Showing papers in "Liver International in 2018"

Liver diseases: A major, neglected global public health problem requiring urgent actions and large-scale screening.

Abstract: CLDs represent an important, and certainly underestimated, global public health problem. CLDs are highly prevalent and silent, related to different, sometimes associated causes. The distribution of the causes of these diseases is slowly changing, and within the next decade, the proportion of virus-induced CLDs will certainly decrease significantly while the proportion of NASH will increase. There is an urgent need for effective global actions including education, prevention and early diagnosis to manage and treat CLDs, thus preventing cirrhosis-related morbidity and mortality. Our role is to increase the awareness of the public, healthcare professionals and public health authorities to encourage active policies for early management that will decrease the short- and long-term public health burden of these diseases. Because necroinflammation is the key mechanism in the progression of CLDs, it should be detected early. Thus, large-scale screening for CLDs is needed. ALT levels are an easy and inexpensive marker of liver necroinflammation and could be the first-line tool in this process.

Global epidemiology of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis: What we need in the future.

Abstract: The estimated prevalence of non-alcoholic fatty liver disease (NAFLD) worldwide is approximately 25%. However, the real prevalence of NAFLD and the associated disorders is unknown mainly because reliable and applicable diagnostic tests are lacking. This is further complicated by the lack of consensus on the terminology of different entities such as NAFLD or nonalcoholic steatohepatitis (NASH). Although assessing fatty infiltration in the liver is simple by ultrasound, the gold standard for the assessment of fibrosis, the only marker of progression towards more severe liver disease is still liver biopsy. Although other non-invasive tests have been proposed, they must still be validated in large series. Because NAFL/NAFLD/NASH and related metabolic diseases represent an economic burden, finding an inexpensive method to diagnose and stage fatty liver is a priority. A translational approach with the use of cell and/or animal models could help to reach this goal.

Hepatotoxicity of immune checkpoint inhibitors: An evolving picture of risk associated with a vital class of immunotherapy agents.

Abstract: Immune checkpoint inhibitors (ICIs) block CTLA-4, PD-1 and PD-L1, or other molecules that control antitumour activities of lymphocytes. These products are associated with a broad array of immune-related toxicities affecting a variety of organs, including the liver. ICI-associated immune-mediated hepatitis (IMH) ranges in severity between mild and life-threatening and is marked by findings that bear both similarities as well as differences with idiopathic autoimmune hepatitis. Hepatotoxic events are often detected in clinical trials of ICIs that are powered for efficacy. Risk levels for ICI-induced liver injury may be impacted by the specific checkpoint molecule targeted for treatment, the ICI dose levels, and the presence of a pre-existing autoimmune diathesis, chronic infection or tumour cells which infiltrate the liver parenchyma. When patients develop liver injury during ICI treatment, a prompt assessment of the cause of injury, in conjunction with the application of measures to optimally manage the adverse event, should be made. Strategies to manage the risk of IMH include the performance of pretreatment liver tests with regular monitoring during and after ICI treatment and patient education. Using Common Terminology Criteria for Adverse Events developed at the National Cancer Institute to measure the severity level of liver injury, recommended actions may include continued ICI treatment with close patient monitoring, ICI treatment suspension or discontinuation and/or administration of corticosteroids or, when necessary, a non-steroidal immunosuppressive agent. The elucidation of reliable predictors of tumour-specific ICI treatment responses, as well as an increased susceptibility for clinically serious immune-related adverse events, would help optimize treatment decisions for individual patients.

Dual PPARα/γ agonist saroglitazar improves liver histopathology and biochemistry in experimental NASH models

Abstract: Background & aims Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are common clinico-pathological conditions that affect millions of patients worldwide. In this study, the efficacy of saroglitazar, a novel PPARα/γ agonist, was assessed in models of NAFLD/NASH. Methods & results HepG2 cells treated with palmitic acid (PA;0.75 mM) showed decreased expression of various antioxidant biomarkers (SOD1, SOD2, glutathione peroxidase and catalase) and increased expression of inflammatory markers (TNFα, IL1β and IL6). These effects were blocked by saroglitazar, pioglitazone and fenofibrate (all tested at 10μM concentration). Furthermore, these agents reversed PA-mediated changes in mitochondrial dysfunction, ATP production, NFkB phosphorylation and stellate cell activation in HepG2 and HepG2-LX2 Coculture studies. In mice with choline-deficient high-fat diet-induced NASH, saroglitazar reduced hepatic steatosis, inflammation, ballooning and prevented development of fibrosis. It also reduced serum alanine aminotransferase, aspartate aminotransferase and expression of inflammatory and fibrosis biomarkers. In this model, the reduction in the overall NAFLD activity score by saroglitazar (3 mg/kg) was significantly more prominent than pioglitazone (25 mg/kg) and fenofibrate (100 mg/kg). Pioglitazone and fenofibrate did not show any improvement in steatosis, but partially improved inflammation and liver function. Antifibrotic effect of saroglitazar (4 mg/kg) was also observed in carbon tetrachloride-induced fibrosis model. Conclusions Saroglitazar, a dual PPARα/γ agonist with predominant PPARα activity, shows an overall improvement in NASH. The effects of saroglitazar appear better than pure PPARα agonist, fenofibrate and PPARγ agonist pioglitazone.

