 and BAROS evaluated HrQoL in early and late postoperative phases, both procedures demonstrated comparable and relevant improvements. Further (preferably randomized) studies should include evaluation of preoperative HrQoL.

Two-dimensional shear wave elastography predicts survival in advanced chronic liver disease.

OBJECTIVE: Liver stiffness measurement (LSM) is a tool used to screen for significant fibrosis and portal hypertension. The aim of this retrospective multicentre study was to develop an easy tool using LSM for clinical outcomes in advanced chronic liver disease (ACLD) patients. DESIGN: This international multicentre cohort study included a derivation ACLD patient cohort with valid two-dimensional shear wave elastography (2D-SWE) results. Clinical and laboratory parameters at baseline and during follow-up were recorded. LSM by transient elastography (TE) was also recorded if available. The primary outcome was overall mortality. The secondary outcome was the development of first/further decompensation. RESULTS: After screening 2148 patients (16 centres), 1827 patients (55 years, 62.4% men) were included in the 2D-SWE cohort, with median liver SWE (L-SWE) 11.8 kPa and a model for end stage liver disease (MELD) score of 8. Combination of MELD score and L-SWE predict independently of mortality (AUC 0.8). L-SWE cut-off at ≥20 kPa combined with MELD ≥10 could stratify the risk of mortality and first/further decompensation in ACLD patients. The 2-year mortality and decompensation rates were 36.9% and 61.8%, respectively, in the 305 (18.3%) high-risk patients (with L-SWE ≥20 kPa and MELD ≥10), while in the 944 (56.6%) low-risk patients, these were 1.1% and 3.5%, respectively. Importantly, this M10LS20 algorithm was validated by TE-based LSM and in an additional cohort of 119 patients with valid point shear SWE-LSM. CONCLUSION: The M10LS20 algorithm allows risk stratification of patients with ACLD. Patients with L-SWE ≥20 kPa and MELD ≥10 should be followed closely and receive intensified care, while patients with low risk may be managed at longer intervals.

Roux-en-Y Versus One Anastomosis Gastric Bypass as Redo-Operations Following Sleeve Gastrectomy: A Retrospective Study.

BACKGROUND: Aim of this study was to improve knowledge about the best conversional bariatric procedure following sleeve gastrectomy (SG). METHODS: Data of conversional Roux-en-Y gastric bypass (RYGB) and of one anastomosis gastric bypass (OAGB) after SG were collected prospectively and analyzed retrospectively. Weight loss parameters, gastroesophageal reflux disease (GERD) and comorbidities outcomes were recorded. RESULTS: Total of 123 patients (90 female, mean age 44 ± 0.9 years, mean body mass index (BMI) 42 ± 0.8 kg/m2) had either RYGB (n = 68) or OAGB (n = 55). Perioperative mortality was zero. Mean surgery time was significantly shorter for OAGB (168 ± 7.2 vs. 201 ± 6.8 min). Perioperative complication rates were not significantly (ns) different between RYGB and OAGB. Total body weight loss (TBWL) in RYGB and OAGB was 18 ± 2.2% and 18 ± 1.9% (12 months) and 18 ± 3.0% and 23 ± 2.6% (24 months; ns), respectively. Length of (individualized) biliopancreatic limb (BPL) correlated significantly with weight loss. Remission rates after 12 months of RYGB and OAGB for arterial hypertension (aHt) were 89% and 92%, for obstructive sleep apnea (OSAS) 56% and 82%, for Type 2 diabetes mellitus (T2DM) 100% and 92%, for osteoarthritis 64% and 85% and for GERD 89% versus 87% (ns), respectively. Nutritional deficiencies were comparable in RYGB (n = 11) and OAGB (n = 14) group (ns). CONCLUSION: Both RYGB and OAGB are effective conversional procedures after SG, leading to comparable TBWL, BMI-loss and high remission rates of comorbidities including GERD. Significantly shorter operation times were in favor of OAGB. BPL, which was longer in OAGB was significantly related to higher %TBWL and %BMI-loss compared to RYGB.

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

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.

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

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.

Cardiodynamic state is associated with systemic inflammation and fatal acute-on-chronic liver failure.

BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is characterized by high short-term mortality and systemic inflammation (SI). Recently, different cardiodynamic states were shown to independently predict outcomes in cirrhosis. The relationship between cardiodynamic states, SI, and portal hypertension and their impact on ACLF development remains unclear. The aim of this study was therefore to evaluate the interplay of cardiodynamic state and SI on fatal ACLF development in cirrhosis. RESULTS: At inclusion, hemodynamic measures including cardiac index (CI) and hepatic venous pressure gradient of 208 patients were measured. Patients were followed prospectively for fatal ACLF development (primary endpoint). SI was assessed by proinflammatory markers such as interleukins (ILs) 6 and 8 and soluble IL-33 receptor (sIL-33R). Patients were divided according to CI (<3.2; 3.2-4.2; >4.2 L/min/m2 ) in hypo- (n = 84), normo- (n = 69) and hyperdynamic group (n = 55). After a median follow-up of 3 years, the highest risk of fatal ACLF was seen in hyperdynamic (35%) and hypodynamic patients (25%) compared with normodynamic (14%) (P = .011). Hyperdynamic patients showed the highest rate of SI. The detectable level of IL-6 was an independent predictor of fatal ACLF development. CONCLUSIONS: Cirrhotic patients with hyperdynamic and hypodynamic circulation have a higher risk of fatal ACLF. Therefore, the cardiodynamic state is strongly associated with SI, which is an independent predictor of development of fatal ACLF.

Recent Advances in Practical Methods for Liver Cell Biology: A Short Overview.

Molecular and cellular research modalities for the study of liver pathologies have been tremendously improved over the recent decades. Advanced technologies offer novel opportunities to establish cell isolation techniques with excellent purity, paving the path for 2D and 3D microscopy and high-throughput assays (e.g., bulk or single-cell RNA sequencing). The use of stem cell and organoid research will help to decipher the pathophysiology of liver diseases and the interaction between various parenchymal and non-parenchymal liver cells. Furthermore, sophisticated animal models of liver disease allow for the in vivo assessment of fibrogenesis, portal hypertension and hepatocellular carcinoma (HCC) and for the preclinical testing of therapeutic strategies. The purpose of this review is to portray in detail novel in vitro and in vivo methods for the study of liver cell biology that had been presented at the workshop of the 8th meeting of the European Club for Liver Cell Biology (ECLCB-8) in October of 2018 in Bonn, Germany.

Combination of CCl4 with alcoholic and metabolic injuries mimics human liver fibrosis.

Metabolic and alcoholic liver injuries result in nonalcoholic (NAFLD) or alcoholic (ALD) fatty liver disease, respectively. In particular, presence of fibrosis in NAFLD and ALD requires treatment, but development of drugs is hampered by the lack of suitable models with significant fibrosis. The carbon tetrachloride (CCl4) liver fibrosis model does not reflect human NAFLD or ALD, but CCl4 may serve as a fibrosis accelerator in addition to another injury. Ethanol in drinking water (16%) or Western diet (WD) were administered for 7 wk in mice either alone or in combination with CCl4 intoxications. Extent of fibrosis, steatosis, and inflammation was assessed by histology, transcription, and biochemistry. Furthermore, transcription of fibrosis, proliferation, and inflammation-related genes was studied on human liver samples with fibrosis resulting from hepatitis C virus infection (n = 7), NAFLD (n = 8), or ALD (n = 7). WD or ethanol alone induced only mild steatosis and inflammation. Combination of CCl4 and WD induced the most severe steatosis together with significant liver fibrosis and moderate inflammation. Combination of CCl4 and ethanol induced the strongest inflammation, with significant liver fibrosis and moderate steatosis. The relationship pattern between fibrosis, proliferation, and inflammation of human ALD was mostly similar in mice treated with CCl4 and ethanol. The combination of CCl4 intoxication with WD validates previous data suggesting it as an appropriate model for human nonalcoholic steatohepatitis. Especially, CCl4 plus ethanol for 7 wk induces ALD in mice, providing a model suitable for further basic research and drug testing.NEW & NOTEWORTHY Alcoholic fatty liver disease with significant fibrosis is generated within 7 wk using carbon tetrachloride as a fibrosis accelerator and administering gradually ethanol (up to 16%) in mice. The similarity in the pattern of steatosis, inflammation, and fibrosis involved in alcoholic fatty liver disease to those of the human condition renders this mouse model suitable as a preclinical model for drug development.

Stage of fibrosis is not a predictive determinant of weight loss in patients undergoing bariatric surgery.

