With more than 240 million people infected, hepatitis B virus (HBV) is a major health concern. The inability to mimic the complexity of the liver using cell lines and regular primary human hepatocyte ...(PHH) cultures pose significant limitations for studying host/pathogen interactions. Here, we describe a 3D microfluidic PHH system permissive to HBV infection, which can be maintained for at least 40 days. This system enables the recapitulation of all steps of the HBV life cycle, including the replication of patient-derived HBV and the maintenance of HBV cccDNA. We show that innate immune and cytokine responses following infection with HBV mimic those observed in HBV-infected patients, thus allowing the dissection of pathways important for immune evasion and validation of biomarkers. Additionally, we demonstrate that the co-culture of PHH with other non-parenchymal cells enables the identification of the cellular origin of immune effectors, thus providing a valuable preclinical platform for HBV research.
Hepatocellular carcinoma (HCC) ranks third in overall global cancer-related mortality. Symptomatic presentation often means advanced disease where potentially curative treatment options become very ...limited. Numerous international guidelines propose the routine monitoring of those with the highest risk factors for the condition in order to diagnose potential tumourigenesis early. To aid this, the fields of metabonomic- and proteomic-based biomarker discovery have applied advanced tools to identify early changes in protein and metabolite expression in HCC patients vs controls. With robust validation, it is anticipated that from these candidates will rise a high-performance non-invasive test able to diagnose early HCC and related conditions. This review gathers the numerous markers proposed by studies using mass spectrometry and proton nuclear magnetic resonance spectroscopy and evaluates areas of consistency as well as discordance.
Summary
Chronic hepatitis C virus (HCV) infection leads to liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The recent Global Burden of Disease project estimated that in 2010 among ...170 million people living with chronic HCV, an estimated 483 100 people died from HCV‐related liver failure or HCC. The last two decades has seen progressive improvements in treatment of HCV infection with the most recent therapies offering simple, tolerable, short‐duration therapy with extremely high efficacy. The development of public health strategies addressing emerging epidemics requires sound epidemiological data. This study covers epidemiological data collection, detailed expert opinion input and country‐specific mathematical modelling of the HCV epidemic and potential impact of improved HCV treatment strategies in 16 countries. The analysis demonstrates that the HCV epidemics vary considerably in terms of age distribution of the infected population across countries. In addition, the burden of advanced liver disease varies widely. This burden is dependent upon factors including chronic HCV prevalence, age distribution (and duration of infection) of those infected, prevalence of cofactors for disease progression (particularly heavy alcohol intake) and uptake and success of therapeutic intervention. Introduction of new therapies with assumed sustained virological response (SVR) rate of >90% will have a modest impact on projected advanced liver disease burden. A combination of enhanced treatment efficacy and improved treatment uptake will have a greater impact on population‐level disease burden. However public health advocacy and both public and private sector investment in the HCV response are required to demonstrate significant reduction in HCV disease burden.
In SE Asia, where the tumour is quite common, the associated risk factors are: - liver flukes-Opisthorchis viverrini and Clonorchis sinensis, - chronic typhoid carriers-sixfold increased risk of all ...hepatobiliary malignancy. 2.2 Anatomical classification 3- 5 "Cholangiocarcinoma" originally referred only to primary tumours of the intrahepatic bile ducts and was not used for extrahepatic bile duct tumours but the term is now regarded as inclusive of intrahepatic, perihilar, and distal extrahepatic tumours of the bile ducts (fig 1). The WHO classifications are given below. 2.3.1 WHO classification of carcinomas of the liver Hepatocellular carcinoma Combined hepatocellular cholangiocarcinoma Cholangiocarcinoma, intrahepatic Bile duct cystadenocarcinoma Undifferentiated carcinoma 2.3.2 WHO classification of carcinomas of the extrahepatic bile ducts Carcinoma in situ Adenocarcinoma Papillary adenocarcinoma Adenocarcinoma, intestinal-type Mucinous adenocarcinoma Clear cell adenocarcinoma Signet ring cell carcinoma Adenosquamous carcinoma Squamous cell carcinoma Small cell carcinoma (oat cell carcinoma) Undifferentiated carcinoma 2.3.3 Histological grade Most cholangiocarcinomas (95%) are adenocarcinomas.
