Alcohol-related liver disease (ALD), which includes a range of disorders of different severity and is one of the most prevalent types of liver disease worldwide, has recently regained increased ...attention. Among other reasons, the realisation that any alcohol intake, regardless of type of beverage represents a health risk, and the new therapeutic strategies tested in recently published or undergoing clinical trials spur scientific interest in this area.In April 2019, Gut convened a round table panel of experts during the European Association for the Study of the Liver International Liver Congress in Vienna to discuss critical and up-to-date issues and clinical trial data regarding ALD, its epidemiology, diagnosis, management, pathomechanisms, possible future treatments and prevention. This paper summarises the discussion and its conclusions.
Despite effective and safe hepatitis B virus (HBV) vaccine and antiviral therapies, HBV-related hepatocellular carcinoma (HCC) remains a major cause of deaths in young adults in Africa. There are ...multiple barriers to control the burden of HBV infection and HCC. In comparison to other major infectious diseases, HBV infection and liver diseases have received remarkably little attention from the global health community. There is an urgent need to improve birth dose vaccine coverage and implementing screening and treatment interventions. This requires a dramatic simplification of the management of chronic hepatitis B in Africa, with access to reliable, robust and inexpensive diagnostic tools and strong support from the local governments and the international health community. This review analyses 1) the characteristics of HBV hepatitis and HCC epidemics in Africa and 2) the barriers and potential solutions to control it.
Alcoholic hepatitis is a clinical syndrome characterized by jaundice and liver impairment that occurs in patients with a history of heavy and prolonged alcohol use. The short-term mortality among ...patients with severe disease exceeds 30%. Prednisolone and pentoxifylline are both recommended for the treatment of severe alcoholic hepatitis, but uncertainty about their benefit persists.
We conducted a multicenter, double-blind, randomized trial with a 2-by-2 factorial design to evaluate the effect of treatment with prednisolone or pentoxifylline. The primary end point was mortality at 28 days. Secondary end points included death or liver transplantation at 90 days and at 1 year. Patients with a clinical diagnosis of alcoholic hepatitis and severe disease were randomly assigned to one of four groups: a group that received a pentoxifylline-matched placebo and a prednisolone-matched placebo, a group that received prednisolone and a pentoxifylline-matched placebo, a group that received pentoxifylline and a prednisolone-matched placebo, or a group that received both prednisolone and pentoxifylline.
A total of 1103 patients underwent randomization, and data from 1053 were available for the primary end-point analysis. Mortality at 28 days was 17% (45 of 269 patients) in the placebo-placebo group, 14% (38 of 266 patients) in the prednisolone-placebo group, 19% (50 of 258 patients) in the pentoxifylline-placebo group, and 13% (35 of 260 patients) in the prednisolone-pentoxifylline group. The odds ratio for 28-day mortality with pentoxifylline was 1.07 (95% confidence interval CI, 0.77 to 1.49; P=0.69), and that with prednisolone was 0.72 (95% CI, 0.52 to 1.01; P=0.06). At 90 days and at 1 year, there were no significant between-group differences. Serious infections occurred in 13% of the patients treated with prednisolone versus 7% of those who did not receive prednisolone (P=0.002).
Pentoxifylline did not improve survival in patients with alcoholic hepatitis. Prednisolone was associated with a reduction in 28-day mortality that did not reach significance and with no improvement in outcomes at 90 days or 1 year. (Funded by the National Institute for Health Research Health Technology Assessment program; STOPAH EudraCT number, 2009-013897-42 , and Current Controlled Trials number, ISRCTN88782125 ).
The introduction of efficacious new hepatitis C virus (HCV) treatments galvanized the World Health Organization to define ambitious targets for eliminating HCV as a public health threat by 2030. ...Formidable obstacles to reaching this goal can best be overcome through a micro-elimination approach, which entails pursuing elimination goals in discrete populations through multi-stakeholder initiatives that tailor interventions to the needs of these populations. Micro-elimination is less daunting, less complex, and less costly than full-scale, country-level initiatives to eliminate HCV, and it can build momentum by producing small victories that inspire more ambitious efforts. The micro-elimination approach encourages stakeholders who are most knowledgeable about specific populations to engage with each other and also promotes the uptake of new models of care. Examples of micro-elimination target populations include medical patients, people who inject drugs, migrants, and prisoners, although candidate populations can be expected to vary greatly in different countries and subnational areas.