Treatment of hepatitis C virus infection with direct-acting antiviral agents: 100% cure?

Abstract: Around 71 million people are chronically infected with HCV worldwide. HCV antiviral drug development has been remarkable. The availability of pangenotypic direct-acting antivirals with excellent efficacy and good tolerability profiles offer a unique opportunity to achieve HCV elimination worldwide. IFN-free DAA combinations can now cure HCV in more than 95% of patients with HCV infection after 8-12 weeks of treatment. Programmes to eliminate HCV must include increased screening (risk-based and universal), linkage to care, as well as increased access to treatment worldwide. In this paper, we will review the available data on recently approved direct-acting antiviral agents, with sustained virological response that reaches almost 100%.

Infections complicating cirrhosis.

Abstract: Patients with cirrhosis have a high risk of bacterial infections. Bacterial infections induce systemic inflammation that may lead to organ failure and acute-on-chronic liver failure (ACLF) resulting in a high risk of short term mortality. The early diagnosis and treatment of bacterial infections is essential to improve the patient's prognosis. However, in recent years, the spread of multidrug resistant (MDR) bacterial infections has reduced the efficacy of commonly used antibiotics such as third generation cephalosporins. In patients at high risk of MDR bacteria, such as those with nosocomial infections, the early administration of broad spectrum antibiotics has been shown to improve the prognosis. However, early de-escalation of antibiotics is recommended to reduce a further increase in antibiotic resistance. Strategies to prevent acute kidney injury and other organ failures should be implemented. Although prophylaxis of bacterial infections with antibiotics improves the prognosis in selected patients, their use should be limited to patients at high risk of developing infections. In this article, we review the pathogenesis and management of bacterial infections in patients with cirrhosis.

The impact of treatment of hepatitis C with DAAs on the occurrence of HCC.

Abstract: Hepatitis C virus infection is a major cause of chronic hepatitis resulting in cirrhosis and hepatocellular carcinoma (HCC). The recent introduction of direct acting antivirals (DAA), results in sustained virological response (SVR) rates of >90% in treated patients whatever the stage of liver fibrosis with an excellent safety profile. This major advancement has allowed treatment of a larger number of patients, some with more advanced liver dysfunction and a higher risk of HCC. An SVR is associated with a reduced risk of hepatic decompensation, the need for liver transplantation and both liver-related and overall mortality. This high rate of SVR has raised hopes that there would be a significant reduction in the incidence of HCC. However, the impact of DAA-based regimens on the occurrence of HCC in patients with cirrhosis, and in particular the recurrence of HCC following successful curative treatment is controversial. Published studies suggest that DAA does not increase the risk of de novo HCC following SVR. A more controversial topic is the effect of a DAA-based SVR on the recurrence of HCC following curative treatment of early HCC. Well-designed studies with robust comparisons are needed to determine the effect of DAA on the recurrence of HCC. At present, patients with HCV cirrhosis who have undergone resection or ablation for HCC should not be dissuaded from receiving DAA therapy to prevent the progression of liver disease. Monitoring for HCC with liver imaging and AFP should be performed twice a year indefinitely post-SVR in patients with HCV cirrhosis.

The pathophysiology of arterial vasodilatation and hyperdynamic circulation in cirrhosis.

Abstract: Patients with cirrhosis and portal hypertension often develop complications from a variety of organ systems leading to a multiple organ failure. The combination of liver failure and portal hypertension results in a hyperdynamic circulatory state partly owing to simultaneous splanchnic and peripheral arterial vasodilatation. Increases in circulatory vasodilators are believed to be due to portosystemic shunting and bacterial translocation leading to redistribution of the blood volume with central hypovolemia. Portal hypertension per se and increased splanchnic blood flow are mainly responsible for the development and perpetuation of the hyperdynamic circulation and the associated changes in cardiovascular function with development of cirrhotic cardiomyopathy, autonomic dysfunction and renal dysfunction as part of a cardiorenal syndrome. Several of the cardiovascular changes are reversible after liver transplantation and point to the pathophysiological significance of portal hypertension. In this paper, we aimed to review current knowledge on the pathophysiology of arterial vasodilatation and the hyperdynamic circulation in cirrhosis.

Sarcopenic obesity in cirrhosis-The confluence of 2 prognostic titans.

Abstract: Sarcopenia and obesity are 2 major health conditions with a growing prevalence in cirrhosis. The concordance of these 2 conditions, sarcopenic obesity, is associated with higher rates of mortality and impact on the metabolic profile and physical function than either condition alone. To date, there is little consensus surrounding the diagnostic criteria for sarcopenia, obesity or as a result, sarcopenic obesity in patients with cirrhosis. Cross-sectional imaging, although the most accurate diagnostic technique, has practical limitations for routine use in clinical practice. Management strategies are focused on increasing muscle mass and strength. The present review provides an overview of the diagnosis, pathophysiology, prognostic implications and management strategies available for sarcopenic obesity in cirrhosis. We also discuss the associated condition myosteatosis, the pathological accumulation of fat in skeletal muscle. Much work needs to be done to advance both clinical care and research in this area. Future directions require consensus definitions for sarcopenia, obesity and sarcopenic obesity, an expansion of our understanding of the complex pathogenesis of the muscle-liver-adipose tissue axis in cirrhosis and evidence to support management recommendations for nutrition, exercise and pharmacological therapies.

