The Role of Hypoxia-Inducible Factor 1 Alpha in Acute-on-Chronic Liver Failure.

Acute-on-chronic liver failure (ACLF) is associated with increased mortality. Specific therapy options are limited. Hypoxia-inducible factor 1 alpha (HIF-1α) has been linked to the pathogenesis of chronic liver disease (CLD), but the role of HIF-1α in ACLF is poorly understood. In the current study, different etiologies of CLD and precipitating events triggering ACLF were used in four rodent models. HIF-1α expression and the intracellular pathway of HIF-1α induction were investigated using real-time quantitative PCR. The results were verified by Western blotting and immunohistochemistry for extrahepatic HIF-1α expression using transcriptome analysis. Exploratory immunohistochemical staining was performed to assess HIF-1α in human liver tissue. Intrahepatic HIF-1α expression was significantly increased in all animals with ACLF, regardless of the underlying etiology of CLD or the precipitating event. The induction of HIF-1α was accompanied by the increased mRNA expression of NFkB1 and STAT3 and resulted in a marked elevation of mRNA levels of its downstream genes. Extrahepatic HIF-1α expression was not elevated. In human liver tissue samples, HIF-1α expression was elevated in CLD and ACLF. Increased intrahepatic HIF-1α expression seems to play an important role in the pathogenesis of ACLF, and future studies are pending to investigate the role of therapeutic HIF inhibitors in ACLF.

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.

Impact of colonization with multidrug-resistant organisms on antibiotic prophylaxis in patients with cirrhosis and variceal bleeding.

BACKGROUND: The efficacy of antibiotic prophylaxis to prevent rebleeding or infection after variceal bleeding in patients with liver cirrhosis colonized with multidrug-resistant organisms (MDROs) is unknown. METHODS: In this retrospective study, patients with liver cirrhosis and endoscopically confirmed variceal bleeding who were treated at a tertiary care center in Germany and were screened for MDROs at the time of bleeding were eligible for inclusion. Efficacy of antibiotic prophylaxis was evaluated in patients stratified according to microbiological susceptibility testing. RESULTS: From 97 patients, the majority had decompensated liver cirrhosis (median MELD Score 17) and ACLF was present in half of the patients (47.4%). One third of patients were colonized with MDRO at baseline. De-novo infection until day 10 or the combination of de-novo infection or rebleeding were comparable among both groups (p = 0.696 and p = 0.928, log-rank-test). Risk of de-novo infection or rebleeding was not significantly increased in patients who received antibiotic prophylaxis that did not cover the MDRO found upon baseline screening. Acute-on-chronic liver failure at baseline was the strongest and only independent risk factor that was associated with both outcomes (OR 5.52, 95%-CI 1.48-20.61, p = 0.011 and OR 11.5, 95%-CI 2.70-48.62, p<0.001). Neither MDRO colonization at baseline nor covering all detected MDRO with antibiotic prophylaxis (i.e. "adequate" prophylaxis) impacted transplant-free survival. Again, the presence of ACLF was the strongest independent risk factor associated with mortality (OR 9.85, 95%-CI 3.58-27.12, p<0.0001). CONCLUSION: In this study, MDRO colonization did not increase the risk of rebleeding, infections nor death, even if antibiotic prophylaxis administered did not cover all MDRO detected at MDRO screening. Patients with ACLF had an increased risk of bleeding, infections and death.

Stool and sputum microbiome during quinolone prophylaxis of spontaneous bacterial peritonitis: an exploratory study.

INTRODUCTION: Quinolone prophylaxis is recommended for patients with advanced cirrhosis at high risk of spontaneous bacterial peritonitis (SBP) or with prior SBP. Yet, the impact of long-term antibiotic prophylaxis on the microbiome of these patients is poorly characterized. METHODS: Patients with liver cirrhosis receiving long-term quinolone prophylaxis to prevent SBP were prospectively included and sputum and stool samples were obtained at baseline, 1, 4 and 12 weeks thereafter. Both bacterial DNA and RNA were assessed with 16S rRNA sequencing. Relative abundance, alpha and beta diversity were calculated and correlated with clinical outcome. RESULTS: Overall, 35 stool and 19 sputum samples were obtained from 11 patients. Two patients died (day 9 and 12) all others were followed for 180 days. Reduction of Shannon diversity and bacterial richness was insignificant after initiation of quinolone prophylaxis (p > 0.05). Gut microbiota were significantly different between patients (p < 0.001) but non-significantly altered between the different time points before and after initiation of antibiotic prophylaxis (p > 0.05). A high relative abundance of Enterobacteriaceae > 20% during quinolone prophylaxis was found in three patients. Specific clinical scenarios (development of secondary infections during antibiotic prophylaxis or the detection of multidrug-resistant Enterobacteriaceae) characterized these patients. Sputum microbiota were not significantly altered in individuals during prophylaxis. CONCLUSION: The present exploratory study with small sample size showed that inter-individual differences in diversity of gut microbiota were high at baseline, yet quinolone prophylaxis had only a moderate impact. High relative abundances of Enterobacteriaceae during follow-up might indicate failure of or non-adherence to quinolone prophylaxis. However, our results may not be clinically significant given the limitations of the study and therefore future studies are needed to further investigate this phenomenon.

Efficacy of Norfloxacin Prophylaxis to Prevent Spontaneous Bacterial Peritonitis: A Systematic Review and Meta-Analysis.

INTRODUCTION: With the emergence of multidrug-resistant organisms, the efficacy of antibiotic prophylaxis to prevent spontaneous bacterial peritonitis (SBP) has been debated. The aim of this study was to assess factors impacting effectiveness of SBP prophylaxis. METHODS: We searched PubMed, Embase, and the Cochrane Registry from inception to May 2019 to identify randomized controlled trials of patients with liver cirrhosis that assessed SBP occurrence/recurrence during antibiotic prophylaxis with the common antibiotic agents. Network meta-analysis was performed, pooling data with regard to incidence rate ratios (IRRs) of SBP, death, or extraperitoneal infections. RESULTS: Overall, 1,626 patients in 12 randomized controlled trials were included. During primary prophylaxis, the incidence rate of SBP and death in the norfloxacin-treated patients was 0.117 and 0.438 per patient-year, respectively, and IRRs of placebo vs norfloxacin were significantly higher (IRR 5.35, 95% confidence interval 1.99-14.38, P = 0.0009 for SBP and IRR 2.04, 95% confidence interval 1.20-3.44, P = 0.008 for death). The efficacy of norfloxacin to prevent SBP, but not death, decreased over time (annual percent change from 1992 to 2015 8.2%, P = 0.019), The positive treatment effect was lower in studies including patients with increased ascites protein (P = 0.021) or exceedingly high serum bilirubin (P = 0.012) levels. Norfloxacin was not superior to other antibiotics. The incidence rate of SBP was 2.5-fold higher in patients treated with norfloxacin as secondary compared with primary prophylaxis. No significant differences between treatment designs were observed in secondary prophylaxis. DISCUSSION: Norfloxacin remained superior to placebo in preventing SBP, yet the efficacy to prevent SBP, not death, decreased over time. Further studies to understand this phenomenon are urgently needed.