Summary
Background
The scale of depression in patients with chronic liver disease (CLD) and those who have received orthotopic liver transplantation (OLT) is poorly characterised. Clinicians are ...uncertain of how best to manage depression within these patients.
Aims
To review the literature evaluating both the prevalence and impact of depression in patients with CLD and post‐OLT, and to assess the safety and efficacy of antidepressant use within this context.
Methods
A PubMed search using the phrases ‘chronic liver disease’, ‘cirrhosis’, ‘liver transplantation’, ‘depression’, ‘antidepressant’ and the names of specific causes of liver disease and individual antidepressants.
Results
Over 30% of cirrhotic patients have depressive features, and they experience worse clinical outcomes than nondepressed cirrhotic patients. CLD patients with chronic hepatitis C are particularly prone to depression, partly related to the use of interferon therapy. OLT patients with depression have higher mortality rates than nondepressed patients; appropriate antidepressant use reverses this effect. Selective serotonin reuptake inhibitors (SSRIs) and selective noradrenaline reuptake inhibitors (SNRIs) are effective and generally safe in both CLD and OLT patients.
Conclusions
Depression is much more prevalent in CLD or OLT patients than is generally recognised, and it adversely affects clinical outcomes. The reasons for this relationship are complex and multifactorial. Antidepressants are effective in both CLD and post‐OLT, although lower doses or a reduced dosing frequency may be required to minimise side effects, e.g. exacerbation of hepatic encephalopathy. Further research is needed to establish optimal management of depression in these patients, including the potential role of nonpharmacological treatments.
Summary
Background
Chronic hepatitis C virus infection is one of the most important health problems in Egypt. The Ministry of Health's National Treatment Programme introduced sofosbuvir‐based therapy ...in October 2014.
Aim
To assess the clinical effectiveness and predictors of response to SOF‐based treatment regimens, either dual therapy, with SOF/ribavirin (RBV) for 6 months or triple therapy with SOF/peg‐IFN‐alfa‐2a/RBV for 3 months, in a cohort of patients treated in National Treatment Programme affiliated centres in Egypt.
Methods
Between October 2014 and end of 2014, patients who were eligible for treatment were classified according to their eligibility for interferon therapy: Group 1 (interferon eligible) were treated with triple therapy for 12 weeks and Group 2 (interferon ineligible) were treated with dual therapy for 24 weeks. Difficult to treat patients included those with F3‐F4 on Metavir score, Fib‐4 >3.25, albumin ≤3.5, total Bilirubin >1.2 mg/dL, INR >1.2 and platelet count <150 000 mm3.
Results
Twelve weeks post‐treatment data were available on 14 409 patients; 8742 in group 1 and 5667 in group 2. In group 1, the sustained virological response at week 12 (SVR12) was 94% and in group 2 the SVR12 was 78.7%. Multivariate logistic regression analysis in which treatment failure is the dependent variable was done. Male gender, being a difficult to treat patient and previous interferon therapy were significant predictors of nonresponse in both treatment groups.
Conclusion
Results of sofosbuvir‐based therapies in Egypt achieved similar rates of SVR12 as seen in phase III efficacy studies.
Several scoring systems predict mortality in alcohol-associated hepatitis (AH), including the Maddrey discriminant function (mDF) and model for end-stage liver disease (MELD) score developed in the ...United States, Glasgow alcoholic hepatitis score in the United Kingdom, and age, bilirubin, international normalized ratio, and creatinine score in Spain. To date, no global studies have examined the utility of these scores, nor has the MELD-sodium been evaluated for outcome prediction in AH. In this study, we assessed the accuracy of different scores to predict short-term mortality in AH and investigated additional factors to improve mortality prediction.
