Risk Of Liver Cirrhosis Research Articles

The Risk of Cirrhosis and Its Complications Based on PNPLA3 rs738409 G Allele Frequency

Background: Data regarding the influence of patatin-like phospholipase domain-containing 3 (PNPLA3) polymorphism for patients with liver cirrhosis (LC) are scarce. Objective: This study assesses the role of the PNPLA3 polymorphism for the development of LC and its complications by the findings of genetic examinations. Methods: Patients with LC caused by virus (n = 157), alcohol (n = 104), nonalcoholic fatty liver disease (NAFLD) (n = 106), or autoimmune disease (n = 33) and without LC (n = 128) were enrolled. LC was composed of the presence and absence of complications, such as variceal bleeding, hepatic ascites, and hepatic encephalopathy. To assess the role of the PNPLA3 polymorphism, odds ratio (OR) for the rs738409 variant was calculated for the patients between (i) with LC and without LC in the entire cohort and (ii) the presence and absence of complications in the patients with LC. Results: There was a significant difference among the patients without LC and those with alcohol, NAFLD-related LC in the frequency of G alleles (p < 0.001, both). According to complications of LC, the OR for NAFLD-related cirrhosis significantly increased in the presence of the two mutated alleles (OR = 3.165; p = 0.046) when the wild type was used as the reference. However, there were no significant risks for the complications in the virus and alcohol-related cirrhosis unless there was a presence of G alleles. Conclusion: The PNPLA3 polymorphism was associated with the risk of NAFLD-related LC and its complications.

Trans-anethole attenuates diet-induced nonalcoholic steatohepatitis through suppressing TGF-β-mediated fibrosis

BackgroundNonalcoholic Steatohepatitis (NASH) is the most severe type of non-alcoholic fatty liver disease (NAFLD) and one of the most common chronic liver diseases, leading to the increased risk of liver failure, cirrhosis and hepatocellular carcinoma. Trans-anethole was reported to have anti-inflammatory, anti-obesity and anti-diabetic activities. However, its role in NASH remains unknown. Therefore, we aimed to explore the effect of Trans-anethole on NASH. MethodsEight-week-old C57BL/6 mice were fed on a methionine- and choline-deficient (MCD) diet for 8 weeks to induce NASH in mice, and on the meanwhile, mice were also orally administrated with or without 100 mg/kg Trans-anethole daily to evaluate the effect of Trans-anethole on NASH. ResultsTrans-anethole dose-dependently ameliorated liver injury in MCD diet-fed mice, then the most effective dose of Trans-anethole 100 mg/kg was chosen. Trans-anethole significantly attenuated hepatic steatosis, inflammation and hepatic fibrosis in MCD diet-induced NASH mice. Moreover, Trans-anethole reduced hepatic fibrosis by inhibiting transforming growth factor-beta signaling pathway both in vivo and in vitro. ConclusionTrans-anethole effectively ameliorated NASH in MCD diet-fed mice, which suggested that Trans-anethole might serve as a therapeutic strategy for NASH.

Risk of Liver Cirrhosis in HBV/HCV-Infected Individuals with First-Degree Relatives Who Have Liver Cancer: Development and Validation of a Simple Model.

Identification of high-risk population among hepatitis B virus (HBV)/hepatitis C virus (HCV)-infected individuals with first-degree relatives (FDR) who have liver cancer is important to implement precise intervention. A cross-sectional study was conducted under the framework of a population-based Cancer Screening Program in Urban China (CanSPUC), aimed to develop and validate a simple noninvasive model that could assess and stratify cirrhosis risk, in HBV/HCV-infected individuals with FDRs who have liver cancer. People who participated in liver cancer screening in Henan province were enrolled. Using the data set consisting of participants admitted from October 1, 2013, to December 31, 2016, a 24-point scale risk score model was developed through logistic regression, based on educational background, dietary habit, smoking index, cooking oil fume exposure, history of severe trauma, HBV/HCV infection status, history of diabetes, history of hyperlipidemia, and parent history of liver cancer. The model showed excellent discrimination with area under the receiver operator characteristic curve (AUROC) of 0.875 [95% confidence interval (CI), 0.853-0.896] and fair calibration with a Hosmer-Lemeshow test P = 0.106. The prevalence rates in the medium- and high-risk groups were 2.87 (95% CI, 1.94-4.25) and 47.57 (95% CI, 31.59-71.63) times of low-risk group, respectively. After internal validation, bias-corrected AUROC was 0.874 (95% CI, 0.873-0.875). In the external validation data set consisting of participants admitted from January 1, 2017, to October 31, 2018, the model had achieved similar discrimination, calibration, and risk stratification ability. In conclusion, the risk score model we developed can be a practical tool for the screening and prevention of liver cirrhosis among HBV/HCV-infected individuals with FDRs who have liver cancer. PREVENTION RELEVANCE: We created a simple and noninvasive cirrhosis risk model for individuals infected by HBV/HCV who have FDRs with liver cancer. This model is useful not only for the prognosis of HBV/HCV infection, but also for the prevention of hepatocellular carcinoma.

