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ImportanceThere are no useful treatments to prevent the development of severe complications of liver cirrhosis. Simvastatin and rifaximin have shown beneficial effects in liver cirrhosis.ObjectiveTo assess whether simvastatin combined with rifaximin improves outcomes in patients with decompensated cirrhosis.Design, Setting, and ParticipantsDouble-blind, placebo-controlled, phase 3 trial conducted among patients with decompensated cirrhosis in 14 European hospitals between January 2019 and December 2022. The last date of follow-up was December 2022.InterventionsPatients were randomly assigned to receive simvastatin, 20 mg/d, plus rifaximin, 1200 mg/d (n = 117), or identical-appearing placebo (n = 120) for 12 months in addition to standard therapy, stratified according to Child-Pugh class B or C.Main Outcomes and MeasuresThe primary end point was incidence of severe complications of liver cirrhosis associated with organ failure meeting criteria for acute-on-chronic liver failure. Secondary outcomes included transplant or death and a composite end point of complications of cirrhosis (ascites, hepatic encephalopathy, variceal bleeding, acute kidney injury, and infection).ResultsAmong the 237 participants randomized (Child-Pugh class B: n = 194; Child-Pugh class C: n = 43), 72% were male and the mean age was 57 years. There were no differences between the 2 groups in terms of development of acute-on-chronic liver failure (21 [17.9%] vs 17 [14.2%] patients in the treatment and placebo groups, respectively; hazard ratio, 1.23; 95% CI, 0.65-2.34; P = .52); transplant or death (22 [18.8%] vs 29 [24.2%] patients in the treatment and placebo groups, respectively; hazard ratio, 0.75; 95% CI, 0.43-1.32; P = .32); or development of complications of cirrhosis (50 [42.7%] vs 55 [45.8%] patients in the treatment and placebo groups, respectively; hazard ratio, 0.93; 95% CI, 0.63-1.36; P = .70). Incidence of adverse events was similar in both groups (426 vs 419; P = .59), but 3 patients in the treatment group (2.6%) developed rhabdomyolysis.Conclusions and RelevanceThe addition of simvastatin plus rifaximin to standard therapy does not improve outcomes in patients with decompensated liver cirrhosis.Trial RegistrationClinicalTrials.gov Identifier: NCT03780673

Background and Aims: Fatty liver disease is a major public health threat due to its very high prevalence and related morbidity and mortality. Focused and dedicated interventions are urgently needed to target disease prevention, treatment, and care. Approach and Results: We developed an aligned, prioritized action agenda for the global fatty liver disease community of practice. Following a Delphi methodology over 2 rounds, a large panel (R1 n = 344, R2 n = 288) reviewed the action priorities using Qualtrics XM, indicating agreement using a 4-point Likert-scale and providing written feedback. Priorities were revised between rounds, and in R2, panelists also ranked the priorities within 6 domains: epidemiology, treatment and care, models of care, education and awareness, patient and community perspectives, and leadership and public health policy. The consensus fatty liver disease action agenda encompasses 29 priorities. In R2, the mean percentage of “agree” responses was 82.4%, with all individual priorities having at least a super-majority of agreement (> 66.7% “agree”). The highest-ranked action priorities included collaboration between liver specialists and primary care doctors on early diagnosis, action to address the needs of people living with multiple morbidities, and the incorporation of fatty liver disease into relevant non-communicable disease strategies and guidance. Conclusions: This consensus-driven multidisciplinary fatty liver disease action agenda developed by care providers, clinical researchers, and public health and policy experts provides a path to reduce the prevalence of fatty liver disease and improve health outcomes. To implement this agenda, concerted efforts will be needed at the global, regional, and national levels.

