Hepatitis D virus (HDV) infection causes the most severe form of viral hepatitis with rapid progression to cirrhosis, hepatic decompensation, and hepatocellular carcinoma. Although discovered > 40 years ago, little attention has been paid to this pathogen from both scientific and public communities. However, effectively combating hepatitis D requires advanced scientific knowledge and joint efforts from multi-stakeholders. In this review, we emphasized the recent advances in HDV virology, epidemiology, clinical feature, treatment, and prevention. We not only highlighted the remaining challenges but also the opportunities that can move the field forward.
Carcinoma, Hepatocellular/complications* ; Hepatitis B virus ; Hepatitis D/epidemiology* ; Hepatitis Delta Virus/genetics* ; Humans ; Liver Cirrhosis/etiology* ; Liver Neoplasms/complications*

BACKGROUND: China and the United States (US) ranked first and third in terms of new liver cancer cases and deaths globally in 2020. Therefore, a comprehensive assessment of trends in the incidence of primary liver cancer with four major etiological factors between China and the US during the past 30 years with age-period-cohort (APC) analyses is warranted. METHODS: Data were obtained from the Global Burden of Disease 2019, and period/cohort relative risks were estimated by APC modeling from 1990 to 2019. RESULTS: In 2019, there were 211,000 new liver cancer cases in China and 28,000 in the US, accounting for 39.4% and 5.2% of global liver cancer cases, respectively. For China, the age-standardized incidence rate (ASIR) consecutively decreased before 2005 but increased slightly since then, whereas the ASIR continuously increased in the US. Among the four etiological factors of liver cancer, the fastest reduction in incidence was observed in hepatitis B virus-related liver cancer among Chinese women, and the fastest increase was in nonalcoholic steatosis hepatitis (NASH)-related liver cancer among American men. The greatest reduction in the incidence of liver cancer was observed at the age of 53 years in Chinese men (-5.2%/year) and 33 years in Chinese women (-6.6%/year), while it peaked at 58 years old in both American men and women (4.5%/year vs . 2.8%/year). Furthermore, the period risks of alcohol- and NASH-related liver cancer among Chinese men have been elevated since 2013. Simultaneously, leveled- off period risks were observed in hepatitis C viral-related liver cancer in both American men and women. CONCLUSIONS Currently, both viral and lifestyle factors have been and will continue to play an important role in the time trends of liver cancer in both countries. More tailored and efficient preventive strategies should be designed to target both viral and lifestyle factors to prevent and control liver cancer.
Male ; Humans ; United States/epidemiology* ; Female ; Middle Aged ; Incidence ; Global Burden of Disease ; Non-alcoholic Fatty Liver Disease/complications* ; Cohort Studies ; Liver Neoplasms/etiology* ; China/epidemiology*

BACKGROUND: Hepatitis B is a viral infection that attacks the liver and can cause both potentially life-threatening acute and chronic liver disease. China has the world's largest burden of hepatitis B and is considered to be a major contributor toward the goal of World Health Organization (WHO) of eliminating hepatitis B virus (HBV) as a global health threat by 2030. This study aimed to analyze data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) to determine the trends in mortality of liver disease due to hepatitis B in China between 1990 and 2019 and the gap with the WHO's goal. METHODS: Annual deaths and age-standardized mortality rates (ASMRs) of liver disease due to hepatitis B in China between 1990 and 2019 were collected from GBD 2019. We calculated the percentage changes in deaths and estimated annual percentage changes (EAPCs) of ASMRs of liver disease due to hepatitis B. RESULTS: In China, deaths of total liver disease due to hepatitis B decreased by 29.13% from 229 thousand in 2016 to 162 thousand in 2019, and ASMR decreased by an average of 4.92% (95% confidence interval [CI]: 4.45-5.39%) per year in this period. For the spectrum of liver disease due to hepatitis B, deaths decreased by 74.83%, 34.71%, and 23.34% for acute hepatitis, cirrhosis and other chronic liver diseases, and liver cancer from 1990 to 2019, respectively, and ASMRs of acute hepatitis (EAPC = -7.63; 95% CI: -8.25, -7.00), cirrhosis and other chronic liver diseases (EAPC = -4.15; 95% CI: -4.66, -3.65), and liver cancer (EAPC = -5.17; 95% CI: -6.00, -4.33) decreased between 1990 and 2019. The proportions of older adults aged ≥70 years among all deaths of the spectrum of liver disease due to hepatitis B increased from 1990 to 2019. Deaths of liver cancer due to hepatitis B increased by 7.05% from 2015 to 2019. CONCLUSIONS Although a favorable trend in the mortality of liver disease due to hepatitis B was observed between 1990 and 2019, China still faces challenges in achieving the WHO's goal of eliminating HBV as a public threat by 2030. Therefore, efforts to increase the coverage of diagnosis and treatment of liver disease due to hepatitis B, especially of liver cancer due to hepatitis B, are warranted in China.
Humans ; Aged ; Global Burden of Disease ; Hepatitis B/complications* ; Hepatitis B virus ; Liver Cirrhosis/complications* ; China/epidemiology* ; Liver Neoplasms/etiology*