Decreased portal vein velocity is predictive of the development of portal vein thrombosis: A matched case-control study

Abstract: Background & Aims Portal vein thrombosis (PVT) in cirrhosis may lead to hepatic decompensation and increased mortality. We aimed to investigate if decreased portal vein (PV) velocity is associated with future PVT. Methods Data on adult patients with cirrhosis and PVT between January 1, 2005 and July 30, 2015 were obtained. Cases with PVT were matched by age, gender and Model for End stage Liver Disease (MELD) score to corresponding controls without PVT. Cox proportional hazards models, receiver operator curves and Kaplan Meier curves were constructed. Results One hundred subjects (50 matched pairs) with mean age 53.8 +/- 13.1 years and MELD score 14.9 +/- 5.5 were included in our analysis. 64% were male and 76% were Child-Turcotte-Pugh Class A or B. Baseline characteristics (prior to development of PVT) were similar, except for baseline PV velocity (16.9 cm/s, 95% CI 13.9-20.0 PVT vs. 25.0, 95% CI 21.8-28.8 no PVT, p<0.001). 30 PVT subjects had PV velocity <15 cm/s compared to five without PVT (p<0.001). On adjusted multivariable analysis, PV velocity was the strongest independent risk factor predicting PVT development (HR 0.86, 95% CI 0.80-0.93). The predictive value for PVT development was greatest for flow < 15 cm/s (c-statistic 0.77). PV velocity <15cm/s had a highly significant association with future PVT (HR 6.00, 95% CI 2.20-16.40, p=<0.001). Conclusions Decreased PV velocity is associated with increased risk of future PVT. Patients with cirrhosis and decreased PV velocity are a high-risk subgroup that warrants further investigation with prospective study. This article is protected by copyright. All rights reserved.

Role and mechanisms of autophagy in acetaminophen‐induced liver injury

Abstract: Acetaminophen (APAP) overdose is the most frequent cause of acute liver failure in the USA and many other countries. Although the metabolism and pathogenesis of APAP has been extensively investigated for decades, the mechanisms by which APAP induces liver injury are incompletely known, which hampers the development of effective therapeutic approaches to tackle this important clinical problem. Autophagy is a highly conserved intracellular degradation pathway, which aims at recycling cellular components and damaged organelles in response to adverse environmental conditions and stresses as a survival mechanism. There is accumulating evidence indicating that autophagy is activated in response to APAP overdose in specific liver zone areas, and pharmacological activation of autophagy protects against APAP-induced liver injury. Increasing evidence also suggests that hepatic autophagy is impaired in nonalcoholic fatty livers (NAFLD), and NAFLD patients are more susceptible to APAP-induced liver injury. Here, we summarized the current progress on the role and mechanisms of autophagy in protecting against APAP-induced liver injury.

Metformin and risk of hepatocellular carcinoma in patients with type 2 diabetes.

Abstract: BACKGROUND Whether metformin may reduce hepatocellular carcinoma (HCC) risk requires confirmation. METHODS Type 2 diabetes patients newly diagnosed during 1999-2005 and with 2 or more prescriptions of antidiabetic drugs were enrolled from the Taiwan's National Health Insurance database. A total of 173 917 ever-users and 21 900 never-users of metformin were identified (unmatched cohort). A 1:1 matched-pair cohort of 21 900 ever-users and 21 900 never-users based on a propensity score (PS) was created. Hazard ratios were estimated by Cox regression incorporated with the inverse probability of treatment weighting using the PS. In addition, interactions with aspirin and statin were evaluated. RESULTS In the unmatched cohort, 619 never-users and 2642 ever-users developed HCC, with a respective incidence of 668.0 and 330.7 per 100 000 person-years and an overall hazard ratio of 0.49 (95% confidence interval: 0.45-0.54). The hazard ratios for the first ( 56.9 months) tertile of cumulative duration of metformin therapy were 0.89 (0.81-0.98), 0.50 (0.46-0.56) and 0.23 (0.21-0.26) respectively. Analyses of the matched cohort showed an overall hazard ratio of 0.76 (0.67-0.85), and the hazard ratios for the respective tertiles were 1.39 (1.19-1.62), 0.77 (0.65-0.91) and 0.37 (0.30-0.45). Aspirin and statin were observed to have a significant interaction with metformin. CONCLUSIONS Metformin was associated with a reduced risk of HCC in a dose-response pattern. Users of both metformin and aspirin or metformin and statin had the lowest risk.

Bacterial infection-triggered acute-on-chronic liver failure is associated with increased mortality.