Fecal microbiota transplantation (FMT) is effective for treating recurrent Clostridioides difficile infection (CDI), but there are concerns about its long-term safety. Understanding the mechanisms of ...the effects of FMT could help us design safer, targeted therapies. We aimed to identify microbial metabolites that are important for C difficile growth.
We used a CDI chemostat model as a tool to study the effects of FMT in vitro. The following analyses were performed: C difficile plate counts, 16S rRNA gene sequencing, proton nuclear magnetic resonance spectroscopy, and ultra-performance liquid chromatography and mass spectrometry bile acid profiling. FMT mixtures were prepared using fresh fecal samples provided by donors enrolled in an FMT program in the United Kingdom. Results from chemostat experiments were validated using human stool samples, C difficile batch cultures, and C57BL/6 mice with CDI. Human stool samples were collected from 16 patients with recurrent CDI and healthy donors (n = 5) participating in an FMT trial in Canada.
In the CDI chemostat model, clindamycin decreased valerate and deoxycholic acid concentrations and increased C difficile total viable counts and valerate precursors, taurocholic acid, and succinate concentrations. After we stopped adding clindamycin, levels of bile acids and succinate recovered, whereas levels of valerate and valerate precursors did not. In the CDI chemostat model, FMT increased valerate concentrations and decreased C difficile total viable counts (94% decrease), spore counts (86% decrease), and valerate precursor concentrations; concentrations of bile acids were unchanged. In stool samples from patients with CDI, valerate was depleted before FMT but restored after FMT. Clostridioides difficile batch cultures confirmed that valerate decreased vegetative growth, and that taurocholic acid was required for germination but had no effect on vegetative growth. Clostridioides difficile total viable counts were decreased by 95% in mice with CDI given glycerol trivalerate compared with phosphate buffered saline.
We identified valerate as a metabolite that is depleted with clindamycin and only recovered with FMT. Valerate is a target for a rationally designed recurrent CDI therapy.
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Although metabolic risk factors are associated with more severe COVID-19, there is little evidence on outcomes in patients with non-alcoholic fatty liver disease (NAFLD). We here describe the ...clinical characteristics and outcomes of NAFLD patients in a cohort hospitalised for COVID-19.
This study included all consecutive patients admitted for COVID-19 between February and April 2020 at Imperial College Healthcare NHS Trust, with either imaging of the liver available dated within one year from the admission or a known diagnosis of NAFLD. Clinical data and early weaning score (EWS) were recorded. NAFLD diagnosis was based on imaging or past medical history and patients were stratified for Fibrosis-4 (FIB-4) index. Clinical endpoints were admission to intensive care unit (ICU)and in-hospital mortality.
561 patients were admitted. Overall, 193 patients were included in the study. Fifty nine patients (30%) died, 9 (5%) were still in hospital, and 125 (65%) were discharged. The NAFLD cohort (n = 61) was significantly younger (60 vs 70.5 years, p = 0.046) at presentation compared to the non-NAFLD (n = 132). NAFLD diagnosis was not associated with adverse outcomes. However, the NAFLD group had higher C reactive protein (CRP) (107 vs 91.2 mg/L, p = 0.05) compared to non-NAFLD(n = 132). Among NAFLD patients, male gender (p = 0.01), ferritin (p = 0.003) and EWS (p = 0.047) were associated with in-hospital mortality, while the presence of intermediate/high risk FIB-4 or liver cirrhosis was not.
The presence of NAFLD per se was not associated with worse outcomes in patients hospitalised for COVID-19. Though NAFLD patients were younger on admission, disease stage was not associated with clinical outcomes. Yet, mortality was associated with gender and a pronounced inflammatory response in the NAFLD group.
Progress towards viral hepatitis elimination goals relies on accurate estimates of chronic hepatitis B virus (HBV)-infection prevalence. We compared existing sources of country-level estimates from ...2013 to 2017 to investigate the extent and underlying drivers of differences between them.
The four commonly cited sources of global-prevalence estimates, i.e. the Institute for Health Metrics and Evaluation, Schweitzer et al., the World Health Organization (WHO) and the CDA Foundation, were compared by calculating pairwise differences between sets of estimates and assessing their within-country variation. Differences in underlying empirical data and modelling methods were investigated as contributors to differences in sub-Saharan African estimates.