New Australian guidelines for the treatment of alcohol problems: an overview of recommendations.

New Australian guidelines for the treatment of alcohol problems: an overview of recommendations.

Genetic variants in IL33 and IL1RL1 genes confer susceptibility to HBV-related liver cirrhosis in Chinese Han population.

Previous studies indicate that the IL-33/ST2 pathway is involved in hepatitis B virus (HBV) -related liver diseases. This study aimed to determine the relationship between genetic variants in IL-33/ST2 pathway with susceptibility to liver cirrhosis. A total of 2632 Han Chinese samples met the inclusion and exclusion criteria, including 840 negative controls (NeC), 691 chronic hepatitis B (CHB), 680 HBV-related liver cirrhosis (LC) and 421 HBV-related hepatocellular carcinoma (HCC) (without LC) patients. Four polymorphisms (IL33-rs4742170, rs1048274, rs10975519 and IL1RL1-rs1041973) were selected and genotyping was performed. All statistical analyses were performed by SPSS21.0, mainly using the Hardy-Weinberg equilibrium test, Pearson chi-square, unconditional Logistic regression and haplotype analysis. After adjusting for age, sex, smoking and drinking, significant associations were observed between IL33-rs4742170, rs1048274 and rs10975519 polymorphisms with LC risk. NeC with IL33-rs4742170 CC genotype was 1.80 times more likely to develop LC compared with TT genotype, while NeC with rs10975519(TC + CC) genotype was 1.32 times more likely to develop LC when compared with the TT genotype. CHB cases with rs4742170(CC + TC) genotype had 1.30 times higher susceptibility to develop LC compared with the TT genotype. The IL33-rs1048274G allele occurred more frequently in the LC group compared with the HCC group in codominant model (AG/AA: P = 0.001, OR = 1.66, 95%CI = 1.22-2.25; GG/AA: P = 0.018, OR = 1.54, 95%CI = 1.08-2.20). The IL33 haplotype CG conformed by rs10975519C and rs1048274G was more frequent in the LC group than in the NeC group and CHB group. Moreover, the IL33 haplotype CCG conformed by rs4742170C, rs10975519C and rs1048274G was found to be more frequent in the LC group than the HCC group. However, there was no association between IL1RL1-rs1041973 and LC risk. Our findings demonstrate the association between genetic variants in IL33 with susceptibility to liver cirrhosis. IL33-rs4742170C, rs1048274G and rs10975519C could serve as biomarkers of LC.

S1225 Multivariate Analysis of Causes of Death Among Hepatocellular Carcinoma Patients: A SEER-Based Study