BACKGROUND/AIMS: This study aimed to clarify the effect of obesity on the development of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients receiving antiviral treatment. METHODS: This study applied a retrospective analysis to a historical cohort in Bundang Jesaeng Hospital. In total, 102 CHB patients were treated with entecavir as an initial treatment for CHB and checked for obesity using a body composition analyzer. Hepatic steatosis was measured semiquantitatively using Hamaguchi’s scoring system in ultrasonography. Risk factors for the development of HCC were analyzed, including obesity-related factors (body mass index [BMI], waist circumference [WC], waist-to-hip ratio [WHR], visceral fat area [VFA], and hepatic steatosis). RESULTS: The median follow-up duration of the patients was 45.2 months (interquartile range: 36.0-58.3 months). The cumulative incidence rates of HCC at 1 year, 3 years, and 5 years were 0%, 5.3%, and 9.0%, respectively. Univariable analysis revealed that the risk factors for HCC development were a platelet count of <120,000 /mm² (hazard ratio [HR]=5.21, P=0.031), HBeAg negativity (HR=5.61, P=0.039), and liver cirrhosis (HR=10.26, P=0.031). Multivariable analysis showed that the significant risk factor for HCC development was liver cirrhosis (HR=9.07, P=0.042). However, none of the obesity-related risk factors were significantly associated with HCC: BMI ≥25 kg/m² (HR=0.90, P=0.894), WC ≥90 cm (HR=1.10, P=0.912), WHR ≥0.9 (HR=1.94, P=0.386), VFA ≥100 cm² (HR=1.69, P=0.495), and hepatic steatosis (HR=0.57, P=0.602). CONCLUSION: HCC development is associated with liver cirrhosis but not obesity-related factors in CHB patients receiving entecavir.
Adult ; Antiviral Agents/*therapeutic use ; Body Mass Index ; Carcinoma, Hepatocellular/epidemiology/*etiology ; Cohort Studies ; DNA, Viral/blood ; Female ; Guanine/*analogs & derivatives/therapeutic use ; Hepatitis B virus/genetics/isolation & purification ; Hepatitis B, Chronic/complications/*drug therapy/virology ; Humans ; Incidence ; Liver Cirrhosis/complications ; Liver Neoplasms/epidemiology/*etiology ; Male ; Middle Aged ; Obesity/*complications ; Proportional Hazards Models ; Retrospective Studies ; Risk Factors ; Viral Load

