Loss of histone macroH2A1 in hepatocellular carcinoma cells promotes paracrine-mediated chemoresistance and CD4+CD25+FoxP3+ regulatory T cells activation

Rationale: Loss of histone macroH2A1 induces appearance of cancer stem cells (CSCs)-like cells in hepatocellular carcinoma (HCC). How CSCs interact with the tumor microenvironment and the adaptive immune system is unclear. Methods: We screened aggressive human HCC for macroH2A1 and CD44 CSC marker expression. We also knocked down (KD) macroH2A1 in HCC cells, and performed integrated transcriptomic and secretomic analyses. Results: Human HCC showed low macroH2A1 and high CD44 expression compared to control tissues. MacroH2A1 KD CSC-like cells transferred paracrinally their chemoresistant properties to parental HCC cells. MacroH2A1 KD conditioned media transcriptionally reprogrammed parental HCC cells activated regulatory CD4+/CD25+/FoxP3+ T cells (Tregs). Conclusions: Loss of macroH2A1 in HCC cells drives cancer stem-cell propagation and evasion from immune surveillance

Validation of the Baveno Vi Criteria to Identify Low Risk Cirrhotic Patients not Requiring Endoscopic Surveillance for Varices

BACKGROUND: The Baveno VI guidelines propose that cirrhotic patients with a liver stiffness measurement (LSM) 150000/μL can avoid screening endoscopy as their combination is highly specific for excluding clinically significant varices. The aim of the study was to validate these criteria. METHODS: Transient elastography data was collected from two institutions from 2006-2015. Inclusion criteria were a LSM ⩾10kPa and an upper gastrointestinal endoscopy within 12 months, with a diagnosis of compensated chronic liver disease. Exclusion criteria were porto-mesenteric-splenic vein thrombosis and non-cirrhotic portal hypertension. Varices were graded as low risk (grade 150) are at low risk of having varices and do not need a screening endoscopy. Varices are a complication of cirrhosis, confer a risk of serious bleeding, and can be diagnosed and treated by endoscopy. Our study reviewed the clinical records of patients who have had liver stiffness scans and endoscopy over a 9 year period at two hospitals. The results show that only about 2% of patients who meet the Baveno VI criteria will be miss classified as not having varices

Review article: non-alcoholic fatty liver disease and cardiovascular diseases: associations and treatment considerations

Background: There are increasing data on the association between non-alcoholic fatty liver disease (NAFLD) and cardiovascular diseases (CVD). // Aim: To summarise evidence on the association between NAFLD and CVD in the clinical setting and provide potential therapeutic implications. // Methods: We searched PubMed. Evidence was primarily derived from meta-analyses. and then, if data were insufficient, from clinical trials, and then from observational studies. // Results: NAFLD has been linked to arterial hypertension, arterial stiffness, atherosclerosis, coronary artery disease, atrial fibrillation and aortic valvular sclerosis. Advanced liver fibrosis is a crucial prognostic factor for end-stage liver disease and for cardiovascular and overall mortality. Weight loss through lifestyle modifications (diet and exercise) remains the cornerstone of the management of both NAFLD and CVD, but is difficult to achieve and possibly more difficult to sustain long term. Therefore, pharmacological management of NAFLD seems to be important, although no licenced medication currently exists. Pioglitazone, proposed for non-alcoholic steatohepatitis (NASH) by most guidelines, increases weight and should be avoided in congestive heart failure. Statins should not be avoided in NAFLD patients at risk for CVD. Glucagon-like peptide 1 receptor agonists and sodium-glucose cotransporter-2 inhibitors, two classes of anti-diabetic drugs, have shown promising results in NAFLD and CVD, but more studies with hard end points are needed. Obeticholic acid, a promising medication for NASH under investigation, should be carefully considered, owing to its adverse effect on lipid profile. // Conclusions: NAFLD is associated with CVD, which may have certain clinical and therapeutic implications

Top research priorities in liver and gallbladder disorders in the UK

OBJECTIVES: There is a mismatch between research questions considered important by patients, carers and healthcare professionals and the research performed in many fields of medicine. The non-alcohol-related liver and gallbladder disorders priority setting partnership was established to identify the top research priorities in the prevention, diagnostic and treatment of gallbladder disorders and liver disorders not covered by the James-Lind Alliance (JLA) alcohol-related liver disease priority setting partnership. DESIGN: The methods broadly followed the principles of the JLA guidebook. The one major deviation from the JLA methodology was the final step of identifying priorities: instead of prioritisation by group discussions at a consensus workshop involving stakeholders, the prioritisation was achieved by a modified Delphi consensus process. RESULTS: A total of 428 unique valid diagnostic or treatment research questions were identified. A literature review established that none of these questions were considered 'answered' that is, high-quality systematic reviews suggest that further research is not required on the topic. The Delphi panel achieved consensus (at least 80% Delphi panel members agreed) that a research question was a top research priority for six questions. Four additional research questions with highest proportion of Delphi panel members ranking the question as highly important were added to constitute the top 10 research priorities. CONCLUSIONS: A priority setting process involving patients, carers and healthcare professionals has been used to identify the top 10priority areas for research related to liver and gallbladder disorders. Basic, translational, clinical and public health research are required to address these uncertainties