BACKGROUND: Obesity and nonalcoholic fatty liver disease (NAFLD) are an increasing health care burden worldwide. Weight loss is currently the best option to alleviate NAFLD and is efficiently achieved by bariatric surgery. Presence of NAFLD seems to be predictive for postoperative weight loss. To date, only few predictive factors for postbariatric weight loss (age, diabetes, psychiatric disorders) are established. OBJECTIVES: Since liver fibrosis is the pathogenic driver for the progression of liver disease, we investigated its role in predicting postoperative weight loss. This study focuses on the correlation between fibrosis stage and weight loss. SETTING: University and university-affiliated cooperation, Germany. METHODS: We used a prospective, single-center cohort study including 164 patients who underwent bariatric surgery with simultaneous liver biopsies. Liver fibrosis was determined histologically according to Kleiner score and noninvasively by APRI and FIB-4 score. Percentage of total body weight loss was calculated at 1-year follow up visit. RESULTS: Thirty-two patients were found without fibrosis, whereas 91 patients showed mild fibrosis (F1), 37 significant fibrosis (F2), and only 4 patients presented advanced fibrosis (F3) at the time of bariatric surgery. Weight loss was similar across different degrees of fibrosis stage. Accordingly, linear regression analysis did not identify predictors of weight loss among fibrosis scores. In multivariable analysis, age and presence of diabetes showed the strongest predictive value. CONCLUSIONS: Baseline presence of fibrosis was not associated with postoperative weight loss, while age and diabetes were independent predictors of weight loss. Bariatric surgery should be applied independently of the fibrosis stage.

Association between endotoxemia and blood no in the portal circulation of cirrhotic patients: results of a pilot study.

Pathophysiology of portal vein thrombosis (PVT) in cirrhosis is still not entirely understood. Elevated levels of lipopolysaccharides (LPS) in portal circulation are significantly associated with hypercoagulation, increased platelet activation and endothelial dysfunction. The aim of the study was to investigate if LPS was associated with reduced portal venous flow, the third component of Virchow's triad, and the underlying mechanism. Serum nitrite/nitrate, as a marker of nitric oxide (NO) generation, and LPS were measured in the portal and systemic circulation of 20 patients with cirrhosis undergoing transjugular intrahepatic portosystemic shunt (TIPS) procedure; portal venous flow velocity (PVV) was also measured in each patient and correlated with NO and LPS levels. Serum nitrite/nitrate and LPS were significantly higher in the portal compared to systemic circulation; a significant correlation was found between LPS and serum nitrite/nitrate (R = 0.421; p < 0.01). Median PVV before and after TIPS was 15 cm/s (6-40) and 31 cm/s (14-79), respectively. Correlation analysis of PVV with NO and LPS showed a statistically significant negative correlation of PVV with portal venous NO concentration (R = - 0.576; p = 0.020), but not with LPS. In vitro study with endothelial cells showed that LPS enhanced endothelial NO biosynthesis, which was inhibited by L-NAME, an inhibitor of NO synthase, or TAK-242, an inhibitor of TLR4, the LPS receptor; this effect was accomplished by up-regulation of eNOS and iNOS. The study shows that in cirrhosis, endotoxemia may be responsible for reduced portal venous flow via overgeneration of NO and, therefore, contribute to the development of PVT.

Terlipressin therapy is associated with increased risk of colonisation with multidrug-resistant bacteria in patients with decompensated cirrhosis.