Introduction: Hepatocellular Carcinoma (HCC), has a very poor prognosis and meek survival rates. Despite decades of research, a clear understanding of various causes of death among HCC patients is not well established. Identifying the causative factors helps develop targeted therapeutic regimens and formulate prophylactic measures. This study was therefore undertaken to identify various cancer and non-cancer causes of death in hepatocellular carcinoma (HCC) patients over different time periods after diagnosis, and to compare the mortality risk of each cause in HCC patients with the general population. Methods: In this retrospective cohort study, data of 67,637 HCC patients from 1975 to 2016 were collected from the Surveillance, Epidemiology, and End Results (SEER) database. We investigated the association between different causes of death and the following variables: age, race, tumor stage at diagnosis, and treatment (surgery, chemotherapy, and radiotherapy); each according to the periods of < 1 year, 1-5 years, 5-10 years, and >10 years following the diagnosis. Standardized mortality ratios (SMRs) and their 95% confidence intervals (CIs) were calculated for cancer and non-cancer deaths in each of the mentioned periods following diagnosis. Results: Data of 67,637 patients, of whom 50,571 patients died during the follow-up period, were analyzed. Most deaths were due to HCC itself (35,535, 70.3%), followed by other cancers (3,983, 7.9%). The most common non-cancer causes of death, with higher mortality risk in HCC patients than in the general population, included infectious and parasitic diseases including HIV (2,823 patients, SMR = 105.68, 95% CI: 101.82-109.65), chronic liver disease and cirrhosis (2,719 patients, SMR = 76.56, 95% CI: 73.71,79.5), and heart diseases (1,265 patients, SMR = 2.26, 95% CI: 2.14-2.39). Conclusion: The mortality rates showed a declining trend from the high of within the first year after diagnosis to a low of 10 years after diagnosis. The leading cause of death in HCC patients remains HCC itself over all time intervals after diagnosis. The commonest non-cancer causes of death were chronic liver disease and cirrhosis, infectious and parasitic diseases including HIV, and they had varying incidences across different time intervals. HCC patients had a higher risk of chronic liver disease, cirrhosis, infectious and parasitic diseases including HIV as compared to the general population whereas mortality risk due to heart diseases among HCC patients was similar to the general population.

Alcohol drinking and risks of liver cancer and non-neoplastic chronic liver diseases in China: a 10-year prospective study of 0.5 million adults

BackgroundAlcohol consumption is an important risk factor for hepatic neoplastic and non-neoplastic diseases. Questions remain, however, about the relevance to disease risk of drinking patterns and alcohol tolerability, which differ appreciably between Chinese and Western populations.MethodsThe prospective China Kadoorie Biobank included 512,715 adults (41% men) aged 30–79 years recruited from ten areas during 2004–2008, recording alcohol intake, drinking patterns, and other characteristics. After median 10 years’ follow-up, 2531 incident liver cancer, 2040 liver cirrhosis, 260 alcoholic liver disease (ALD), and 1262 non-alcoholic fatty liver disease (NAFLD) cases were recorded among 492,643 participants without prior cancer or chronic liver disease at baseline. Cox regression was used to estimate adjusted hazard ratios (HR) relating alcohol intake and drinking patterns to each disease.ResultsOverall, 33% of men and 2% of women drank alcohol regularly (i.e. at least weekly) at baseline. Among male current regular drinkers, alcohol consumption showed positive dose-response associations with risks of several major chronic liver diseases, with HRs per 280 g/week (i.e. around four drinks/day) higher usual alcohol intake of 1.44 (95% CI 1.23–1.69) for liver cancer (n = 547), 1.83 (1.60–2.09) for liver cirrhosis (n = 388), 2.01 (1.77–2.28) for ALD (n = 200), 1.71 (1.35–2.16) for NAFLD (n = 198), and 1.52 (1.40–1.64) for total liver disease (n = 1775). The association with ALD appeared stronger among men reporting flushing (i.e., with low alcohol tolerance). After adjustment for the total amount of weekly alcohol consumption, daily drinkers had significantly increased risk of ALD (2.15, 1.40–3.31) compared with non-daily drinkers, and drinking without meals was associated with significantly greater risks of liver cancer (1.32, 1.01–1.72), liver cirrhosis (1.37, 1.02–1.85), and ALD (1.60, 1.09–2.33) compared with drinking with meals. Female current regular drinkers had significantly higher risk of ALD, but not other liver diseases, than female abstainers.ConclusionsIn Chinese men, alcohol intake was associated with significantly increased risks of several major chronic liver diseases, and certain drinking patterns (e.g. drinking daily, drinking without meals) may further exacerbate the disease risks.

Hepatitis C Virus Infection in Pregnancy and Children: Its Implications and Treatment Considerations with Directly Acting Antivirals: A Review.

