Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver disease worldwide. We estimated the global prevalence, incidence, progression, and outcomes of NAFLD and nonalcoholic steatohepatitis (NASH). PubMed/MEDLINE were searched from 1989 to 2015 for terms involving epidemiology and progression of NAFLD. Exclusions included selected groups (studies that exclusively enrolled morbidly obese or diabetics or pediatric) and no data on alcohol consumption or other liver diseases. Incidence of hepatocellular carcinoma (HCC), cirrhosis, overall mortality, and liver‐related mortality were determined. NASH required histological diagnosis. All studies were reviewed by three independent investigators. Analysis was stratified by region, diagnostic technique, biopsy indication, and study population. We used random‐effects models to provide point estimates (95% confidence interval [CI]) of prevalence, incidence, mortality and incidence rate ratios, and metaregression with subgroup analysis to account for heterogeneity. Of 729 studies, 86 were included with a sample size of 8,515,431 from 22 countries. Global prevalence of NAFLD is 25.24% (95% CI: 22.10‐28.65) with highest prevalence in the Middle East and South America and lowest in Africa. Metabolic comorbidities associated with NAFLD included obesity (51.34%; 95% CI: 41.38‐61.20), type 2 diabetes (22.51%; 95% CI: 17.92‐27.89), hyperlipidemia (69.16%; 95% CI: 49.91‐83.46%), hypertension (39.34%; 95% CI: 33.15‐45.88), and metabolic syndrome (42.54%; 95% CI: 30.06‐56.05). Fibrosis progression proportion, and mean annual rate of progression in NASH were 40.76% (95% CI: 34.69‐47.13) and 0.09 (95% CI: 0.06‐0.12). HCC incidence among NAFLD patients was 0.44 per 1,000 person‐years (range, 0.29‐0.66). Liver‐specific mortality and overall mortality among NAFLD and NASH were 0.77 per 1,000 (range, 0.33‐1.77) and 11.77 per 1,000 person‐years (range, 7.10‐19.53) and 15.44 per 1,000 (range, 11.72‐20.34) and 25.56 per 1,000 person‐years (range, 6.29‐103.80). Incidence risk ratios for liver‐specific and overall mortality for NAFLD were 1.94 (range, 1.28‐2.92) and 1.05 (range, 0.70‐1.56). Conclusions : As the global epidemic of obesity fuels metabolic conditions, the clinical and economic burden of NAFLD will become enormous. (H epatology 2016;64:73–84)
Hepatitis C virus (HCV) exhibits high genetic diversity, characterized by regional variations in genotype prevalence. This poses a challenge to the improved development of vaccines and pan‐genotypic treatments, which require the consideration of global trends in HCV genotype prevalence. Here we provide the first comprehensive survey of these trends. To approximate national HCV genotype prevalence, studies published between 1989 and 2013 reporting HCV genotypes are reviewed and combined with overall HCV prevalence estimates from the Global Burden of Disease (GBD) project. We also generate regional and global genotype prevalence estimates, inferring data for countries lacking genotype information. We include 1,217 studies in our analysis, representing 117 countries and 90% of the global population. We calculate that HCV genotype 1 is the most prevalent worldwide, comprising 83.4 million cases (46.2% of all HCV cases), approximately one‐third of which are in East Asia. Genotype 3 is the next most prevalent globally (54.3 million, 30.1%); genotypes 2, 4, and 6 are responsible for a total 22.8% of all cases; genotype 5 comprises the remaining <1%. While genotypes 1 and 3 dominate in most countries irrespective of economic status, the largest proportions of genotypes 4 and 5 are in lower‐income countries. Conclusion : Although genotype 1 is most common worldwide, nongenotype 1 HCV cases—which are less well served by advances in vaccine and drug development—still comprise over half of all HCV cases. Relative genotype proportions are needed to inform healthcare models, which must be geographically tailored to specific countries or regions in order to improve access to new treatments. Genotype surveillance data are needed from many countries to improve estimates of unmet need. (H epatology 2015;61:77–87)