Patients admitted to hospital with a definite or probable AH were recruited by 85 tertiary centers in 11 countries and across 3 continents. Baseline demographic and laboratory variables were obtained. The primary outcome was all-cause mortality at 28 and 90 days.
In total, 3,101 patients were eligible for inclusion. After exclusions (n = 520), 2,581 patients were enrolled (74.4% male, median age 48 years, interquartile range 40.9-55.0 years). The median MELD score was 23.5 (interquartile range 20.5-27.8). Mortality at 28 and 90 days was 20% and 30.9%, respectively. The area under the receiver operating characteristic curve for 28-day mortality ranged from 0.776 for MELD-sodium to 0.701 for mDF, and for 90-day mortality, it ranged from 0.773 for MELD to 0.709 for mDF. The area under the receiver operating characteristic curve for mDF to predict death was significantly lower than all other scores. Age added to MELD obtained only a small improvement of AUC.
These results suggest that the mDF score should no longer be used to assess AH's prognosis. The MELD score has the best performance in predicting short-term mortality.
Worldwide, the hepatitis B virus (HBV) and the hepatitis C virus (HCV) cause, respectively, 600 000 and 350 000 deaths each year. Viral hepatitis is the leading cause of cirrhosis and liver cancer, ...which in turn ranks as the third cause of cancer death worldwide. Within the WHO European region, approximately 14 million people are chronically infected with HBV, and nine million people are chronically infected with HCV. Lack of reliable epidemiological data on HBV and HCV is one of the biggest hurdles to advancing policy. Risk groups such as migrants and injecting drug users (IDU) tend to be under‐represented in existing prevalence studies; thus, targeted surveillance is urgently needed to correctly estimate the burden of HBV and HCV. The most effective means of prevention against HBV is vaccination, and most European Union (EU) countries have universal vaccination programmes. For both HBV and HCV, screening of individuals who present a high risk of contracting the virus is critical given the asymptomatic, and thereby silent, nature of disease. Screening of migrants and IDUs has been shown to be effective and potentially cost‐effective. There have been significant advances in the treatment of HCV and HBV in recent years, but health care professionals remain poorly aware of treatment options. Greater professional training is needed on the management of hepatitis including the treatment of liver cancer to encourage adherence to guidelines and offer patients the best possible outcomes. Viral hepatitis knows no borders. EU Member States, guided by the EU, need to work in a concerted manner to implement lasting, effective policies and programmes and make tackling viral hepatitis a public health priority.
Abstract
Background
Alcohol consumption causes a spectrum of liver abnormalities and leads to over 3 million deaths per year. Alcoholic hepatitis (AH) is a florid presentation of alcoholic liver ...disease characterized by liver failure in the context of recent and heavy alcohol consumption. The aim of this study is to explore the potential benefits of the IL-1β antibody, canakinumab, in the treatment of AH.
Methods
This is a multicentre, double-blind, randomised placebo-controlled trial. Participants will be diagnosed with AH using clinical criteria. Liver biopsy will then confirm that all histological features of AH are present. Up to 58 participants will be recruited into two groups from 15 centres in the UK. Patients will receive an infusion of Canakinumab or matched placebo by random 1:1 allocation. The primary outcome is the difference between groups in the proportion of patients demonstrating histological improvement and will compare histological appearances at baseline with appearances at 28 days to assign a category of “improved” or “not improved”. Patients with evidence of ongoing disease activity will receive a second infusion of canakinumab or placebo. Participants will be followed up for 90 days. Secondary outcomes include mortality and change in MELD score at 90 days.
Discussion
This phase II study will explore the benefits of the IL-1β antibody, canakinumab, in the treatment of AH to provide proof of concept that inhibition of IL-1β signalling may improve histology and survival for patients with AH.
Trial registration
EudraCT
2017-003724-79
. Prospectively registered on 13 April 2018.
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