Abstract: Background & Aims Acute-on-chronic liver failure (ACLF) is characterized by an acute deterioration of liver function in patients with liver cirrhosis in combination with recently defined organ failures. Our aim was to independently validate the prognostic value of the recently established EASL-CLIF-Consortium definition of ACLF and to identify new predictors of short-term mortality. Methods Patients with liver cirrhosis and the ICD-10 diagnosis of (sub)acute liver failure were retrospectively categorized according to the EASL-CLIF-Consortium definition. Logistic regression analyses were performed to identify clinical and epidemiological predictors of 30- and 90-day mortality. Results From 2008-2015, 257 patients were included. Overall, 173 (67%) patients met the EASL criteria for ACLF [grade 1: n=43 (25%), grade 2: n=52 (30%), grade 3: n=79 (45%)]. Mortality within 30 days in patients without ACLF was 3.6%, and 18.6%, 37.3% and 62.0% in patients with ACLF grades 1, 2, and 3, respectively. Outcome of patients with bacterial infection-triggered ACLF was distinct from non-infection triggered ACLF (71.6% vs. 33.8% 30-day survival, P<0.001), and infection-triggered ACLF was independently associated with increased mortality (OR 4.28, P<0.001). Pneumonia was a particularly frequent infection and burdened with high mortality. In addition, infections with multi-drug-resistant organisms were frequent and independently associated with mortality (P=0.030, OR=4.41), as was glycopeptide antibiotic therapy as initial empirical antibiotic therapy (P=0.005). Conclusion This study confirmed the EASL-CLIF-Consortium definition of ACLF as strong predictor of mortality in patients with acute decompensation of liver cirrhosis. However, we have observed a remarkably higher mortality in infection-triggered ACLF compared to other precipitating events. This article is protected by copyright. All rights reserved.

Osteoporosis in chronic liver disease.

Abstract: Osteoporosis is a frequent complication in patients with chronic liver disease, especially in end-stages and in chronic cholestasis, in addition to non-alcoholic fatty liver disease, haemochromatosis and alcoholism. Mechanisms underlying osteoporosis are poorly understood, but osteoporosis mainly results from low bone formation. In this setting, sclerostin, a key regulator of the Wnt/β-catenin signalling pathway which regulates bone formation, in addition to the effects of the retained substances of cholestasis such as bilirubin and bile acids on osteoblastic cells, may influence the decreased bone formation in chronic cholestasis. Similarly, the damaging effects of iron and alcohol on osteoblastic cells may partially explain bone disease in haemochromatosis and alcoholism. A role for proinflammatory cytokines has been proposed in different conditions. Increased bone resorption may occur in cholestatic women with advanced disease. Low vitamin D, poor nutrition and hypogonadism, may be contributing factors to the full picture of bone disorders in chronic liver disease.

Prevalence and severity of nonalcoholic fatty liver disease by transient elastography: Genetic and metabolic risk factors in a general population

Abstract: BACKGROUND & AIMS The worldwide spread of obesity is leading to a dramatic increase in the prevalence of nonalcoholic fatty liver disease (NAFLD) and its complications. We aimed to evaluate both prevalence and factors associated with NAFLD in a general population in a Mediterranean area. METHODS We considered 890 consecutive individuals included in the community-based ABCD (Alimentazione, Benessere Cardiovascolare e Diabete) study (ISRCTN15840340). Controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) were measured with FibroScan. Participants were genotyped for PNPLA3 rs738409 and TM6SF2 rs58542926 variants. RESULTS The prevalence of NAFLD in the cohort was 48%. NAFLD participants exhibited elevated LSM values, suggesting advanced fibrosis (6.5% of cases). Both NAFLD and advanced fibrosis were independently associated with traditional risk factors (NAFLD: age >50 years, obesity, hypertension, elevated ALT and low HDL-cholesterol serum concentrations. Advanced fibrosis: IFG/diabetes, elevated ALT serum concentrations). A high prevalence (>60%) of NAFLD was found in obese people, while it varied widely in non-obese people according to the presence of metabolic risk factors. PNPLA3 G variant (OR = 1.33, 95% C.I. = 1.01-1.8; P < .05) was independently associated with NAFLD. Prevalence of advanced fibrosis (high LSM values) ranged from 3.4% (no risk factors) to 60% (presence of all risk factors). TM6SF2 T variant (OR = 3.06, 95% C.I. = 1.08-8.65, P < .05) was independently associated with advanced fibrosis (high LSM values). CONCLUSIONS In a cohort of a general population, the prevalence of NAFLD was very high, and among NAFLD patients a significant proportion had advanced fibrosis (high LSM values). Apart from traditional risk factors, genetic factors may have a significant role that needs to be further investigated.

Clinical and virological heterogeneity of hepatitis delta in different regions world-wide: The Hepatitis Delta International Network (HDIN)

Abstract: Background & Aims Chronic hepatitis D (delta) is a major global health burden Clinical and virological characteristics of patients with hepatitis D virus (HDV) infection and treatment approaches in different regions world-wide are poorly defined Methods The Hepatitis Delta International Network (HDIN) registry was established in 2011 with centres in Europe, Asia, North- and South America Here, we report on clinical/ virological characteristics of the first 1576 patients with ongoing or past HDV infection included in the database until October 2016 and performed a retrospective outcome analysis The primary aim was to investigate if the region of origin was associated with HDV replication and clinical outcome Results The majority of patients was male (n = 979, 62%) and the mean age was 367 years (range 1-79, with 9% of patients younger than 20 years) Most patients were HBeAg-negative (77%) and HDV-RNA positive (85%) Cirrhosis was reported in 487% of cases which included 13% of patients with previous or ongoing liver decompensation Hepatocellular carcinoma (HCC) developed in 30 patients (25%) and 44 (36%) underwent liver transplantation Regions of origin were independently associated with clinical endpoints and detectability of HDV RNA Antiviral therapy was administered to 356 patients with different treatment uptakes in different regions Of these, 264 patients were treated with interferon-a and 92 were treated with HBV-Nucs only Conclusions The HDIN registry confirms the severity of hepatitis delta but also highlights the heterogeneity of patient characteristics and clinical outcomes in different regions There is an urgent need for novel treatment options for HDV infection

Improvement of hepatic fibrosis and patient-reported outcomes in non-alcoholic steatohepatitis treated with selonsertib.