In efforts to inform public health decision makers, the Global Burden of Diseases, Injuries, and Risk Factors 2010 (GBD2010) Study aims to estimate the burden of disease using available parameters. This study was conducted to collect and analyze available prevalence data to be used for estimating the hepatitis C virus (HCV) burden of disease. In this systematic review, antibody to HCV (anti‐HCV) seroprevalence data from 232 articles were pooled to estimate age‐specific seroprevalence curves in 1990 and 2005, and to produce age‐standardized prevalence estimates for each of 21 GBD regions using a model‐based meta‐analysis. This review finds that globally the prevalence and number of people with anti‐HCV has increased from 2.3% (95% uncertainty interval [UI]: 2.1%‐2.5%) to 2.8% (95% UI: 2.6%‐3.1%) and >122 million to >185 million between 1990 and 2005. Central and East Asia and North Africa/Middle East are estimated to have high prevalence (>3.5%); South and Southeast Asia, sub‐Saharan Africa, Andean, Central, and Southern Latin America, Caribbean, Oceania, Australasia, and Central, Eastern, and Western Europe have moderate prevalence (1.5%‐3.5%); whereas Asia Pacific, Tropical Latin America, and North America have low prevalence (<1.5%). Conclusion : The high prevalence of global HCV infection necessitates renewed efforts in primary prevention, including vaccine development, as well as new approaches to secondary and tertiary prevention to reduce the burden of chronic liver disease and to improve survival for those who already have evidence of liver disease. (H EPATOLOGY 2013)
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the Western world, strongly associated with insulin resistance and the metabolic syndrome. Nonalcoholic steatohepatitis, i.e., fatty liver accompanied by necroinflammatory changes, is mostly defined by the NAFLD activity score (NAS). The aim of the current study was to determine disease‐specific mortality in NAFLD, and evaluate the NAS and fibrosis stage as prognostic markers for overall and disease‐specific mortality. In a cohort study, data from 229 well‐characterized patients with biopsy‐proven NAFLD were collected. Mean follow‐up was 26.4 (±5.6, range 6‐33) years. A reference population was obtained from the National Registry of Population, and information on time and cause of death were obtained from the Registry of Causes of Death. NAFLD patients had an increased mortality compared with the reference population (hazard ratio [HR] 1.29, confidence interval [CI] 1.04‐1.59, P = 0.020), with increased risk of cardiovascular disease (HR 1.55, CI 1.11‐2.15, P = 0.01), hepatocellular carcinoma (HR 6.55, CI 2.14‐20.03, P = 0.001), infectious disease (HR 2.71, CI 1.02‐7.26, P = 0.046), and cirrhosis (HR 3.2, CI 1.05‐9.81, P = 0.041). Overall mortality was not increased in patients with NAS 5‐8 and fibrosis stage 0‐2 (HR 1.41, CI 0.97‐2.06, P = 0.07), whereas patients with fibrosis stage 3‐4, irrespective of NAS, had increased mortality (HR 3.3, CI 2.27‐4.76, P < 0.001). Conclusion : NAFLD patients have increased risk of death, with a high risk of death from cardiovascular disease and liver‐related disease. The NAS was not able to predict overall mortality, whereas fibrosis stage predicted both overall and disease‐specific mortality. (H epatology 2015;61:1547–1554)
The 2005 consensus proposal for the classification of hepatitis C virus (HCV) presented an agreed and uniform nomenclature for HCV variants and the criteria for their assignment into genotypes and subtypes. Since its publication, the available dataset of HCV sequences has vastly expanded through advancement in nucleotide sequencing technologies and an increasing focus on the role of HCV genetic variation in disease and treatment outcomes. The current study represents a major update to the previous consensus HCV classification, incorporating additional sequence information derived from over 1,300 (near‐)complete genome sequences of HCV available on public databases in May 2013. Analysis resolved several nomenclature conflicts between genotype designations and using consensus criteria created a classification of HCV into seven confirmed genotypes and 67 subtypes. There are 21 additional complete coding region sequences of unassigned subtype. The study additionally describes the development of a Web resource hosted by the International Committee for Taxonomy of Viruses (ICTV) that maintains and regularly updates tables of reference isolates, accession numbers, and annotated alignments (http://talk.ictvonline.org/links/hcv/hcv-classification.htm). The Flaviviridae Study Group urges those who need to check or propose new genotypes or subtypes of HCV to contact the Study Group in advance of publication to avoid nomenclature conflicts appearing in the literature. While the criteria for assigning genotypes and subtypes remain unchanged from previous consensus proposals, changes are proposed in the assignment of provisional subtypes, subtype numbering beyond “w,” and the nomenclature of intergenotypic recombinant. Conclusion : This study represents an important reference point for the consensus classification of HCV variants that will be of value to researchers working in clinical and basic science fields. (H epatology 2014;59:318‐327)