BACKGROUND: The incidence and etiology of hepatocellular carcinoma (HCC) vary widely according to race and geographic regions. The insertional mutagenesis of adeno-associated virus 2 (AAV2) has recently been considered a new viral etiology of HCC. The aim of this study was to investigate the frequency and clinical characteristics of AAV2 in Korean patients with HCC. METHODS: A total of 289 unrelated Korean patients with HCC, including 159 Hepatitis-B-related cases, 16 Hepatitis-C-related cases, and 114 viral serology-negative cases, who underwent surgery at the Samsung Medical Center in Korea from 2009 to 2014 were enrolled in this study. The presence of AAV2 in fresh-frozen tumor tissues was investigated by DNA PCR and Sanger sequencing. The clinical and pathological characteristics of AAV2-associated HCC in these patients were compared with previous findings in French patients. RESULTS: The AAV2 detection rate in Korean patients (2/289) was very low compared with that in French patients (11/193). Similar to the French patients, the Korean patients with AAV2-related HCC showed no signs of liver cirrhosis. The Korean patients were younger than the French patients with the same AAV2-associated HCC; the ages at diagnosis of the two Korean patients were 47 and 39 yr, while the median age of the 11 French patients was 55 yr (range 43-90 yr). CONCLUSIONS: AAV2-associated HCC was very rare in Korean patients with HCC. Despite a limited number of cases, this study is the first to report the clinical characteristics of Korean patients with AAV2-associated HCC. These findings suggest epidemiologic differences in viral hepatocarcinogenesis between Korean and European patients.
Adult ; Asian Continental Ancestry Group ; Capsid Proteins/genetics ; Carcinoma, Hepatocellular/etiology/*pathology/virology ; DNA, Viral/chemistry/genetics/metabolism ; DNA-Binding Proteins/genetics ; Dependovirus/*genetics/isolation & purification/pathogenicity ; Female ; Humans ; Incidence ; Inverted Repeat Sequences/genetics ; Liver Neoplasms/etiology/*pathology/virology ; Male ; Middle Aged ; Parvoviridae Infections/complications/epidemiology ; Polymerase Chain Reaction ; Republic of Korea ; Sequence Analysis, DNA ; Viral Proteins/genetics

BACKGROUND/AIMS: Hepatic damage during transarterial chemoembolization (TACE) is a critical complication in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Apart from its role in preventing HBV reactivation, there is some evidence for the benefits of preemptive antiviral therapy in TACE. This study evaluated the effect of preemptive antiviral therapy on acute hepatic deterioration following TACE. METHODS: This retrospective observational study included a prospectively collected cohort of 108 patients with HBV-related HCC who underwent TACE between January 2007 and January 2013. Acute hepatic deterioration following TACE was evaluated. Treatment-related hepatic decompensation was defined as newly developed encephalopathy, ascites, variceal bleeding, elevation of the bilirubin level, prolongation of prothrombin time, or elevation of the Child-Pugh score by ≥2 within 2 weeks following TACE. Univariate and multivariate analyses were conducted to identify factors influencing treatment-related decompensation. Preemptive antiviral therapy involves directing prophylaxis only toward high-risk chronic hepatitis B patients in an attempt to prevent the progression of liver disease. We regarded at least 6 months as a significant duration of preemptive antiviral treatment before diagnosis of HCC. RESULTS: Of the 108 patients, 30 (27.8%) patients received preemptive antiviral therapy. Treatment-related decompensation was observed in 25 (23.1%) patients during the follow-up period. Treatment-related decompensation following TACE was observed more frequently in the nonpreemptive group than in the preemptive group (29.5% vs. 6.7%, P=0.008). In the multivariate analysis, higher serum total bilirubin (Hazard ratio [HR] =3.425, P=0.013), hypoalbuminemia (HR=3.990, P=0.015), and absence of antiviral therapy (HR=7.597, P=0.006) were significantly associated with treatment-related hepatic decompensation. CONCLUSIONS: Our findings suggest that preemptive antiviral therapy significantly reduces the risk of acute hepatic deterioration. Preventing hepatic deterioration during TACE by applying such a preemptive approach may facilitate the continuation of anticancer therapy and thus improve long-term outcomes.
Aged ; Antiviral Agents/*therapeutic use ; Bilirubin/blood ; Carcinoma, Hepatocellular/*therapy ; Chemoembolization, Therapeutic/*adverse effects ; Female ; Gastrointestinal Hemorrhage/etiology ; Guanine/*analogs & derivatives/therapeutic use ; Hepatitis B/complications/*drug therapy ; Humans ; Hypoalbuminemia/etiology ; Incidence ; Liver/physiopathology ; Liver Diseases/epidemiology/*etiology ; Liver Neoplasms/*therapy ; Male ; Middle Aged ; Proportional Hazards Models ; Retrospective Studies ; Risk Factors ; Treatment Outcome

INTRODUCTIONLarge, recent population-based data for evaluating the predictors of oesophageal variceal bleeding (OVB) among cirrhotic patients is still lacking. This study aimed to determine the cumulative incidence of OVB among cirrhotic patients and identify the predictors of OVB occurrence.

