Portal hypertension and cirrhosis: the role of inflammation and nitric oxide.

Patients with cirrhosis characteristically develop haemodynamic changes which include increased cardiac output, decreased systemic vascular resistance and paradoxically, increased portal pressure. Studies to date largely in animal models, have suggested that a decrease in hepatic nitric oxide may be important. The studies described in this thesis provide evidence for significantly elevated portal pressure in alcoholic hepatitis patients, who were shown to have a marked additional inflammatory response on the background of cirrhosis, and a more severe expression of disease. Studies in patients and a galactosamine rodent model confirmed a decrease in endothelial nitric oxide synthase (NOS) activity in the context of inflammatory liver injury. Following on from these observations, further studies explored the role of potential regulators of NOS which may have accounted for its decrease in activity in liver disease. Studies of asymmetric dimethylarginine (ADMA), an endogenous NOS inhibitor, showed that it was markedly increased in liver failure in both patients and in an animal model. The data suggested this may result from a decreased metabolism (through reduced expression of its metabolizing enzyme, dimethylarginine-dimethylaminohydrolase) or/and increased synthesis by protein arginine methyltransferases. ADMA was shown to correlate with severity of portal pressure, and with increased organ failure and death in decompensated cirrhosis, suggesting that it may have a potential use as a biomarker of disease severity. Other novel regulators of endothelial NOS were also explored including the recently described potential NOS inhibitor, NOSTRIN (nitric oxide synthase traffic inducer). It was demonstrated that NOSTRIN was up-regulated at both message and protein levels in liver disease patients and this was most marked in those with additional inflammation. A further novel observation was the identification of a variant of NOSTRIN which was only found in cirrhosis patients and not in normal liver tissue. The findings from these studies provide a better understanding of the importance of inflammation in the context of vascular dysfunction in cirrhosis and highlight some potential novel therapeutic targets

Worsening of cerebral hyperemia by the administration of terlipressin in acute liver failure with severe hepatic encephalopathy

There is increasing evidence that terlipressin is useful in patients with cirrhosis and hepatorenal syndrome, but there are no data of its use in patients with acute liver failure (ALF) in whom hepatorenal syndrome is common. Although terlipressin produces systemic vasoconstriction, it produces cerebral vasodilatation and may increase cerebral blood flow (CBF). Increased CBF contributes to intracranial hypertension in patients with ALF. The aim of this study was to evaluate the safety of terlipressin in patients with ALF with respect to cerebral haemodynamics. Six successive patients with ALF were electively ventilated for grade IV hepatic encephalopathy. Patients were monitored invasively and CBF was measured (Kety- Schmidt technique). Measurements were made before, at 1, 3 hour and 5 hours after intravenous (single bolus) administration of terlipressin (0.005 mg/kg) )intravenously (single bolus), median 0.25mg (range 0.2-0.3). There was no significant change in heart rate, mean arterial pressure or cardiac output. CBF and jugular venous oxygen saturation both increased significantly at 1 hour (p<0.0=0.016) respectively. Intracranial pressure increased significantly at 21 hours (p<0=.0.031), returning back to baseline values at 42 hours. This study shows that administration of terlipressin, at a dose that did not alter systemic haemodynamicshemodynamics, resulted in worsening of cerebral hyperemia and intracranial hypertension in patients with ALF and severe hepatic encephalopathy. These data suggest the need to exercise extreme caution in the use of terlipressin in these patients in view of its potentially deleterious consequences on cerebral haemodynamics

Treatment with non-selective beta blockers is associated with reduced severity of systemic inflammation and improved survival of patients with acute-on-chronic liver failure

Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Addressing Profiles of Systemic Inflammation Across the Different Clinical Phenotypes of Acutely Decompensated Cirrhosis

Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Geographical and temporal distribution of SARS-CoV-2 clades in the WHO European Region, January to June 2020

We show the distribution of SARS-CoV-2 genetic clades over time and between countries and outline potential genomic surveillance objectives. We applied three available genomic nomenclature systems for SARS-CoV-2 to all sequence data from the WHO European Region available during the COVID-19 pandemic until 10 July 2020. We highlight the importance of real-time sequencing and data dissemination in a pandemic situation. We provide a comparison of the nomenclatures and lay a foundation for future European genomic surveillance of SARS-CoV-2.Peer reviewe

