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Metabolic Cause of Cirrhosis Is the Emerging Etiology for Primary Liver Cancer in the Asia-Oceania Region: Analysis of Global Burden of Disease (GBD) Study 2021
Abstract
Introduction
Studies have shown a change in the etiological profile of liver cancer globally. We aimed to analyze the burden and changes in etiology of liver cancer in the Asia‐Oceania region.
Methods
The burden of liver cancer in Asia‐Oceania was estimated using data from the 2021 Global Burden of Disease (GBD) Study. The analysis included age‐standardized incidence (ASIR), prevalence (ASPR), mortality (ASMR), and disability‐adjusted life years (DALY) per 100 000 population.
Results
The Asia‐Oceania region contributed 68.6%, 68.8%, and 67.3% of the global incidence, prevalence, and mortality of liver cancer in 2021. In 2021, Mongolia, Tonga, and South Korea had the highest ASIR, ASPR, and ASMR, whereas Australia, New Zealand, and Guam had the greatest increase in incidence and mortality rates. Viral hepatitis remained the most common etiology of liver cancer, with 47.7% and 26.1% of cases being related to hepatitis B virus (HBV) and hepatitis C virus (HCV), respectively. Around 14.5% and 7.1% of cases were related to alcohol and nonalcoholic steatohepatitis (NASH), respectively; however, the annual change in the ASIR was the highest for NASH. Alcohol, drug abuse, tobacco use, and metabolic syndrome, contributed to 15.2%, 11.7%, 11.5%, and 9.0% of liver cancer mortality in 2021; however, the change in death from 1990 to 2021 was the highest for metabolic syndrome.
Conclusion
Viral hepatitis remains the most common cause of liver cancer, with NASH having the highest annual rate of change in ASIR and liver cancer deaths in Asia‐Oceania.
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Background Detailed, comprehensive, and timely reporting on population health by underlying causes of disability and premature death is crucial to understanding and responding to complex patterns of disease and injury burden over time and across age groups, sexes, and locations. The availability of disease burden estimates can promote evidence-based interventions that enable public health researchers, policy makers, and other professionals to implement strategies that can mitigate diseases. It can also facilitate more rigorous monitoring of progress towards national and international health targets, such as the Sustainable Development Goals. For three decades, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) has filled that need. A global network of collaborators contributed to the production of GBD 2021 by providing, reviewing, and analysing all available data. GBD estimates are updated routinely with additional data and refined analytical methods. GBD 2021 presents, for the first time, estimates of health loss due to the COVID-19 pandemic.
This article presents global cancer statistics by world region for the year 2022 based on updated estimates from the International Agency for Research on Cancer (IARC). There were close to 20 million new cases of cancer in the year 2022 (including nonmelanoma skin cancers [NMSCs]) alongside 9.7 million deaths from cancer (including NMSC). The estimates suggest that approximately one in five men or women develop cancer in a lifetime, whereas around one in nine men and one in 12 women die from it. Lung cancer was the most frequently diagnosed cancer in 2022, responsible for almost 2.5 million new cases, or one in eight cancers worldwide (12.4% of all cancers globally), followed by cancers of the female breast (11.6%), colorectum (9.6%), prostate (7.3%), and stomach (4.9%). Lung cancer was also the leading cause of cancer death, with an estimated 1.8 million deaths (18.7%), followed by colorectal (9.3%), liver (7.8%), female breast (6.9%), and stomach (6.8%) cancers. Breast cancer and lung cancer were the most frequent cancers in women and men, respectively (both cases and deaths). Incidence rates (including NMSC) varied from four‐fold to five‐fold across world regions, from over 500 in Australia/New Zealand (507.9 per 100,000) to under 100 in Western Africa (97.1 per 100,000) among men, and from over 400 in Australia/New Zealand (410.5 per 100,000) to close to 100 in South‐Central Asia (103.3 per 100,000) among women. The authors examine the geographic variability across 20 world regions for the 10 leading cancer types, discussing recent trends, the underlying determinants, and the prospects for global cancer prevention and control. With demographics‐based predictions indicating that the number of new cases of cancer will reach 35 million by 2050, investments in prevention, including the targeting of key risk factors for cancer (including smoking, overweight and obesity, and infection), could avert millions of future cancer diagnoses and save many lives worldwide, bringing huge economic as well as societal dividends to countries over the forthcoming decades.