Treatment options for patients with hepatitis C virus (HCV) genotype 3 infection are limited, with the currently approved all‐oral regimens requiring 24‐week treatment and the addition of ribavirin (RBV). This phase III study (ALLY‐3; ClinicalTrials.gov : NCT02032901) evaluated the 12‐week regimen of daclatasvir (DCV; pangenotypic nonstructural protein [NS]5A inhibitor) plus sofosbuvir (SOF; pangenotypic NS5B inhibitor) in patients infected with genotype 3. Patients were either treatment naïve (n = 101) or treatment experienced (n = 51) and received DCV 60 mg plus SOF 400 mg once‐daily for 12 weeks. Coprimary endpoints were the proportions of treatment‐naïve and treatment‐experienced patients achieving a sustained virological response (SVR) at post‐treatment week 12 (SVR12). SVR12 rates were 90% (91 of 101) and 86% (44 of 51) in treatment‐naïve and treatment‐experienced patients, respectively; no virological breakthrough was observed, and ≥99% of patients had a virological response (VR) at the end of treatment. SVR12 rates were higher in patients without cirrhosis (96%; 105 of 109) than in those with cirrhosis (63%; 20 of 32). Five of seven patients who previously failed treatment with an SOF‐containing regimen and 2 of 2 who previously failed treatment with an alisporivir‐containing regimen achieved SVR12. Baseline characteristics, including gender, age, HCV‐RNA levels, and interleukin‐28B genotype, did not impact virological outcome. DCV plus SOF was well tolerated; there were no adverse events (AEs) leading to discontinuation and only 1 serious AE on‐treatment, which was unrelated to study medications. The few treatment‐emergent grade 3/4 laboratory abnormalities that were observed were transient. Conclusion : A 12‐week regimen of DCV plus SOF achieved SVR12 in 96% of patients with genotype 3 infection without cirrhosis and was well tolerated. Additional evaluation to optimize efficacy in genotype 3–infected patients with cirrhosis is underway. (H epatology 2015;61:1127–1135)
Noncoding RNAs play important roles in cancer biology, providing potential targets for cancer intervention. As a new class of endogenous noncoding RNAs, circular RNAs (circRNAs) have been recently identified in cell development and function, and certain types of pathological responses, generally acting as a microRNA (miRNA) sponge to regulate gene expression. Identifying the deregulated circRNAs and their roles in cancer has attracted much attention. However, the expression profile and function of circRNAs in human hepatocellular carcinoma (HCC) remain to be investigated. Here, we analyzed the expression profile of human circRNAs in HCC tissues and identified circMTO1 (mitochondrial translation optimization 1 homologue; hsa_circRNA_0007874/hsa_circRNA_104135 ) as one circRNA significantly down‐regulated in HCC tissues. HCC patients with low circMTO1 expression had shortened survival. By using a biotin‐labeled circMTO1 probe to perform RNA in vivo precipitation in HCC cells, we identified miR‐9 as the circMTO1‐associated miRNA. Furthermore, silencing of circMTO1 in HCC could down‐regulate p21, the target of oncogenic miR‐9, resulting in the promotion of HCC cell proliferation and invasion. In addition, the tumor‐promoting effect of circMTO1 silencing was blocked by miR9 inhibitor. Intratumoral administration of cholesterol‐conjugated circMTO1 small interfering RNA promoted tumor growth in HCC‐bearing mice in vivo . Conclusion: circMTO1 suppresses HCC progression by acting as the sponge of oncogenic miR‐9 to promote p21 expression, suggesting that circMTO1 is a potential target in HCC treatment. The decrease of circMTO1 in HCC tissues may serve as a prognosis predictor for poor survival of patients. (H epatology 2017;66:1151‐1164).