Patients with decompensated cirrhosis, particularly those with acute‐on‐chronic liver failure (ACLF), show profound alterations in plasma metabolomics. The aim of this study was to investigate the effect of treatment with simvastatin and rifaximin on plasma metabolites of patients with decompensated cirrhosis, specifically on compounds characteristic of the ACLF plasma metabolomic profile. Two cohorts of patients were investigated. The first was a descriptive cohort of patients with decompensated cirrhosis (n = 42), with and without ACLF. The second was an intervention cohort from the LIVERHOPE‐SAFETY randomized, double‐blind, placebo‐controlled trial treated with simvastatin 20 mg/day plus rifaximin 1,200 mg/day (n = 12) or matching placebo (n = 13) for 3 months. Plasma samples were analyzed using ultrahigh performance liquid chromatography–tandem mass spectroscopy for plasma metabolomics characterization. ACLF was characterized by intense proteolysis and lipid alterations, specifically in pathways associated with inflammation and mitochondrial dysfunction, such as the tryptophan–kynurenine and carnitine beta‐oxidation pathways. An ACLF‐specific signature was identified. Treatment with simvastatin and rifaximin was associated with changes in 161 of 985 metabolites in comparison to treatment with placebo. A remarkable reduction in levels of metabolites from the tryptophan–kynurenine and carnitine pathways was found. Notably, 18 of the 32 metabolites of the ACLF signature were affected by the treatment. Conclusion: Treatment with simvastatin and rifaximin modulates some of the pathways that appear to be key in ACLF development. This study unveils some of the mechanisms involved in the effects of treatment with simvastatin and rifaximin in decompensated cirrhosis and sets the stage for the use of metabolomics to investigate new targeted therapies in cirrhosis to prevent ACLF development.

AbstractWhether tubular injury develops in patients with acute kidney injury owing to hepatorenal syndrome (AKI‐HRS) is controversial. We performed repeated measurements of biomarkers of tubular injury during a 14‐day period in 60 patients with cirrhosis and AKI (34 with AKI‐HRS meeting the classical definition of type 1 HRS and 26 with AKI owing to acute tubular necrosis, AKI‐ATN). Nineteen of 34 patients had resolution of AKI‐HRS, while the remainder had persistent AKI‐HRS. The persistence of AKI‐HRS was associated with remarkably high short‐term mortality. There were no significant differences in urinary NGAL or IL‐18 between patients with resolution vs those with persistent AKI‐HRS throughout the 14‐day period. By contrast, biomarker levels were significantly lower in AKI‐HRS, even if persistent, compared to AKI‐ATN. These findings are highly suggestive of lack of significant tubular injury in AKI‐HRS and could be of value in the clinical decision between combined liver–kidney or liver transplantation alone in patients with cirrhosis and AKI candidates to transplantation.

Abstract Cirrhosis, highly prevalent worldwide, develops after years of hepatic inflammation triggering progressive fibrosis. Currently, the main etiologies of cirrhosis are non‐alcoholic fatty liver disease and alcohol‐related liver disease, although chronic hepatitis B and C infections are still major etiological factors in some areas of the world. Recent studies have shown that liver fibrosis can be assessed with relatively high accuracy noninvasively by serological tests, transient elastography, and radiological methods. These modalities may be utilized for screening for liver fibrosis in at‐risk populations. Thus far, a limited number of population‐based studies using noninvasive tests in different areas of the world indicate that a significant percentage of subjects without known liver disease (around 5% in general populations and a higher rate −18% to 27%‐in populations with risk factors for liver disease) have significant undetected liver fibrosis or established cirrhosis. Larger international studies are required to show the harms and benefits before concluding that screening for liver fibrosis should be applied to populations at risk for chronic liver diseases. Screening for liver fibrosis has the potential for changing the current approach from diagnosing chronic liver diseases late when patients have already developed complications of cirrhosis to diagnosing liver fibrosis in asymptomatic subjects providing the opportunity of preventing disease progression.

OBJECTIVES: Hepatic encephalopathy (HE) is common in advanced cirrhosis and is characterized by marked neuropsychiatric abnormalities. However, despite its severity and effects on brain function, the impact of HE on psychological status of patients has not been adequately assessed. The aim of this study was to evaluate the effect of HE on psychological status of patients and their informal caregivers. METHODS: Fifteen patients with cirrhosis and episodic or persistent HE and their corresponding informal caregivers were included. Semistructured interviews were performed in patients and caregivers. Quality of life (QoL) was assessed by the short-form 36 in both patients and caregivers, and the Zarit burden score was measured in caregivers. The analysis of interviews was performed using qualitative methodology. RESULTS: HE causes a major psychological impact on patients with HE. The first episode of HE caused a very significant impact that was reported with deep feelings, mainly of fear, anger, misery, anxiety, and sorrow, which persisted with time. Symptoms causing more psychological impact on patients were impaired ability to walk and speak. All effects were associated with a marked impairment in QoL. The psychological impact was also marked in caregivers who had a major burden, as assessed by the Zarit score. Moreover, QoL, particularly the mental component score, was markedly impaired in caregivers in intensity similar to that of patients. DISCUSSION: HE has a profound psychological impact on patients and their informal caregivers, associated with a marked negative influence on QoL. The psychological effects of HE on patients and caregivers should be evaluated and treated.