Elastic fibres in alcoholic liver disease

The literature on the contribution of elastic fibre deposition to alcohol-related liver disease (ARLD) is limited. We studied: (1) 180 liver biopsies from ARLD patients; (2) 20 ARLD explant livers; (3) 213 liver biopsies with non-ARLD injury. Elastic fibres were assessed in terms of their distribution around hepatocytes [pericellular elastosis (PCE)] and within bridging fibrous septa (septal elastosis) and scored using a semiquantitative system. We also investigated the composition of the elastic fibres (oxytalan, elaunin and mature elastic fibres) in 20 cases. PCE was associated with steatohepatitis in ARLD patients and with ARLD when compared to non-ARLD cases (p < 0.001). Oxytalan fibres were identified in PCE in ARLD biopsies and broken dense perisinusoidal mature elastic fibres in explanted livers. Septal elastosis increased from intermediate to advanced fibrosis stage. Early septal elastosis contained oxytalan fibres, whereas septal elastosis at more advanced stages contained mainly mature elastic fibres. PCE is a typical feature of steatohepatitis in ARLD and includes oxytalan fibres. Septal elastosis is a gradual process with a transition from oxytalan to mature elastic fibres usually present in explanted livers. There may be different dynamics in the assembly and reabsorption of pericellular and septal elastic fibres, and a potential role for stratification of patients with advanced stage ARLD

Treatment of severe alcoholic hepatitis: A systematic review

Severe alcoholic hepatitis is the most severe form of alcohol-related liver disease. Corticosteroids remain the first choice of treatment. However, they are only effective in a subset of patients and are associated with an increased infection risk. Furthermore, nonresponders to corticosteroids have a poor prognosis with a mortality of 70% over 6 months. As such, there is a high need for a more personalized use of corticosteroids and the development and identification of alternative therapeutic strategies. In this review, we summarize the recent and ongoing randomized controlled trials concerning the treatment of severe alcoholic hepatitis

Liver test abnormalities in patients with HIV mono-infection : assessment with simple non-invasive fibrosis markers

BACKGROUND: Patients with HIV mono-infection may develop chronic liver disease due to a number of factors including hepatic steatosis. We estimated the prevalence and predictors of hepatic steatosis and fibrosis in a cohort of HIV-mono-infected patients with persistently deranged liver function tests. METHODS: Of 2398 consecutive patients at one UK clinical center, 156 (6.5%) had persistently abnormal transaminases in at least two measurements six months apart. We used APRI and FIB4 scores to determine the presence of significant and/or advanced fibrosis in this group as well as its potential associations. RESULTS: Mean age was 47.5\ub18.5 years and 91% (142/156) were males. Diabetes mellitus was present in 11% of patients; hypertension in 18%; and dyslipidemia in 52%. Almost all were on antiretroviral therapy (ART) (97%) and most were virologically suppressed (94%). Steatosis was detected by ultrasound in 71% of patients. The prevalence of FIB4 641.45, 1.46-3.24 and &gt;3.25 was 67%, 29% and 4%, respectively, and that of APRI 640.5, 0.51-1.49 and &gt;1.5 was 52%, 45% and 3% respectively. In multivariate analysis, only cumulative ART exposure was associated with FIB4&gt;1.45 (odds ratio [OR] 1.008, 95% confidence interval [CI] 1.000-1.016), while APRI&gt;0.5 was associated with higher alanine aminotransferase levels (OR 1.033, 95%CI 1.015-1.510). Twenty patients had a liver biopsy, of whom 13 had non-alcoholic fatty liver disease (NAFLD). CONCLUSIONS: Elevated transaminases are often present in HIV-mono-infected patients and this may be associated with NAFLD and/or ART. Non-invasive screening for the presence of NAFLD and fibrosis in all HIV-mono-infected patients as part of their routine clinical management should be further explore

International Liver Transplantation Consensus Statement on end-stage liver disease due to nonalcoholic steatohepatitis and liver transplantation