The AASLD/EASL Practice Guideline Subcommittee on Hepatic Encephalopathy are: Jayant A. Talwalkar (Chair, AASLD), Hari S. Conjeevaram, Michael Porayko, Raphael B. Merriman, Peter L. M. Jansen, and Fabien Zoulim. This guideline has been approved by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver and represents the position of both associations.
Chronic hepatitis C virus (HCV) infection with advanced cirrhosis or post‐liver transplantation recurrence represents a high unmet medical need with no approved therapies effective across all HCV genotypes. The open‐label ALLY‐1 study assessed the safety and efficacy of a 60‐mg once‐daily dosage of daclatasvir (pan‐genotypic NS5A inhibitor) in combination with sofosbuvir at 400 mg once daily (NS5B inhibitor) and ribavirin at 600 mg/day for 12 weeks with a 24‐week follow‐up in two cohorts of patients with chronic HCV infection of any genotype and either compensated/decompensated cirrhosis or posttransplantation recurrence. Patients with on‐treatment transplantation were eligible to receive 12 additional weeks of treatment immediately after transplantation. The primary efficacy measure was sustained virologic response at posttreatment week 12 (SVR12) in patients with a genotype 1 infection in each cohort. Sixty patients with advanced cirrhosis and 53 with posttransplantation recurrence were enrolled; HCV genotypes 1 (76%), 2, 3, 4, and 6 were represented. Child‐Pugh classifications in the advanced cirrhosis cohort were 20% A, 53% B, and 27% C. In patients with cirrhosis, 82% (95% confidence interval [CI], 67.9%‐92.0%) with genotype 1 infection achieved SVR12, whereas the corresponding rates in those with genotypes 2, 3, and 4 were 80%, 83%, and 100%, respectively; SVR12 rates were higher in patients with Child‐Pugh class A or B, 93%, versus class C, 56%. In transplant recipients, SVR12 was achieved by 95% (95% CI, 83.5%‐99.4%) and 91% of patients with genotype 1 and 3 infection, respectively. Three patients received peritransplantation treatment with minimal dose interruption and achieved SVR12. There were no treatment‐related serious adverse events. Conclusion : The pan‐genotypic combination of daclatasvir, sofosbuvir, and ribavirin was safe and well tolerated. High SVR rates across multiple HCV genotypes were achieved by patients with post‐liver transplantation recurrence or advanced cirrhosis. (H epatology 2016;63:1493‐1505)
All‐oral combinations of direct‐acting antivirals may improve efficacy and safety outcomes for patients with hepatitis C virus (HCV) infection, particularly those who are poor candidates for current interferon/ribavirin‐based regimens. In this open‐label, phase 3 study, 135 interferon‐ineligible/intolerant and 87 nonresponder patients with chronic HCV genotype 1b infection were enrolled at 24 centers in Japan. Patients received daclatasvir 60 mg once daily plus asunaprevir 100 mg twice daily for 24 weeks. The primary endpoint was sustained virologic response 24 weeks after treatment (SVR 24 ). This study is registered with ClinicalTrials.gov (NCT01497834). SVR 24 was achieved by 87.4% of interferon‐ineligible/intolerant patients and 80.5% of nonresponder (null and partial) patients; rates were similar in cirrhosis (90.9%) and noncirrhosis (84.0%) patients, and in patients with IL28B CC (84.5%) or non‐CC (84.8%) genotypes. Fourteen patients in each group (12.6%) discontinued dual therapy, mainly due to adverse events or lack of efficacy. Nine nonresponder patients received additional treatment with peginterferon/ribavirin per protocol‐defined criteria. The rate of serious adverse events was low (5.9%) and varied among patients. The most common adverse events were nasopharyngitis, increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST), headache, diarrhea, and pyrexia. Conclusion : Interferon‐free, ribavirin‐free all‐oral therapy with daclatasvir and asunaprevir for 24 weeks is well tolerated and can achieve a high rate of SVR in patients with HCV genotype 1b who were ineligible, intolerant, or had not responded to prior interferon‐based therapy. (H epatology 2014;59:2083–2091)