Abstract: BACKGROUND Patient-reported outcomes (PROs) represent patients' perspective about their well-being. AIM To assess PRO changes in patients with non-alcoholic steatohepatitis (NASH) after treatment with selonsertib (SEL) and to associate them with different biomarkers. METHODS Patients with NASH and stage 2-3 fibrosis received SEL 6 mg or 18 mg orally QD alone or in combination with simtuzumab (SIM, 125 mg SC weekly) or SIM alone for 24 weeks. Biopsies were obtained at baseline and at treatment week 24. PROs were assessed using SF-36, CLDQ and WPAI:SHP. RESULTS Seventy-two patients with NASH were included (54 ± 10 years, 31% male, 65% stage 3, 71% diabetes). Baseline physical health-related PRO scores were significantly lower than population norms (P .05). However, NASH subjects who experienced ≥2 decrease in NAFLD Activity Score or ≥1-stage reduction in fibrosis showed significant improvements in their PROs (up to +15.5% of a PRO range size, P 17% increase in their collagen experienced PRO worsening (up to -13.9%, P < .05). Baseline serum CK-18, IL-6 and CRP significantly correlated with PROs (rho from -0.24 to -0.38, P < .05). CONCLUSIONS A decrease in hepatic collagen is the most prominently associated with improvement of PROs in NASH patients with F2-F3 treated with SEL. Furthermore, serum cytokines are associated with baseline PROs and with treatment-emergent changes in PROs in patients with NASH.

Autoimmune hepatitis: From current knowledge and clinical practice to future research agenda.

Abstract: Autoimmune hepatitis is a chronic inflammatory liver disease. Unknown triggers lead to a mainly T cell-mediated immune response targeting the liver, the main auto-antigen of which has not been identified yet. The diagnosis of autoimmune hepatitis is based on the elevation of immunoglobulin G/hypergammaglobulinemia, detection of characteristic autoantibodies as well as a typical pattern on liver histology. Exclusion of other causes of hepatitis and response to immunosuppressive treatment support the diagnosis of autoimmune hepatitis. The mainstay of autoimmune hepatitis treatment has, from its first description to the current time, consisted of predniso(lo)ne to induce remission, in combination with azathioprine, which is used to maintain it. Nonetheless, side effects and non-response with ongoing inflammation despite standard therapy demand treatment alternatives. Only through a better understanding of the pathogenesis of autoimmune hepatitis can a more selective and effective treatment be offered to patients in the future. Until this goal is reached, improvement of diagnostic approaches and optimization of current therapy rank highest on the research agenda for autoimmune hepatitis.

Intestinal microbiota in patients with chronic hepatitis C with and without cirrhosis compared with healthy controls

Abstract: Background and Aims The importance of the intestinal microbiota for the onset and clinical course of many diseases, including liver diseases like non-alcoholic steatohepatitis and cirrhosis, is increasingly recognized However, the role of intestinal microbiota in chronic HCV infection remains unclear Methods In a cross sectional approach the intestinal microbiota of 95 patients chronically infected with HCV (n=57 without cirrhosis [NO-CIR]; n=38 with cirrhosis [CIR]) and 50 healthy controls (HC) without documented liver diseases was analysed Results Alpha diversity, measured by number of phylotypes (S) and Shannon diversity index (H’), decreased significantly from HC to NO-CIR to CIR S and H’ correlated negatively with liver elastography Analysis of similarities (ANOSIM) revealed highly statistically significant differences in the microbial communities between HC, NO-CIR and CIR (R=0090; p<10*10-6) Stratifying for HCV genotypes even increased the differences Additionally, we observed distinct patterns in the relative abundance of genera being either positive or negative correlated with diseases status Conclusions This study shows that not only the stage of liver disease but also HCV infection is associated with a reduced alpha diversity and different microbial community patterns These differences might be caused by direct interactions between HCV and the microbiota or indirect interactions facilitated by the immune system This article is protected by copyright All rights reserved

Validation of the Baveno VI and the expanded Baveno VI criteria to identify patients who could avoid screening endoscopy

Abstract: BACKGROUND & AIMS The Baveno VI and the expanded Baveno VI criteria were proposed to help identify patients who could safely avoid screening endoscopies for clinically significant varices among patients with compensated advanced chronic liver disease. However, these criteria require cross-validation, especially in Asian populations where the aetiologies of liver disease are different. METHODS A total of 1035 patients, including 282 patients with compensated advanced chronic liver disease of different aetiology, were analysed. The compensated advanced chronic liver disease was defined by liver stiffness measurement ≥10 kPa, Child-Pugh class A and absence of prior liver decompensation. High-risk varix was defined as a grade ≥2 oesophageal varix, any varix with a red colour sign or gastric varices. RESULTS High-risk varixs were present in 19.5% (55/282 patients) with compensated advanced chronic liver disease. Among compensated advanced chronic liver disease patients, the expanded criteria could spare more endoscopies (51.7%) than the original criteria (27.6%). However, the expanded criteria missed a greater number of high-risk varixs (6.8%) than the original criteria (3.8%). When stratified according to liver disease aetiology, the negative predictive values for the original Baveno VI criteria were 0.92, 1.00, 1.00 and 1.00, and the negative predictive values for the expanded criteria were 0.92, 0.96, 0.92 and 0.93 for hepatitis B, hepatitis C, alcohol and non-alcoholic fatty liver disease, respectively. High-risk varixs were rarely detected in patients without compensated advanced chronic liver disease (1.1%, 8/753 patients). CONCLUSIONS In this Asian cohort study, the Baveno VI criteria were able to identify who could safely avoid screening endoscopy. The expanded Baveno VI criteria could spare more endoscopies but also could increase the odds of missing a high-risk varix.