METHODSPatient information on 38,172 cirrhotic patients without a history of OVB, who were discharged between 1 January 2007 and 31 December 2007, was obtained from the Taiwan National Health Insurance Database for this study. All patients were followed up for three years. Death was the competing risk when calculating the cumulative incidences and hazard ratios (HRs) of OVB.

RESULTSOVB was present in 2,609 patients (OVB group) and absent in 35,563 patients (non-OVB group) at hospitalisation. During the three-year follow-up period, the cumulative incidence of OVB was 44.5% and 11.3% in the OVB and non-OVB group, respectively (p < 0.001). Modified Cox regression analysis showed that the HR of OVB history was 4.42 for OVB occurrence (95% confidence interval [CI] 4.13-4.74). Other predictors for OVB occurrence included hepatocellular carcinoma (HR 1.16, 95% CI 1.09-1.24), young age (HR 0.98, 95% CI 0.98-0.98), ascites (HR 1.46, 95% CI 1.37-1.56), alcohol-related disorders (HR 1.20, 95% CI 1.12-1.28), peptic ulcer bleeding (HR 1.26, 95% CI 1.13-1.41) and diabetes mellitus (HR 1.14, 95% CI 1.06-1.23).

CONCLUSIONCirrhotic patients have a fourfold increased risk of future OVB following the first incidence of OVB.

Adult ; Aged ; Alcoholism ; complications ; Ascites ; complications ; Carcinoma, Hepatocellular ; complications ; Databases, Factual ; Diabetes Complications ; Esophageal and Gastric Varices ; epidemiology ; etiology ; Female ; Gastrointestinal Hemorrhage ; epidemiology ; etiology ; Humans ; Incidence ; Liver Cirrhosis ; complications ; physiopathology ; Liver Neoplasms ; complications ; Male ; Middle Aged ; Peptic Ulcer ; complications ; Proportional Hazards Models ; Recurrence ; Retrospective Studies ; Risk ; Taiwan

BACKGROUND/AIMS: Data on the epidemiology of alcoholic cirrhosis, especially in Asian countries, are limited. We compared the temporal evolution of patterns of alcoholic and nonalcoholic cirrhosis over the last decade. METHODS: We retrospectively examined the inpatient datasets of five referral centers during 2002 and 2011. The study included patients who were admitted due to specific complications of liver cirrhosis. We compared the causes of hospital admissions and in-hospital deaths between patients with alcoholic and nonalcoholic cirrhosis. RESULTS: Among the included 2,799 hospitalizations (2,165 patients), 1,496 (1,143 patients) were from 2002, and 1,303 (1,022 patients) were from 2011. Over time, there was a reduction in the rate of hepatic encephalopathy (HE) as a cause of hospitalization and an increase in the rate of hepatocellular carcinoma. Deaths that were attributable to HE or spontaneous bacterial peritonitis (SBP) significantly decreased, whereas those due to hepatorenal syndrome (HRS) significantly increased over time in patients with alcoholic cirrhosis. However, in patients with nonalcoholic cirrhosis, hepatic failure and HRS remained the principal causes of in-hospital death during both time periods. CONCLUSIONS: The major causes of in-hospital deaths have evolved from acute cirrhotic complications, including HE or SBP to HRS in alcoholic cirrhosis, whereas those have remained unchanged in nonalcoholic cirrhosis during the last decade.
Aged ; Asia/epidemiology ; Bacterial Infections/etiology/mortality ; Carcinoma, Hepatocellular/etiology/mortality ; Cause of Death ; Female ; Hepatic Encephalopathy/etiology/mortality ; Hepatorenal Syndrome/etiology/mortality ; Hospital Mortality/*trends ; Hospitalization/*trends ; Humans ; Liver Cirrhosis/*complications/mortality ; Liver Cirrhosis, Alcoholic/*complications/mortality ; Liver Neoplasms/etiology/mortality ; Male ; Middle Aged ; Peritonitis/microbiology/mortality ; Retrospective Studies ; Risk Factors ; Time Factors