Hepatitis C virus infection (HCV) is a global health problem affecting >71 million people worldwide with chronic hepatitis C, 40% reproductive age group, and 8% pregnant women. Intravenous drug abuse, multi-transfusions are major risk factors in adults, while vertical transmission in pediatric population. It commonly presents as a chronic liver disease, has higher risk of liver cirrhosis and even progression to hepatocellular carcinoma. Therefore, proper screening of high-risk populations including pregnancy is recommended. All diagnosed chronic hepatitis C cases should be treated with directly acting anti-virals (DAAs) including pre-conception which has a cure rate of >95%. This would reduce the disease burden, vertical transmission, and disability associated. However, no DAAs regimens recommendation till date due to lack of evidence on adverse fetal outcomes and are concerned about the pharmacokinetic effect regarding physiological changes during pregnancy. Therefore, in this review, we have tried to explore the possible use of DAAs regimens and their safety issues during pregnancy, and possible consideration of few pan-genotypic regimens in the late 2nd and early 3rd trimester. This would not only prevent vertical transmission and decrease disease burden but also help to meet the WHO 2030 target of HCV elimination as a major public health problem.

Long-standing effect of cholecystectomy in patients with metabolic-associated fatty liver disease.

The role of cholecystectomy as a risk factor in patients with metabolic-associated fatty liver disease (MAFLD) remains unclear. This study aimed to investigate if long-standing cholecystectomy is associated with advanced liver fibrosis and cirrhosis in patients with recently diagnosed MAFLD. A retrospective observational study was performed in four hospitals in Mexico including patients with recently diagnosed MAFLD and a history of cholecystectomy. Subjects were divided into those with cholecystectomy ≥6 months before MAFLD diagnosis (ChBM), and those with cholecystectomy at the time of MAFLD diagnosis (ChAM). Odds ratios (OR) for the association of advanced liver fibrosis and cirrhosis with the timing of cholecystectomy were calculated. Mean age of 211 participants was 49.06 ± 15.12 years and the majority were female (72.5%). Patients from the ChBM (n = 70) group were significantly older (53.14 vs. 47.03 years; P = 0.003), had higher BMI (30.54 vs. 28.52 kg/m2; P = 0.011) and lower platelet count (236.23 vs. 266.72 × 103/µL; P = 0.046) compared with patients from ChAM group (n = 141). In multivariable-adjusted analysis, age (OR = 2.37; P = 0.024), dyslipidemia (OR = 4.28; P = 0.005) and severe liver fibrosis (OR = 4.68; P = 0.0) were independent risk factors associated with long-standing cholecystectomy. Patients with long-standing cholecystectomy (≥6 months) are at increased risk of severe liver fibrosis and cirrhosis at the time of MAFLD diagnosis compared to those with recently done cholecystectomy. Advanced age (>50 years) and dyslipidemia are also commonly found in these subjects.

EGF rs4444903 polymorphism is associated with risk of HCV-related cirrhosis and HBV/HCV-related hepatocellular carcinoma.

The epidermal growth factor (EGF) rs4444903 polymorphism is associated with aberrant expression of EGF, which was a characteristic of cirrhotic liver diseases, induces highly malignant hepatocellular carcinoma (HCC). Numerous studies have uncovered the association of this polymorphism with the risk of liver disease, but with inconsistent findings. Therefore, this meta-analysis was performed to evaluate whether EGF rs4444903 polymorphism conferred susceptibility to liver disease. Totally 18 eligible articles were identified by searching PubMed, Google, CNKI and EMBASE up to December 1, 2020. Our results indicated that there was no significant difference in the minor G allele frequency of rs4444903 polymorphism between HBV/HCV carriers and healthy controls. In other words, EGF rs4444903 polymorphism was not associated with the risk of HBV/HCV. Interestingly, this polymorphism increased the risk of liver cirrhosis in the controls with HCV infection. Additionally, EGF rs4444903 polymorphism is associated with the increased risk of HCC under the five models. Subgroup analysis by ethnicity shows that rs4444903 polymorphism intensifies the risk of HCC among Asians and Caucasians. Strong correlation is also reported in controls with cirrhosis or HCV infection and studies using PCR-RFLP genotyping. The study supports that EGF rs4444903 polymorphism is a genetic contributor to liver cirrhosis and HCC in the overall population. Nevertheless, this conclusion must be confirmed by larger studies with more diverse ethnic populations.