Frailty in advanced liver disease.

Abstract: Prognostication of patients with cirrhosis is complex, depending on more than just the severity of liver disease. Scores such as the model for end-stage liver disease (MELD) and Child Pugh can assist with prognostication, yet by focusing on physiological parameters they fail to completely capture the elements contributing to a patient's clinical status. Evidence is increasing to support an important role for physical functioning in patient outcomes. Frailty has been increasingly recognised in medical literature over recent years, including in hepatology where it is identified in nearly half of cirrhosis patients. It is a complex construct consisting of multisystemic physiological decline and increased vulnerability to stressors. Diagnosis is complicated by lack of a consensus definition and measurement tool for frailty in cirrhosis. Frailty heralds a poor prognosis, predicting increased morbidity and mortality both pre- and postliver transplant, independent of MELD score. It is thought to be reversible, with promising data supporting prehabilitation and lifestyle intervention programs. In the future, assessment of patients with cirrhosis is likely to incorporate a measure of frailty, however, further research is required.

Towards HBV curative therapies.

Abstract: Tremendous progress has been made over the last 2 decades to discover and develop approaches to control hepatitis B virus (HBV) infections and to prevent the development of hepatocellular carcinoma using various interferons and small molecules as antiviral agents. However, none of these agents have significant impact on eliminating HBV from infected cells. Currently the emphasis is on silencing or eliminating cccDNA, which could lead to a cure for HBV. Various approaches are being developed including the development of capsid effectors, CRISPR/Cas9, TALENS, siRNA, entry and secretion inhibitors, as well as immunological approaches. It is very likely that a combination of these modalities will need to be employed to successfully eliminate HBV or prevent virus rebound on discontinuation of therapy. In the next 5 years clinical data will emerge which will provide insight on the safety and feasibility of these approaches and if they can be applied to eradicate HBV infections globally. In this review, we summarize current treatments and we highlight and examine recent therapeutic strategies that are currently being evaluated at the preclinical and clinical stage.

Diabetes impacts prediction of cirrhosis and prognosis by non-invasive fibrosis models in non-alcoholic fatty liver disease.

Abstract: BACKGROUND & AIMS Non-alcoholic fatty liver disease (NAFLD) patients with diabetes are at increased risk of cirrhosis and liver-related death, and thus accurate fibrosis assessment in these patients is important. We examined the ability of non-invasive fibrosis models to determine cirrhosis and outcomes in NAFLD patients with and without diabetes. METHODS Non-alcoholic fatty liver disease patients diagnosed between 2006 and 2015 had Hepascore, NAFLD fibrosis score (NFS), APRI and FIB-4 scores calculated at baseline and were followed up for outcomes of overall and liver-related mortality/liver transplantation, hepatic decompensation and hepatocellular carcinoma (HCC). Model accuracy was determined by Harrell's C-index and by Kaplan-Meier analysis. RESULTS A total of 284 patients (53% diabetic, 15% cirrhotic) were followed up for a median of 51.4 months, (range 6.1-146). During follow-up, diabetic patients had a greater risk of liver-related death/transplantation, HR 3.4 (95% CI 1.2-9.1) decompensation, HR 4.7 (95% CI 2.0-11.3) and HCC, HR 2.9 (95% CI 1.2-7.3). Among 241 subjects with a baseline liver biopsy, the accuracy of Hepascore, APRI and FIB-4 for predicting cirrhosis was lower amongst diabetics compared to non-diabetics (P < .005 for all). Model accuracy apart from Hepascore, was also significantly lower for predicting liver death/transplantation in patients with diabetes. No patient with a low fibrosis score and without diabetes developed liver decompensation or HCC, whereas up to 21% of diabetic patients with a low fibrosis score developed liver decompensation and up to 27% developed HCC at 5 years. CONCLUSIONS Non-invasive scoring systems are less accurate at predicting cirrhosis and liver-related outcomes in patients with NAFLD and diabetes.

Poor adherence to hepatocellular carcinoma surveillance: A systematic review and meta-analysis of a complex issue.