Approximately 80% of hepatocellular carcinoma (HCC) cases arise in sub-Saharan Africa and Eastern Asia, following a similarly high prevalence of chronic hepatitis B virus (HBV) carriers in these regions. The etiology and epidemiology of HCC have recently changed worldwide. Although HBV infection is the main contributor to HCC development, a slow but continuous decline in HBV infection rates has been reported since 1990. Owing to the widespread use of direct-acting antivirals, the incidence of hepatitis C virus-related HCC has remarkably decreased in Japan and European countries. In Korea, Taiwan, and Singapore, the incidence of HBV-related HCC has significantly decreased owing to vaccination against HBV. Globally, while HBV accounted for more than half of HCCs in 1990, this had decreased to 42% in 2019. In contrast, the proportion of patients with alcoholic- and nonalcoholic steatohepatitis (NASH) increased from 13% to 18% and from 5% to 6%, respectively. NASH-related HCC has characteristics that differ from those of virus-associated HCC. Compared with other etiologies, patients with NASHassociated HCC are older, have a higher body mass index, and have higher rates of type 2 diabetes mellitus, hypertension, hyperlipidemia, and cardiovascular disease. Nonalcoholic fatty liver disease (NAFLD)-associated HCC is also known to develop in the absence of cirrhosis, unlike alcohol-related and autoimmune liver diseases. Because patients with NAFLD usually have diabetes or obesity, surveying this population is challenging. Optimal selection of the target population and surveillance tools among patients with NAFLD needs to be determined.
Background
Liver cancer is one of the most common cancers worldwide. We aimed to report the burden of liver cancer at the global, regional, and national levels in 204 countries from 1990 to 2019, stratified by etiology, sex, age, and sociodemographic index (SDI).
Methods
Data of mortality, incidence, and disability-adjusted life years (DALYs) of liver cancer and its etiology were available from the Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study 2019. The trends in the liver cancer burden were assessed by the annual percentage change. All estimates are presented as numbers and age-standardized rates (ASRs) per 100,000 population, with uncertainty intervals (UIs).
Results
Globally, 484,577 (95% UI 444,091–525,798) mortalities, 534,364 (486,550–588,639) incident cases, and 12,528,422 (11,400,671–13,687,675) disability-adjusted life years (DALYs) due to liver cancer occurred in 2019. The ASRs were 5.95 (5.44–6.44), 6.51 (5.95–7.16), and 151.08 (137.53–164.8) per 100,000 population for the mortalities, incidences, and DALYs, respectively. From 1990 to 2019, the numbers increased, whereas the ASRs decreased. Hepatitis B and Hepatitis C are the major causes of liver cancer mortality. The liver cancer mortality in 2019 increased with age, peaking at 65–69 and 70–74 age group in males and females, respectively, and the number was higher in males than in females. Generally, there were nonlinear associations between the ASR and SDIs values at the regional and national levels. China had the highest numbers of mortalities, incident cases, and DALYs, whereas Mongolia has the highest ASR in 2019.
Conclusion
Liver cancer remains a major public health issue worldwide, but etiological and geographical variations exist. It is necessary to increase awareness of the population regarding liver cancer, its etiologies and the importance of early detection, and diagnosis and treatment.
Background and Aims
There is conflicting data regarding the epidemiology of hepatocellular carcinoma (HCC) arising in the context of non-alcoholic and metabolic associated fatty liver disease (NAFLD and MAFLD). We aimed to examine the changing contribution of NAFLD and MAFLD, stratified by sex, in a well-defined geographical area and highly characterized HCC population between 1990 to 2014.
Methods
We identified all HCC cases resident in the canton of Geneva, Switzerland, diagnosed between 1990-2014 from the prospective Geneva Cancer Registry and assessed aetiology-specific age-standardized incidence. NAFLD-HCC was diagnosed when other causes of liver disease were excluded in cases with type 2 diabetes, metabolic syndrome or obesity. Criteria for MAFLD included one or more of the following criteria: overweight/obesity, presence of type 2 diabetes mellitus, or evidence of metabolic dysregulation.
Results
76/920 (8.3%) of patients were diagnosed with NAFLD-HCC in the canton of Geneva between 1990-2014. Between the time periods 1990-94 and 2010-14, there was a significant increase in HCC incidence in women (standardized incidence ratio [SIR] 1.83, 95% CI 1.08-3.13, p=0.026) but not in men (SIR 1.10, 95% CI 0.85-1.43, p=0.468). In the same timeframe, the proportion of NAFLD-HCC increased more in women (0% to 29%, p=0.037) than in men (2% to 12%, p=0.010) while the proportion of MAFLD increased from 21% to 68% in both sexes and 7% to 67% in women (p<0.001). From 2000-04 to 2010-14, the SIR of NAFLD-HCC increased to 1.92 (95% CI 0.77-5.08) for men and 12.7 (95% CI 1.63-545) in women, whereas it decreased or remained stable for other major aetiologies of HCC.
Conclusions
In a populational cohort spanning 25 years, the burden of NAFLD and MAFLD associated HCCs increased significantly, driving an increase in HCC incidence, particularly in women.