BACKGROUND/AIMS: We investigated factors associated with the disease progression and development of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients during long-term oral nucleos(t)ide analog (NA) therapy. METHODS: This retrospective study included 524 naive CHB patients who received oral NA therapy for more than 48 weeks between January 2003 and December 2007. The primary outcome was 5-year cumulative probability of disease progression and HCC development. Disease progression was defined as cirrhosis development, cirrhotic complications, HCC or liver-related mortality. RESULTS: For the 524 patients, the cumulative probabilities of disease progression and HCC development at 1, 2, 3, 4 and 5 years were 1.1%, 6.3%, 9.0%, 11.6%, and 16.2% and 0.2%, 1.8%, 3.6%, 5.8%, and 9.3%, respectively. In multivariate analysis, age >50 years (hazard ratio [HR], 1.05) and cirrhosis (HR, 2.95) were significant factors for disease progression. Similarly, age >50 years (HR, 1.05), family history of HCC (HR, 5.48), and cirrhosis (HR, 17.16) were significant factors for HCC development. Importantly, longer duration (>12 months) of maintained virological response (<20 IU/mL) reduced the risks of disease progression (HR, 0.19) and HCC development (HR, 0.09). CONCLUSIONS: Longer duration of maintained virological response significantly reduces the risk of disease progression or HCC development in CHB patients undergoing long-term oral NA therapy.
Adult ; Age Factors ; Antiviral Agents/*administration & dosage ; Carcinoma, Hepatocellular/epidemiology/etiology ; *Disease Progression ; Female ; Hepatitis B, Chronic/complications/*drug therapy/*pathology ; Humans ; Liver Cirrhosis/epidemiology/etiology ; Liver Neoplasms/epidemiology/etiology ; Male ; Middle Aged ; Proportional Hazards Models ; Retrospective Studies ; Time

The purpose of the present review is to give an overview of the association between alcohol intake and the risk of developing cancer. Two large-scale expert reports; the World Cancer Research Fund (WCRF)/American Institute of Cancer Research (AICR) report from 2007, including its continuous update project, and the International Agency for Research of Cancer (IARC) monograph from 2012 have extensively reviewed this association in the last decade. We summarize and compare their findings, as well as relate these to the public health impact, with a particular focus on region-specific drinking patterns and disease tendencies. Our findings show that alcohol intake is strongly linked to the risk of developing cancers of the oral cavity, pharynx, larynx, oesophagus, colorectum (in men), and female breast. The two expert reports diverge on the evidence for an association with liver cancer and colorectal cancer in women, which the IARC grades as convincing, but the WCRF/AICR as probable. Despite these discrepancies, there does, however, not seem to be any doubt, that the Population Attributable Fraction of alcohol in relation to cancer is large. As alcohol intake varies largely worldwide, so does, however, also the Population Attributable Fractions, ranging from 10% in Europe to almost 0% in countries where alcohol use is banned. Given the World Health Organization's prediction, that alcohol intake is increasing, especially in low- and middle-income countries, and steadily high in high-income countries, the need for preventive efforts to curb the number of alcohol-related cancers seems growing, as well as the need for taking a region- and gender-specific approach in both future campaigns as well as future research. The review acknowledges the potential beneficial effects of small doses of alcohol in relation to ischaemic heart disease, but a discussion of this lies without the scope of the present study.
*Alcohol Drinking ; Breast Neoplasms/epidemiology/etiology/mortality ; Colorectal Neoplasms/epidemiology/etiology/mortality ; Female ; Humans ; Liver Neoplasms/epidemiology/etiology/mortality ; Male ; Mouth Neoplasms/epidemiology/etiology/mortality ; Neoplasms/epidemiology/*etiology/mortality ; Public Health ; Risk Factors ; Sex Factors