Nutritional supplementation for nonalcohol-related fatty liver disease: a network meta-analysis.

Nutritional supplementation for nonalcohol-related fatty liver disease: a network meta-analysis.

Associations of toothbrushing behaviour with risks of vascular and nonvascular diseases in Chinese adults

Accumulating evidence has shown that poor oral hygiene is associated with increased risk of cardiometabolic diseases in Western populations. However, its relevance about the relationships in Chinese adults remains unclear. The China Kadoorie Biobank enrolled 512715 adults aged 30-79years in China during 2004-2008. Cox regression was used to estimate adjusted hazard ratios (HRs) for each disease associated with measures of oral hygiene. Overall 9.3% of the participants reported rarely or never brushing teeth at baseline. Participants who rarely or never brushed teeth had adjusted HR of 1.12 (95% CI: 1.09, 1.15) for MVE, with similar HRs for stroke (1.08, 1.05-1.12), intracerebral haemorrhage (1.18, 1.11-1.26) and pulmonary heart disease (1.22, 1.13-1.32) compared with those who brushed teeth regularly. Those who did not brush teeth also had increased risk of cancer (1.09, 1.04-1.14), chronic obstructive pulmonary disease (COPD) (1.12, 1.05-1.20), liver cirrhosis (1.25, 1.09-1.44) and all-cause death (1.25, 1.21-1.28) but not type 2 diabetes (0.94, 0.86-1.03) and chronic kidney disease (0.98, 0.81-1.18). Among Chinese adults, we found that poor oral hygiene is associated with higher risks of major vascular disease, cancer, COPD, liver cirrhosis and all-cause deaths, but not type 2 diabetes and chronic kidney disease.

Lifestyle modifications for nonalcohol-related fatty liver disease: a network meta-analysis.

The prevalence of nonalcohol-related fatty liver disease (NAFLD) varies between 19% and 33% in different populations. NAFLD decreases life expectancy and increases the risks of liver cirrhosis, hepatocellular carcinoma, and requirement for liver transplantation. There is uncertainty surrounding the relative benefits and harms of various lifestyle interventions for people with NAFLD. To assess the comparative benefits and harms of different lifestyle interventions in the treatment of NAFLD through a network meta-analysis, and to generate rankings of the different lifestyle interventions according to their safety and efficacy. We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, Conference Proceedings Citation Index - Science, World Health Organization International Clinical Trials Registry Platform, and trials registers until February 2021 to identify randomised clinical trials in people with NAFLD. We included only randomised clinical trials (irrespective of language, blinding, or status) in people with NAFLD, whatever the method of diagnosis, age, and diabetic status of participants, or presence of non-alcoholic steatohepatitis (NASH). We excluded randomised clinical trials in which participants had previously undergone liver transplantation. We planned to perform a network meta-analysis with OpenBUGS using Bayesian methods and to calculate the differences in treatments using hazard ratios (HRs), odds ratios (ORs), and rate ratios (RaRs) with 95% credible intervals (CrIs) based on an available-participant analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance. However, the data were too sparse for the clinical outcomes. We therefore performed only direct comparisons (head-to-head comparisons) with OpenBUGS using Bayesian methods. We included a total of 59 randomised clinical trials (3631 participants) in the review. All but two trials were at high risk of bias. A total of 33 different interventions, ranging from advice to supervised exercise and special diets, or a combination of these and no additional intervention were compared in these trials. The reference treatment was no active intervention. Twenty-eight trials (1942 participants) were included in one or more comparisons. The follow-up ranged from 1 month to 24 months. The remaining trials did not report any of the outcomes of interest for this review. The follow-up period in the trials that reported clinical outcomes was 2 months to 24 months. During this short follow-up period, clinical events related to NAFLD such as mortality, liver cirrhosis, liver decompensation, liver transplantation, hepatocellular carcinoma, and liver-related mortality were sparse. This is probably because of the very short follow-up periods. It takes a follow-up of 8 years to 28 years to detect differences in mortality between people with NAFLD and the general population. It is therefore unlikely that differences by clinical outcomes will be noted in trials with less than 5 years to 10 years of follow-up. In one trial, one participant developed an adverse event. There were no adverse events in any of the remaining participants in this trial, or in any of the remaining trials, which seemed to be directly related to the intervention. The evidence indicates considerable uncertainty about the effects of the lifestyle interventions compared with no additional intervention (to general public health advice) on any of the clinical outcomes after a short follow-up period of 2 months to 24 months in people with nonalcohol-related fatty liver disease. Accordingly, high-quality randomised clinical trials with adequate follow-up are needed. We propose registry-based randomised clinical trials or cohort multiple randomised clinical trials (a study design in which multiple interventions are trialed within large longitudinal cohorts of participants to gain efficiencies and align trials more closely to standard clinical practice), comparing aerobic exercise and dietary advice versus standard of care (exercise and dietary advice received as part of national health promotion). The reason for the choice of aerobic exercise and dietary advice is the impact of these interventions on indirect outcomes which may translate to clinical benefit. The outcomes in such trials should be mortality, health-related quality of life, decompensated liver cirrhosis, liver transplantation, and resource use measures including costs of intervention and decreased healthcare use after a minimum follow-up of eight years, to find meaningful differences in the clinically important outcomes.