The four sets of estimates across all ages were comparable overall and agreed on the global distribution of HBV burden. The WHO and the CDA produced the most similar estimates, differing by a median of 0.8 percentage points. Larger discrepancies were seen in estimates of prevalence in children under 5 years of age and in sub-Saharan African countries, where the median pairwise differences were 2.7 percentage and 2.4 percentage points for all-age prevalence and in children, respectively. Recency and representativeness of included data, and different modelling assumptions of the age distribution of HBV burden, seemed to contribute to these differences.
Current prevalence estimates, particularly those from the WHO and the CDA based on more recent empirical data, provide a useful resource to assess the population-level burden of chronic HBV-infection. However, further seroprevalence data in young children are needed particularly in sub-Saharan Africa. This is a priority, as monitoring progress towards elimination depends on improved knowledge of prevalence in this age group.
Problematic alcohol use (PAU) is a leading cause of death and disability worldwide. Although genome-wide association studies have identified PAU risk genes, the genetic architecture of this trait is ...not fully understood. We conducted a proxy-phenotype meta-analysis of PAU, combining alcohol use disorder and problematic drinking, in 435,563 European-ancestry individuals. We identified 29 independent risk variants, 19 of them novel. PAU was genetically correlated with 138 phenotypes, including substance use and psychiatric traits. Phenome-wide polygenic risk score analysis in an independent biobank sample (BioVU, n = 67,589) confirmed the genetic correlations between PAU and substance use and psychiatric disorders. Genetic heritability of PAU was enriched in brain and in conserved and regulatory genomic regions. Mendelian randomization suggested causal effects on liability to PAU of substance use, psychiatric status, risk-taking behavior and cognitive performance. In summary, this large PAU meta-analysis identified novel risk loci and revealed genetic relationships with numerous other traits.
Alcohol-associated liver disease (ALD) is the most common cause of cirrhosis and liver-related mortality in many regions worldwide. Around 75% of patients with cirrhosis are unaware of their disease ...until they are referred to the emergency department. An innovative, noninvasive screening approach is required for an earlier diagnosis of liver fibrosis. In patients with ALD the physician is inevitably dealing with 2 major disorders: the liver disease itself and the alcohol use disorder (AUD). Focus only on the liver disease will inevitably lead to failure because transient improvements in liver function are rapidly overturned if the patient returns to alcohol consumption. For this reason, integrated models of care provided by hepatologists and addiction specialists are an effective approach, which are, however, not widely available. There are multiple pharmacologic and non-pharmacologic therapies for AUD. Progress has recently been made in the management of patients with severe AH who have improved survival through better understanding of the concept of response to medical treatment, improved survival prediction, and the advent of early liver transplantation. The emerging concept is that listing for transplantation a patient with severe ALD could lead to adjusting the duration of abstinence according to the severity and evolution of liver dysfunction and the patient’s addictive profile.
Acute liver failure (ALF) is characterised by overwhelming hepatocyte death and liver inflammation with massive infiltration of myeloid cells in necrotic areas. The mechanisms underlying resolution ...of acute hepatic inflammation are largely unknown. Here, we aimed to investigate the impact of Mer tyrosine kinase (MerTK) during ALF and also examine how the microenvironmental mediator, secretory leucocyte protease inhibitor (SLPI), governs this response.
Flow cytometry, immunohistochemistry, confocal imaging and gene expression analyses determined the phenotype, functional/transcriptomic profile and tissue topography of MerTK+ monocytes/macrophages in ALF, healthy and disease controls. The temporal evolution of macrophage MerTK expression and its impact on resolution was examined in APAP-induced acute liver injury using wild-type (WT) and Mer-deficient (Mer
) mice. SLPI effects on hepatic myeloid cells were determined in vitro and in vivo using APAP-treated WT mice.
We demonstrate a significant expansion of resolution-like MerTK+HLA-DR
cells in circulatory and tissue compartments of patients with ALF. Compared with WT mice which show an increase of MerTK+MHCII
macrophages during the resolution phase in ALF, APAP-treated Mer
mice exhibit persistent liver injury and inflammation, characterised by a decreased proportion of resident Kupffer cells and increased number of neutrophils. Both in vitro and in APAP-treated mice, SLPI reprogrammes myeloid cells towards resolution responses through induction of a MerTK+HLA-DR
phenotype which promotes neutrophil apoptosis and their subsequent clearance.
We identify a hepatoprotective, MerTK+, macrophage phenotype that evolves during the resolution phase following ALF and represents a novel immunotherapeutic target to promote resolution responses following acute liver injury.
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