Abstract: Background & Aims Hepatocellular carcinoma (HCC) surveillance is associated with improved outcomes and long-term survival. Our goal is to evaluate adherence rates to HCC surveillance. Methods We performed a systematic search of the PubMed and Scopus databases and abstract search of relevant studies from recent major liver meetings. All searches and data extraction were performed independently by 2 authors. Analysis was via random-effects models and multivariate meta-regression. Results A total of 22 studies (n=19,511) met inclusion criteria (original non-interventional studies with defined cirrhosis or chronic hepatitis B or chronic hepatitis C with advanced fibrosis populations, and surveillance tests and intervals). Overall adherence rate was 52% (95% CI 38-66%). Adherence was significantly higher in cirrhotic patients compared to chronic hepatitis B and other high risk patients, in European compared to North American studies, in less than 12-month compared to yearly surveillance intervals, and in prospective compared to retrospective studies (71%, 95% CI 64-78% vs. 39%, 95% CI 26-51%, P<0.001). The between-study heterogeneity of all above analyses was significant (P<0.001). Only the study design (retrospective vs. prospective cohort) had statistical significance in a multivariate meta-regression model (P<0.05) and could account for some of the differences above. Conclusions Overall adherence rate to HCC surveillance was suboptimal at 52% with no significant differences by liver disease etiology or study location in multivariate meta-regression analysis. Further research and educational efforts are needed to improve the current rate of HCC surveillance. This article is protected by copyright. All rights reserved.

Combining albumin-bilirubin score with future liver remnant predicts post-hepatectomy liver failure in HBV-associated HCC patients.

Abstract: Background Accurate assessment of liver functional reserve preoperatively is vital for safe hepatic resection. The ALBI score is a new model for assessing liver function. This study aimed to evaluate the value of combining ALBI score with sFLR in predicting postoperative morbidity and PHLF in HCC patients who underwent hepatectomy. Methods Patients undergoing three-dimensional CT reconstruction prior to hepatectomy for HCC between January 2015 and January 2017 were enrolled. The values of the CP score, ALBI score and sFLR in predicting postoperative outcomes were evaluated. Results A total of 229 HCC patients were enrolled; 24 (10.5%) experienced major complications and 21 (9.2%) developed PHLF. The incidence of major complications and PHLF increased with increasing ALBI grade. The ALBI grade classified patients with CP grade A into two subgroups with different incidences of PHLF (P=0.029). sFLR and ALBI score were identified as independent predictors of PHLF. The AUC values for the CP score, ALBI score, sFLR and sFLR×ALBI for predicting major complications were 0.600, 0.756, 0.660 and 0.790, respectively. The AUC values of the CP score, ALBI score, sFLR and sFLR×ALBI for predicting PHLF were 0.646, 0.738, 0.758 and 0.884, respectively. Conclusion The ALBI score showed superior predictive value of postoperative outcomes over CP score, and the combination of sFLR and ALBI score was identified as a stronger predictor of postoperative outcomes than the sFLR or ALBI score alone. This article is protected by copyright. All rights reserved.

Growth differentiation factor 15 predicts advanced fibrosis in biopsy-proven non-alcoholic fatty liver disease.

Abstract: Background & Aims We explored whether growth differentiation factor 15 (GDF15) affects the histological severity of non-alcoholic fatty liver disease (NAFLD) independent of insulin resistance. Methods In a biopsy-proven NAFLD cohort, we measured serum GDF15 levels using enzyme-linked immunosorbent assays. Results Among 190 subjects (mean age, 53±14 years; men, 52.1%), 72 (men, 65.3%) and 78 (men, 44.9%) were diagnosed with biopsy-proven non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), respectively. GDF15 levels were significantly higher in NASH patients than in controls (P = 0.010) or NAFL patients (P = 0.001). Subjects with advanced fibrosis (≥F3) also showed higher GDF15 levels compared to the others (F0–2; P <0.001). Among NAFLD patients, the highest quartile of GDF15 levels was significantly associated with a risk of advanced fibrosis even after adjustment for age, gender, body mass index, smoking status, hypertension, diabetes, aspartate aminotransferase, platelet, albumin, insulin resistance, and low skeletal muscle mass (odds ratio, 4.27; 95% confidence interval, 1.04–17.63), but not with NASH risk. GDF15 levels showed a significant positive correlation with liver stiffness (Spearman's ρ, 0.525; P < 0.001). Palmitate treatment increased the GDF15 mRNA expression level significantly in Kupffer cells, but not in hepatocytes. In LX-2 cells, GDF15 treatment resulted in enhanced expression of α-smooth muscle actin and collagen I, as well as phosphorylation of SMAD2 and SMAD3. Conclusions Our findings suggest that GDF15 may serve as a novel biomarker of advanced fibrosis in NAFLD, thereby indicating the need for urgent anti-fibrotic pharmacotherapy. This article is protected by copyright. All rights reserved.

Acute liver failure induced by idiosyncratic reaction to drugs: Challenges in diagnosis and therapy

Abstract: Acute liver failure (ALF) requires urgent attention to identify etiology and determine prognosis, in order to assess likelihood of survival or need for transplantation. Identifying idiosyncratic drug-induced liver injury (iDILI) may be particularly difficult, but the illness generally follows a subacute course, allowing time to assess outcome and find a liver graft if needed. Not all drugs that cause iDILI lead to ALF; the most common are antibiotics including anti-tuberculous medications, non-steroidal anti-inflammatory agents and herbal and dietary supplements (HDS). Determining causality remains challenging particularly if altered mentation is present; identifying the causative agent depends in part on knowing the propensity of the drugs that have been taken in the proper time interval, plus excluding other causes. In general, iDILI that reaches the threshold of ALF will more often than not require transplantation, since survival without transplant is around 25%. Treatment consists of withdrawal of the presumed offending medication, consideration of N-acetylcysteine (NAC), as well as intensive care. Corticosteroids have not proven useful except perhaps in instances of apparent autoimmune hepatitis caused by a limited number of agents. Recently developed prognostic scoring systems may also aid in predicting outcome in this setting.