Liver disease is a major cause of illness and death worldwide. In China alone, liver diseases, primarily viral hepatitis (predominantly hepatitis B virus [HBV]), nonalcoholic fatty liver disease, and alcoholic liver disease, affect approximately 300 million people. The establishment of the Expanded Program on Immunization in 1992 has resulted in a substantial decline in the number of newly HBV‐infected patients; however, the number of patients with alcoholic and nonalcoholic fatty liver diseases is rising at an alarming rate. Liver cancer, one of the most deadly cancers, is the second‐most common cancer in China. Approximately 383,000 people die from liver cancer every year in China, which accounts for 51% of the deaths from liver cancer worldwide. Over the past 10 years, China has made some significant efforts to shed its “leader in liver diseases” title by investing large amounts of money in funding research, vaccines, and drug development for liver diseases and by recruiting many Western‐trained hepatologists and scientists. Over the last two decades, hepatologists and scientists in China have made significant improvements in liver disease prevention, diagnosis, management, and therapy. They have been very active in liver disease research, as shown by the dramatic increase in the number of publications in H epatology . Nevertheless, many challenges remain that must be tackled collaboratively. In this review, we discuss the epidemiology and characteristics of liver diseases and liver‐related research in China. (H epatology 2014;60:2098–2107)
Liver fibrosis is the most important predictor of mortality in nonalcoholic fatty liver disease (NAFLD). Quantitative risk of mortality by fibrosis stage has not been systematically evaluated. We aimed to quantify the fibrosis stage–specific risk of all‐cause and liver‐related mortality in NAFLD. Through a systematic review and meta‐analysis, we identified five adult NAFLD cohort studies reporting fibrosis stage–specific mortality (0‐4). Using fibrosis stage 0 as a reference population, fibrosis stage–specific mortality rate ratios (MRRs) with 95% confidence intervals (CIs) for all‐cause and liver‐related mortality were estimated. The study is reported according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses statement. Included were 1,495 NAFLD patients with 17,452 patient years of follow‐up. Compared to NAFLD patients with no fibrosis (stage 0), NAFLD patients with fibrosis were at an increased risk for all‐cause mortality, and this risk increased with increases in the stage of fibrosis: stage 1, MRR = 1.58 (95% CI 1.19‐2.11); stage 2, MRR = 2.52 (95% CI 1.85‐3.42); stage 3, MRR = 3.48 (95% CI 2.51‐4.83); and stage 4, MRR = 6.40 (95% CI 4.11‐9.95). The results were more pronounced as the risk of liver‐related mortality increased exponentially with each increase in the stage of fibrosis: stage 1, MRR = 1.41 (95% CI 0.17‐11.95); stage 2, MRR = 9.57 (95% CI 1.67‐54.93); stage 3, MRR = 16.69 (95% CI 2.92‐95.36); and stage 4, MRR = 42.30 (95% CI 3.51‐510.34). Limitations of the study include an inability to adjust for comorbid conditions or demographics known to impact fibrosis progression in NAFLD and the inclusion of patients with simple steatosis and nonalcoholic steatohepatitis without fibrosis in the reference comparison group. Conclusion: The risk of liver‐related mortality increases exponentially with increase in fibrosis stage; these data have important implications in assessing the utility of each stage and benefits of regression of fibrosis from one stage to another. (H epatology 2017;65:1557‐1565).