Patient Management in Non-Alcoholic Fatty Liver Disease and Type 2 Diabetes Mellitus

Aim.A current overview of non-pharmacological and drug-based approaches to non-alcoholic fatty liver disease (NAFLD) combined with type 2 diabetes mellitus (T2D).Key points.NAFLD is associated with an increased cardiovascular risk (due to association with “metabolic syndrome”) and the risks of liver cirrhosis and hepatocellular carcinoma. Macro- and microvascular complications in T2D comorbidity entail a higher overall mortality. A conjunction of lifestyle change and rational medication strategies to reach the target levels of glycosylated haemoglobin, low-density lipoprotein cholesterol, systolic and diastolic blood pressure is key in management of such patients. A body weight loss by 5–7 % or more (through caloric restriction or a bariatric surgery) promotes a marked reduction in liver fat and even reversal of steatohepatitis. Metered exercise exerts this effect even at insignificant weight loss. Minimising alcohol consumption and smoking is critical. A hepatotropic drug therapy is most essential in moderate fibrotic NAFLD. It includes antidiabetic agents (metformin, thiazolidinediones, glucagon-like peptide-1 receptor agonists, sodium-glucose co-transporter-2 inhibitors), bile acid preparations (e.g., 24-nor-ursodeoxycholic acid), farnesoid X receptor agonists (obeticholic acid, tropifexor), statins, acetylsalicylic acid. Combinations are superior to individual-drug schemes.Conclusion.The management of combined NAFLD-T2D requires a close inter-specialty involvement from hepatology, gastroenterology, endocrinology and cardiology. This interdisciplinary problem can be tackled through persuasive lifestyle recommendations and choosing rational medication strategies with a proved hepatoprotective efficacy.

Biochemical and Structural Properties of Entecavir-Resistant Hepatitis B Virus Polymerase with L180M/M204V Mutations.