Hepatic iron is the major determinant of serum ferritin in NAFLD patients

Abstract: Background and Aims Elevated serum ferritin is common in NAFLD, and is associated with more advanced disease and increased mortality. Hyperferritinemia in NAFLD is often attributed to inflammation, while in other conditions ferritin closely reflects body iron stores. The aim of this study was to clarify the underlying cause of hyperferritinemia in NAFLD. Methods Ferritin levels were examined with markers of iron status, inflammation and liver injury across the clinical spectrum of NAFLD using blood, tissue and magnetic resonance (MR) imaging. A separate larger group of NAFLD patients with hepatic iron staining and quantification were used for validation. Results Serum ferritin correlated closely with the iron regulatory hormone hepcidin, and liver iron levels determined by MR. Furthermore, ferritin levels reflected lower serum adiponectin, a marker of insulin resistance, and liver fat, but not cytokine or CRP levels. Ferritin levels differed according to fibrosis stage, increasing from early to moderate disease, and declining in cirrhosis. A similar pattern was found in the validation cohort of NAFLD patients, where ferritin levels were highest in those with macrophage iron deposition. Multivariate analysis revealed liver iron and hepcidin levels as the major determinants of serum ferritin. Conclusions While hyperferritinaemia is associated with markers of liver injury and insulin resistance, serum hepcidin and hepatic iron are the strongest predictors of ferritin levels. These findings highlight the role of disordered iron homeostasis in the pathogenesis of NAFLD, suggesting that therapies aimed at correcting iron metabolism may be beneficial. This article is protected by copyright. All rights reserved.

Altered fatty acid-binding protein 4 (FABP4) expression and function in human and animal models of hepatocellular carcinoma.

Abstract: Background and aims Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality. Risk factors for developing HCC include viral hepatitis, alcohol and obesity. Fatty acid-binding proteins (FABPs) bind long-chain free fatty acids (FFAs) and are expressed in a tissue-specific pattern; FABP1 being the predominant hepatic form, and FABP4 the predominant adipocyte form. The aims of this study were to investigate the expression and function of FABPs1-9 in human and animal models of obesity-related HCC. Methods FABP1-9 expression was determined in a mouse model of obesity-promoted HCC. Based on these data, expression and function of FABP4 was determined in human HCC cells (HepG2 and HuH7) in vitro. Serum from patients with different underlying hepatic pathologies was analysed for circulating FABP4 levels. Results Livers from obese mice, independent of tumour status, exhibited increased FABP4 mRNA and protein expression concomitant with elevated serum FABP4. In vitro, FABP4 expression was induced in human HCC cells by FFA treatment, and led to FABP4 release into culture medium. Treatment of HCC cells with exogenous FABP4 significantly increased proliferation and migration of human HCC cells. Patient serum analysis demonstrated significantly increased FABP4 in those with underlying liver disease, particularly non-alcoholic fatty liver disease (NAFLD) and HCC. Conclusions These data suggest FABP4, an FABP not normally expressed in the liver, can be synthesized and secreted by hepatocytes and HCC cells, and that FABP4 may play a role in regulating tumour progression in the underlying setting of obesity.

Characteristics of systemic inflammation in hepatitis B-precipitated ACLF: differentiate it from No-ACLF

Abstract: Background and aims Patients with severe exacerbation of chronic hepatitis B (SE-CHB) are at risk of developing acute-on-chronic liver failure (ACLF). Systemic inflammation (SI) is a major driver of ACLF. The aim of this study was to identify characteristics of SI in hepatitis B-precipitated-ACLF (HB-ACLF), which may be distinct from No-ACLF patients with SE-CHB. Methods Two cohorts of patients with SE-CHB were enrolled in two tertiary hospitals. The associations between circulating leukocyte counts/subsets and ACLF progression and prognoses were analysed in Cohort A. Cytokine measurements, leukocyte phenotyping and whole blood transcriptomic analyses were performed using peripheral blood samples obtained from patients in Cohort B. Results Circulating leucocyte counts were higher in the HB-ACLF patients than in the No-ACLF patients (P<0.001). Peripheral neutrophilic leucocytosis and monocytosis were associated with lymphopenia. The neutrophil-to-lymphocyte ratio (NLR) and monocyte-to-lymphocyte ratio (MLR) were correlated with risk of death in patients with SE-CHB. NLR independently predicted progression to ACLF in patients without ACLF at enrolment and short-term mortality in ACLF patients. Plasma IL-6, IL-10, G-CSF and GM-CSF levels were higher in ACLF patients (P<0.05). Blood transcriptome analyses showed that genes associated with cell migration and mobility and responses to wounding and bacteria were expressed at higher levels while genes involved in lymphocyte-mediated immunity were expressed at lower levels in HB-ACLF patients than in No-ACLF patients. Conclusions SI in HB-ACLF was characterized by an excessive innate immune response, which was associated with disease progression and mortality. This article is protected by copyright. All rights reserved.