Nonalcoholic steatohepatitis (NASH)-related cirrhosis has become one of the most common indications for liver transplantation (LT), particularly in candidates over the age of 65 years. Typically, NASH candidates have concurrent obesity, metabolic and cardiovascular risks, which directly impact patient evaluation and selection, waitlist morbidity and mortality and eventually posttransplant outcomes. The purpose of these guidelines is to highlight specific features commonly observed in NASH candidates and strategies to optimize pretransplant evaluation and waitlist survival. More specifically, the working group addressed the following clinically-relevant questions providing recommendations based on the GRADE system supported by rigorous systematic reviews and consensus: (1) Is the outcome after LT similar to that of other etiologies of liver disease? (2) Is the natural history of NASH-related cirrhosis different from other etiologies of end-stage liver disease? (3) How should cardiovascular risk be assessed in the candidate for LT? Should the assessment differ from that done in other etiologies? (4) How should comorbidities (hypertension, diabetes, dyslipidemia, obesity, renal dysfunction, etc.) be treated in the candidate for LT? Should treatment and monitoring of these comorbidities differ from that applied in other etiologies? (5) What are the therapeutic strategies recommended to improve the cardiovascular and nutritional status of a NASH patient in the waiting list for LT? (6) Is there any circumstance where obesity should contraindicate LT? (7) What is the optimal time for bariatric surgery: before, during, or after LT? and (8) Donor steatosis: how much relevant is it for LT in NASH patients

Etiology and Severity of Liver Disease in HIV-Positive Patients With Suspected NAFLD: Lessons From a Cohort With Available Liver Biopsies

BACKGROUND: Spectrum of liver injury among HIV-positive people is wide; in particular, prevalence of nonalcoholic fatty liver disease (NAFLD) seems to be higher compared with HIV-negative people. METHODS: We retrospectively evaluated all liver biopsies performed at Royal Free Hospital from 2000 to 2017 in HIV monoinfected patients with abnormal transaminases, to assess the underlying cause of liver disease and to characterize the extent of fibrosis. We furthermore evaluated the diagnostic accuracy of FIB4 and FibroScan as noninvasive tools for fibrosis assessment. RESULTS: Ninety-seven patients were included. Most common histological findings were NAFLD (28%), nonspecific changes (26%), and normal histology (13%). Twenty percent of the patients had significant fibrosis and 11% had advanced fibrosis. FIB4, at a cutoff of 1.3, had a specificity of 82% and negative predictive value (NPV) of 95% for exclusion of advanced fibrosis. FibroScan was available in 28% patients and 33% had a liver stiffness ≥7.5 kPa. FibroScan showed a specificity of 77% and NPV of 94% for exclusion of significant fibrosis. Among patients with NAFLD (n = 27), 18% had advanced fibrosis, whereas the majority (56%) did not have any fibrosis. The NPV of FIB4 for advanced fibrosis in these patients was 93%. CONCLUSIONS: Among HIV-positive patients with elevated transaminases, a surprisingly high number of patients had nonsignificant changes or even normal histological findings. The prevalence of NAFLD was lower than reported in other series. Use of noninvasive tools with a high NPV for significant fibrosis can help reduce the number of required biopsies

Disease burden and economic impact of diagnosed non-alcoholic steatohepatitis (NASH) in the United Kingdom (UK) in 2018

BACKGROUNDS AND AIMS: Non-alcoholic steatohepatitis (NASH) – a progressive subset of non-alcoholic fatty liver disease (NAFLD) – is a chronic liver disease that can progress to advanced fibrosis, cirrhosis, and end-stage liver disease (ESLD) if left untreated. Early-stage NASH is usually asymptomatic, meaning a large proportion of the prevalent population are undiagnosed. Receiving a NASH diagnosis increases the probability that a patient will receive interventions for the purpose of managing their condition. The purpose of this study was to estimate the disease burden and economic impact of diagnosed NASH in the United Kingdom (UK) adult population in 2018. METHODS: The socioeconomic burden of diagnosed NASH from a societal perspective was estimated using cost-of-illness methodology applying a prevalence approach. This involved estimating the number of adults with diagnosed NASH in the UK in a base period (2018) and the economic and wellbeing costs attributable to diagnosed NASH in that period. The analysis was based on a targeted review of the scientific literature, existing databases and consultation with clinical experts, health economists and patient groups. RESULTS: Of the prevalent NASH population in the UK in 2018, an estimated 79.8% were not diagnosed. In particular, of the prevalent population in disease stages F0 to F2, only 2.0% (F0), 2.0% (F1) and 16.5% (F2), respectively, were diagnosed. Total economic costs of diagnosed NASH in the UK ranged from £2.3 billion (lower prevalence scenario, base probability of diagnosis scenario) to £4.2 billion (higher prevalence scenario, base probability of diagnosis scenario). In 2018, people with NASH in the UK were estimated to experience 94,094 to 174,564 disability-adjusted life years (DALYs) overall. Total wellbeing costs associated with NASH in 2018 were estimated to range between £5.6 to £10.5 billion. CONCLUSIONS: The prevention and appropriate management of adult NASH patients could result in reduced economic costs and improvements in wellbeing