Entecavir (ETV) is a widely used anti-hepatitis B virus (HBV) drug. However, the emergence of resistant mutations in HBV reverse transcriptase (RT) results in treatment failure. To understand the mechanism underlying the development of ETV resistance by HBV RT, we analyzed the L180M, M204V, and L180M/M204V mutants using a combination of biochemical and structural techniques. ETV-triphosphate (ETV-TP) exhibited competitive inhibition with dGTP in both wild-type (wt) RT and M204V RT, as observed using Lineweaver-Burk plots. In contrast, RT L180M or L180M/M204V did not fit either competitive, uncompetitive, noncompetitive, or typical mixed inhibition, although ETV-TP was a competitive inhibitor of dGTP. Crystallography of HIV RTY115F/F116Y/Q151M/F160M/M184V, mimicking HBV RT L180M/M204V, showed that the F115 bulge (F88 in HBV RT) caused by the F160M mutation induced deviated binding of dCTP from its normal tight binding position. Modeling of ETV-TP on the deviated dCTP indicated that a steric clash could occur between ETV-TP methylene and the 3'-end nucleoside ribose. ETV-TP is likely to interact primarily with HBV RT M171 prior to final accommodation at the deoxynucleoside triphosphate (dNTP) binding site (Y. Yasutake, S. Hattori, H. Hayashi, K. Matsuda, et al., Sci Rep 8:1624, 2018, https://doi.org/10.1038/s41598-018-19602-9). Therefore, in HBV RT L180M/M204V, ETV-TP may be stuck at M171, a residue that is conserved in almost all HBV isolates, leading to the strange inhibition pattern observed in the kinetic analysis. Collectively, our results provide novel insights into the mechanism of ETV resistance of HBV RT caused by L180M and M204V mutations. IMPORTANCE HBV infects 257 million people in the world, who suffer from elevated risks of liver cirrhosis and cancer. ETV is one of the most potent anti-HBV drugs, and ETV resistance mutations in HBV RT have been extensively studied. Nevertheless, the mechanisms underlying ETV resistance have remained elusive. We propose an attractive hypothesis to explain ETV resistance and effectiveness using a combination of kinetic and structural analyses. ETV is likely to have an additional interaction site, M171, beside the dNTP pocket of HBV RT; this finding indicates that nucleos(t)ide analogues (NAs) recognizing multiple interaction sites within RT may effectively inhibit the enzyme. Modification of ETV may render it more effective and enable the rational design of efficient NA inhibitors.

Hepatitis C virus eradication decreases the risks of liver cirrhosis and cirrhosis-related complications (Taiwanese chronic hepatitis C cohort).

It is currently unknown how hepatitis C virus (HCV) eradication with pegylated interferon and ribavirin (PR) therapy affects the incidence of new-onset liver cirrhosis (LC) in patients without cirrhosis and the incidence of decompensated liver disease (DLD) or hepatocellular carcinoma (HCC) in patients with cirrhosis. Taiwanese chronic hepatitis C cohort (T-COACH) is a nationwide HCV registry cohort from 23 hospitals in Taiwan recruited between 2003 and 2015. This study enrolled 10693 patients with chronic hepatitis C (CHC), linked to the Taiwan National Health Insurance Research Database, receiving PR therapy for at least 4weeks for new-onset LC and liver-related complications (DLD or HCC). Of the 10693 patients, 1372 (12.8%) patients had LC, and the mean age was 54.0±11.4years. The mean follow-up duration was 4.38±2.79years, with overall 46798 person-years. The 10-year cumulative incidence rates of new-onset LC were 5.0% (95% confidence interval [CI]: 3.2-7.7) in patients without cirrhosis with a sustained virologic response (SVR) and 21.9% (95% CI: 13.4-32.4) in those without SVR (hazard ratio [HR]: 0.22, P<0.001). The 10-year cumulative incidence rates of liver-related complications were 21.4% (95% CI: 11.1-37.2) in patients with cirrhosis with SVR and 47.0% (95% CI: 11.1-86.0) in those without SVR after adjustment for age, sex, and competing mortality (HR: 0.52, P<0.001). Hepatitis C virus eradication with PR therapy decreased the incidence of new-onset LC in noncirrhotic patients and the incidence of liver-related complications in cirrhotic patients with CHC.

Soluble type immune checkpoint regulators using multiplex luminex immunoassay in chronic hepatitis B patients

AimsSoluble immune checkpoint regulators (sICs) were reported to have clinical impact on the diagnosis and progress of various diseases. This study compared the serum levels of 16 sICs in patients...

The impact of genetic risk on liver fibrosis in non-alcoholic fatty liver disease as assessed by magnetic resonance elastography.