BACKGROUND: Patients with cirrhosis are susceptible to develop bacterial infections that trigger acute decompensation (AD) and acute-on-chronic liver failure (ACLF). Infections with multidrug-resistant organisms (MDRO) are associated with deleterious outcome. MDRO colonisation frequently proceeds MDRO infections and antibiotic therapy has been associated with MDRO colonisation. AIM: The aim of the study was to assess the influence of non-antibiotic medication contributing to MDRO colonisation. METHODS: Three hundred twenty-four patients with AD and ACLF admitted to the ICU of Frankfurt University Hospital with MDRO screening were included. Regression models were performed to identify drugs associated with MDRO colonisation. Another cohort (n = 129) from Barcelona was included to validate. A third multi-centre cohort (n = 203) with metagenomic sequencing data of stool was included to detect antibiotic resistance genes. RESULTS: A total of 97 patients (30%) were identified to have MDRO colonisation and 35 of them (11%) developed MDRO infection. Patients with MDRO colonisation had significantly higher risk of MDRO infection than those without (p = 0.0098). Apart from antibiotic therapy (odds ratio (OR) 2.91, 95%-confidence interval (CI) 1.82-4.93, p < 0.0001), terlipressin therapy in the previous 14 days was the only independent covariate associated with MDRO colonisation in both cohorts, the overall (OR 9.47, 95%-CI 2.96-30.23, p < 0.0001) and after propensity score matching (OR 5.30, 95%-CI 1.22-23.03, p = 0.011). In the second cohort, prior terlipressin therapy was a risk factor for MDRO colonisation (OR 2.49, 95% CI 0.911-6.823, p = 0.075) and associated with risk of MDRO infection during follow-up (p = 0.017). The validation cohort demonstrated that antibiotic inactivation genes were significantly associated with terlipressin administration (p = 0.001). CONCLUSIONS: Our study reports an increased risk of MDRO colonisation in patients with AD or ACLF, who recently received terlipressin therapy, while other commonly prescribed non-antibiotic co-medications had negligible influence. Future prospective trials are needed to confirm these results.

A Long-Term Comparative Study Between One Anastomosis Gastric Bypass and Sleeve Gastrectomy.

BACKGROUND: One anastomosis gastric bypass (OAGB) has become increasingly accepted in bariatric surgery and meanwhile represents the third most common procedure worldwide. While it shows promising weight loss results and comorbidity resolution, questions about issues such as reflux or nutritional deficiencies (ND) persist in the long term. On the other hand, the most frequently performed sleeve gastrectomy (SG) has to accept growing criticism regarding long-term results and reflux issues. There is a particular lack of long-term comparative data for both procedures. This study presents our long-term experience. METHODS: We evaluated OAGB and SG patients retrospectively comparing for weight loss and resolution of comorbidities as well as perioperative and long-term complications in a follow-up period of 5 years. RESULTS: Nine hundred eleven OAGB and 241 SG were included in the study. OAGB had a shorter operation time and hospital stay. Overall complication rate did not differ in both groups. Ulcers were more frequent in OAGB (7.7% vs. 1.7%, p = 0.001), whereas insufficient weight loss (IWL)/weight regain (WR) proved to be more prevalent in SG (25.7% vs. 6.4%, p < 0.001). The same held true for reflux (17.8% vs. 8.3%, p < .001). On the other hand, ND were more common in OAGB (20.0% vs. 12.0%, p = 0.005). Revisional surgery was more often indicated after SG. Analysis by linear mixed model showed that OAGB achieved a lower BMI/higher loss of BMI. Improvement of T2DM (94.6% vs. 85.2%, p = 0.008) and sleep apnea (88.8% vs. 78.8%, p = 0.01) was superior in OAGB. CONCLUSIONS: OAGB had a superior effect on weight loss as well as improvement of T2DM and sleep apnea. Furthermore, long-term problems such as IWL/WR and reflux were more related to SG. On the other hand, a malabsorptive procedure such as OAGB showed a higher risk for ND. Our findings support the available data in the literature.

Use and outcome of TIPS in hospitalized patients in Germany: A Nationwide study (2007-2018).

BACKGROUND: The number of complications in patients admitted for cirrhosis has increased over time. Portal hypertension is the driver of many complications of cirrhosis. TIPS placement is the most effective treatment of portal hypertension. The aim of this study was to analyze the use and impact of TIPS placement in the last decade in a nationwide study in Germany. METHODS: We analyzed 14,598 admissions of patients for TIPS insertions in Germany from 2007 to 2018 using the DRG system, 12,877 out of 2,000,765 total admissions of patients with cirrhosis. All diagnoses and procedures were coded according to ICD-10-CM and OPS codes. The data were analyzed, focusing on the number of admissions and in-hospital mortality. RESULTS: The number of TIPS placements increased over the last decade. In-hospital mortality of cirrhotic patients with TIPS decreased when it was placed for severe bleeding (15.2% [TIPS] vs. 19.5% [endoscopy treatment]), ascites (8.7% [TIPS] vs. 14.4% [paracentesis]), and hepatorenal syndrome (HRS) (17.1% [TIPS] vs. 43.3% [no-TIPS]). In the case of bleeding, TIPS significantly decreased in-hospital mortality and also in ascites and HRS. During hospitalization, 22.6% admissions of patients with TIPS insertion showed HE. However, in-hospital mortality in patients admitted with HE grades 1 or 2 and TIPS was lower than in patients without TIPS. In the logistic regression, a higher HE grade(3 and 4), infection, and circulatory disease were found to be independently associated with in-hospital mortality in patients with TIPS insertion. CONCLUSION: Our nationwide study demonstrates that TIPS insertion is increasingly used in Germany. TIPS improves outcomes, especially in patients with ascites and HRS, regardless of lower HE grades, while higher HE grades, infection, and circulatory diseases seem to be associated with risk of in-hospital mortality.