Safety of two different doses of simvastatin plus rifaximin in decompensated cirrhosis (LIVERHOPE-SAFETY): a randomised, double-blind, placebo-controlled, phase 2 trial

Background: Statins have beneficial effects on intrahepatic circulation and decrease portal hypertension and rifaximin modulates the gut microbiome and might prevent bacterial translocation in patients with cirrhosis. Therefore, this drug combination might be of therapeutic benefit in patients with decompensated cirrhosis. However, there is concern regarding the safety of statins in patients with decompensated cirrhosis. We assessed the safety of two different doses of simvastatin, in combination with rifaximin, in patients with decompensated cirrhosis. Methods: We did a double-blind, randomised, placebo-controlled, phase 2 trial in patients with decompensated cirrhosis and moderate-to-severe liver failure from nine university hospitals in six European countries (Italy, France, Holland, Germany, the UK, and Spain). Patients older than 18 years with Child-Pugh class B or C disease were eligible. We randomly assigned patients (1:1:1) to receive either simvastatin 40 mg/day plus rifaximin 1200 mg/day, simvastatin 20 mg/day plus rifaximin 1200 mg/day, or placebo of both medications for 12 weeks. Randomisation was stratified according to Child-Pugh class (B vs C) and restricted using blocks of multiples of three. The primary endpoint was development of liver or muscle toxicity, as defined by changes in liver aminotransferases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]), alkaline phosphastase, and creatine kinase. The study is registered with the European Union Clinical Trials Register, 2016-004499-23, and with ClinicalTrials.gov, NCT03150459. Findings: The study recruitment period was between July 28, 2017, and Jan 2, 2018. Follow-up finished on March 12, 2018. 50 patients were randomly assigned to simvastatin 40 mg/day plus rifaximin 1200 mg/day (n=18), simvastatin 20 mg/day plus rifaximin 1200 mg/day (n=16), or placebo of both medications (n=16). Six patients (two from each group) were excluded. Therefore, the full analysis set included 44 patients (16 in the simvastatin 40 mg/day plus rifaximin 1200 mg/day group, 14 in the simvastatin 20 mg/day plus rifaximin mg/day group, and 14 in the placebo group). After a safety analyses when the first ten patients completed treatment, treatment was stopped prematurely in the simvastatin 40 mg/day plus rifaximin group due to recommendations by the data safety monitoring board. Patients in the simvastatin 40 mg/day plus rifaximin group showed a significant increase in AST and ALT compared with the placebo group (mean differences between the groups at the end of treatment for AST 130 IU/L [95% CI 54 to 205; p=0\ub70009] and for ALT 61 IU/L [22 to 100; p=0\ub70025]. We observed no significant differences at 12 weeks in AST and ALT between the simvastatin 20 mg/day plus rifaximin and placebo group (for AST 1214 IU/L [\u201391 to 64; p=0\ub7728] and for ALT 128 IU/L [\u201349 to 33; p=0\ub7698]). We observed no significant differences in alkaline phosphatase between the the simvastatin 40 mg/day plus rifaximin or the simvastatin 20 mg/day plus rifaximin groups compared with placebo. Patients in the simvastatin 40 mg/day plus rifaximin group showed an increase in creatine kinase at the end of treatment compared with patients in the placebo group (1009 IU/L [208 to 1809]; p=0\ub7014). We observed no significant changes in creatine kinase in the simvastatin 20 mg/day plus rifaximin group (4\ub72 IU/L [\u2013804 to 813]; p=0\ub7992). Three (19%) patients in the simvastatin 40 mg/day group developed liver and muscle toxicity consistent with rhabdomyolysis. The number of patients who stopped treatment because of adverse events was significantly higher in the simvastatin 40 mg/day plus rifaximin group (nine [56%] of 16 patients) compared with the other two groups (two [14%] of 14 for both groups; p=0\ub7017). There were no serious unexpected adverse reactions reported during the study. Interpretation: Treatment with simvastatin 40 mg/day plus rifaximin in patients with decompensated cirrhosis was associated with a significant increase in adverse events requiring treatment withdrawal, particularly rhabdomyolysis, compared with simvastatin 20 mg/day plus rifaximin. We recommend simvastatin 20 mg/day as the dose to be used in studies investigating the role of statins in patients with decompensated cirrhosis. Funding: Horizon 20/20 European programme