Variants in multiple genetic loci modify the risk of non-alcoholic fatty liver disease (NAFLD) and cirrhosis but there are limited data on the quantitative impact of variant copies on liver fibrosis. To investigate the effect of PNPLA3, TM6SF2, MBOAT7, GCKR and HSD17B13 genotype on liver fibrosis assessed by magnetic resonance elastography (MRE), a reproducible, accurate, continuous biomarker of liver fibrosis. This is a cross-sectional analysis derived from a well-characterised cohort at risk for NAFLD who underwent genotyping and MRE assessment. Liver stiffness (LS) was estimated using MRE and advanced fibrosis was defined as liver stiffness ≥3.63kilopascals (kPa). Univariable and multivariable linear and logistic regression analysis, were used to assess the association between genotype and MRE. Two hundred sixty-four patients (63% women) with a mean age 53 (±17)years, and 31% Hispanic ethnicity with genotyping and MRE were included. The odds of advanced fibrosis were 3.1 (95% CI: 1.1-8.9, P=0.04) for CG and 6.5 (95% CI: 2.2-18.9, P<0.01) for GG compared to CC PNPLA3 genotype. Each PNPLA3 risk variant copy was associated with 0.40kPa (95% CI: 0.19-0.61, P<0.01) increase in LS on MRE in analysis adjusted for age, sex and BMI and there was significant genotype-age interaction (P<0.01). Conversely, the protective TA allele in HSD17B13 was associated with a -0.41kPa (95% CI: -0.76 to -0.05, P=0.03) decrease in liver stiffness on MRE multivariable analysis. Knowledge of PNPLA3 and HSD17B13 genotype may assist in the non-invasive risk stratification of NAFLD with closer monitoring recommended for those with high genetic risk.

Adolescent Hepatitis C: Prevalence, Impact, and Management Challenges.

The prevalence of Hepatitis C virus infection (HCV), a leading cause of chronic liver disease worldwide, is rising in the United States (US) and other high-income countries, especially among youth and young adults. This surge in cases is closely associated with the opioid crisis and intravenous drug use (IVDU). However, its prevalence and impact on the adolescent population have not been thoroughly studied and therefore is poorly understood. The pediatric population tends to have milder liver disease and progression when compared to adults; however, there is a risk of developing liver cirrhosis, in addition to facing decreased quality of life and stigmatization from the disease. The recent approval of direct-acting antiviral (DAA) regimens for all HCV genotypes and age greater than 3 years has revolutionized its management. Therapy has shifted from the prolonged interferon-based regimens, to shorter duration, once daily oral pills that are highly effective, curative and with fewer side effects. Therapy is now indicated for all adolescents with hepatitis C virus infection, regardless of stage of liver disease, recent IVDU, or coinfection with HIV, therefore eliminating a lifetime risk of chronic liver disease, cirrhosis and hepatocarcinoma. Nonetheless, adolescents are rarely tested or treated for hepatitis C infection, and very few adolescents complete therapy. Implementation of point of care (POC) testing of high-risk youth at drug treatment centers or other juvenile facilities may be a good strategy to increase testing, diagnosis and therapy. This review article aims to educate pediatricians and other primary care providers to help decrease the existing knowledge gap on the subject.

Idiopathic Non-Cirrhotic Portal Hypertension and Porto-Sinusoidal Vascular Disease: Review of Current Data.

Idiopathic non-cirrhotic portal hypertension (INCPH) is a clinicopathologic disease entity characterized by the presence of clinical signs and symptoms of portal hypertension (PH) in the absence of liver cirrhosis or known risk factors accountable for PH. Multiple hematologic, immune-related, infectious, hereditary and metabolic risk factors have been associated with this disorder. Still, the exact etiopathogenesis is largely unknown. The recently proposed porto-sinusoidal vascular disease (PSVD) scheme broadens the spectrum of the disease by also including patients without clinical PH who are found to have similar histopathologic findings on core liver biopsies. Three histomorphologic lesions have been identified as specific for PSVD to include obliterative portal venopathy, nodular regenerative hyperplasia and incomplete septal cirrhosis/fibrosis. However, these findings are often subtle, under-recognized and subjective with low interobserver agreement among pathologists. Additionally, the natural history of the subclinical forms of the disease remains unexplored. The clinical course is more favorable compared to cirrhosis patients, especially in the absence of clinical PH or liver dysfunction. There are no universally accepted guidelines in regard to diagnosis and treatment of INCPH/PSVD. Hence, this review emphasizes the need to raise awareness of this entity by highlighting its complex pathophysiology and clinicopathologic associations. Lastly, formulation of standardized diagnostic criteria with clinical validation is necessary to avoid misclassifying vascular diseases of the liver and to develop and implement targeted therapeutic strategies.