Epidemiology of liver transplantation and post-LT complications in Germany: nationwide study (2005-2018).

BACKGROUND: To date, liver transplantation (LT) is the only curative treatment for cirrhosis and early-diagnosed progressive acute liver failure (ALF). However, LT results in morbidities and mortality even post-LT. Different comorbidities may follow and further increase mortality and morbidity. In this study, we investigated the outcomes and their trends over a period of 14 years among hospitalized patients evaluated for LT, transplant and post-LT in Germany. METHODS: This German nationwide study investigated the number of admissions of patients hospitalized for evaluation of LT and post-LT on related comorbidities and complications between 2005 and 2018 based on the DRG system with ICD-10/OPS codes. 14 745 patients were put on the LT waiting list and 12 836 underwent LT during the observational period. RESULTS: The LT number decreased by 2.3% over time, while the waiting list mortality rate increased by 5%. By contrast, the in-hospital mortality rate decreased by 3%, especially in ALF patients (decrease of 16%). Interestingly, admissions of post-LT patients for complications almost doubled, driven mainly by complications of immunosuppression (tripled). Importantly, post-LT patients with acute kidney injury (20.2%) and biliodigestive anastomosis (18.4%) showed the highest in-hospital mortality rate of all complications. CONCLUSION: In conclusion, the decrease in LT leads most probably to the increased in-hospital mortality of patients on the waiting list. Interestingly, in-hospital mortality decreased in LT patients. Post-LT comorbidities requiring hospitalization increased in the observational period and management of patients post-LT with AKI or biliodigestive anastomosis should be addressed.

Myostatin is associated with the presence and development of acute-on-chronic liver failure.

Background & Aims: Acute-on-chronic liver failure (ACLF) has been linked to different pathophysiological mechanisms, including systemic inflammation and mitochondrial dysfunction. Sarcopenia has also been proposed as a potential mechanism; myostatin is a key factor inducing sarcopenia. Therefore, this study aimed to evaluate the association of myostatin levels with the development of ACLF and mortality in patients with cirrhosis. Methods: We performed a prospective cohort study, including both outpatient and hospitalized patients with cirrhosis. Clinical, biochemical, and nutritional parameters were evaluated, and the development of acute decompensation (AD) or ACLF during follow-up was recorded. ACLF was defined according to the EASL-CLIF criteria. Receiver-operating characteristic, Kaplan-Meier and Cox regression analyses were performed. Results: A total of 186 patients with the whole spectrum of cirrhosis were included; mean age was 53.4 ± 14 years, mean Child-Pugh score was 8 ± 2.5 and mean MELD score was 15 ± 8. There was a stepwise decrease in myostatin levels from a compensated stage to AD and ACLF. Myostatin correlated positively with nutritional markers and negatively with severity scores. The prevalence of sarcopenia was 73.6%. During follow-up, 27.9% of patients developed AD and 25.8% developed ACLF. Most episodes were grade 2-3, mainly (62.5%) precipitated by infections. The most common organ failures observed were in the liver (63.3%) and the kidney (64.6%). Receiver-operating characteristic analysis yielded <1,280 pg/ml as the best serum myostatin cut-off for the prediction of ACLF. In Kaplan-Meier curves and multivariate analysis, myostatin levels remained independently associated with the incidence of ACLF and survival. Conclusions: There is a progressive decrease in myostatin levels as cirrhosis progresses, demonstrating an association of sarcopenia with the development of ACLF and increased mortality. Impact and implications: Myostatin is a muscle hormone, it is decreased in patients with muscle loss and is a marker of impaired muscle function. In this study we show that myostatin levels are decreased in patients with cirrhosis, with lower levels in patients with acute decompensation and acute-on chronic liver failure (ACLF). Low myostatin levels in cirrhosis predict the development of ACLF and mortality independently of liver disease severity and sex.