Primary liver cancer, the major histology of which is hepatocellular carcinoma (HCC), is the second leading cause of cancer death worldwide. We comprehensively examined recent international trends of primary liver cancer and HCC incidence using population‐based cancer registry data. Incidence for all primary liver cancer and for HCC by calendar time and birth cohort was examined for selected countries between 1978 and 2012. For each successive 5‐year period, age‐standardized incidence rates were calculated from Volumes V to XI of the Cancer Incidence in Five Continents (CI5) series using the online electronic databases, CI5plus. Large variations persist in liver cancer incidence globally. Rates of liver cancer remain highest in Asian countries, specifically in the East and South‐East, and Italy. However, rates in these high‐risk countries have been decreasing in recent years. Rates in India and in most countries of Europe, the Americas and Oceania are rising. As the population seroprevalence of hepatitis B virus (HBV) continues to decline, we anticipate rates of HCC in many high‐risk countries will continue to decrease. Treatment of hepatitis C virus (HCV) is likely to bring down rates further in some high‐rate, as well as low‐rate, countries with access to effective therapies. However, such gains in the control of liver cancer are at risk of being reversed by the growing obesity and diabetes epidemics, suggesting diabetes treatment and primary prevention of obesity will be key in reducing liver cancer in the longer‐term.
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, which in turns accounts for the sixth most common cancer worldwide. Despite being the 6th most common cancer it is the second leading cause of cancer related deaths. HCC typically arises in the background of cirrhosis, however, about 20% of cases can develop in a non-cirrhotic liver. This particular subgroup of HCC generally presents at an advanced stage as surveillance is not performed in a non-cirrhotic liver. HCC in non-cirrhotic patients is clinically silent in its early stages because of lack of symptoms and surveillance imaging; and higher hepatic reserve in this population. Interestingly, F3 fibrosis in non-alcoholic fatty liver disease, hepatitis B virus and hepatitis C virus infections are associated with high risk of developing HCC. Even though considerable progress has been made in the management of this entity, there is a dire need for implementation of surveillance strategies in the patient population at risk, to decrease the disease burden at presentation and improve the prognosis of these patients. This comprehensive review details the epidemiology, risk factors, clinical features, diagnosis and management of HCC in non-cirrhotic patients and provides future directions for research.
Background
Traditionally in Asia, hepatitis B (HBV) accounts for the majority of hepatocellular carcinoma (HCC), but increasingly, non-viral or nonalcoholic steatohepatitis (NASH) etiology may play a more prominent role with current socioeconomic changes. There remains a paucity in data comparing NASH–HCC to HBV-related HCC. In this study, we explored the differences in clinical characteristics between HBV- and cryptogenic-related HCC.
Methods
Patients with HCC seen in the Department of Gastroenterology and Hepatology, Singapore General Hospital were enrolled in an ongoing database since 1980. Patients with HCC attributed to HBV or cryptogenic etiology were identified. Comparison of clinical characteristics was performed between the two groups.
Results
There were 916 HBV–HCC patients and 163 cryptogenic HCC patients, accounting for 70.9% and 12.6% of the total HCC cases (1292 patients), respectively. Out of the total cohort enrolled from 1980 to 2005, the ratio of cryptogenic to HBV patients was 1:6.7, while from 2006 to the current year, the ratio of cryptogenic to HBV patients has increased significantly to 1:3.9. Relative to patients with HBV, cryptogenic HCC patients were older (67.6 vs. 59.4 years old; p < 0.001), had lower proportion of male patients (69.9% vs. 83.8%; p < 0.001), and had higher incidence of smoking (32.2% vs. 25.8%; p = 0.008). HBV group had higher alanine transaminase (60.9 ± 85.7 U/L vs. 48.0 ± 52.1 U/L; p = 0.003), hemoglobin (12.7 ± 2.28 g/dL vs. 12.0 ± 2.46 g/dL, p < 0.001), albumin (32.9 ± 6.8 g/L vs. 31.3 ± 7.7 g/L; p = 0.007), and prothrombin time (13.2 ± 2.95 s vs. 12.7 ± 2.01 s, p = 0.023), as compared to the cryptogenic group. Cryptogenic HCC patients presented more frequently with unifocal HCC (55.2% vs. 46.5%; p = 0.002). There was no difference in the proportions of patients receiving surgical resection in both groups (23.5% in HBV group vs. 17.9% in cryptogenic group; p = 0.202). Cox regression analysis revealed no survival difference between cryptogenic-related HCC and HBV-related HCC (p = 0.367).
Conclusion
Temporal trends suggest that HCC attributed to HBV is on the decline, while cryptogenic- or NASH-related HCC is an emerging clinical entity. A paradigm shift in approach to screening, surveillance, and management of HCC may be required in view of the changing landscape of HCC epidemiology into an increasing non-viral etiology.
High-quality data on liver cancers by probable cause are scarce in many regions of the world. The United Nations recently set a goal of eliminating viral hepatitis as a major public health threat by 2030. We aimed to estimate the number of new cases of cancers attributable to hepatitis B virus (HBV) and hepatitis C virus (HCV) at a global, regional and country level, and by development status. We used data on the prevalence of HBV and HCV in hepatocellular carcinoma from a systematic review including 119 000 cases in 260 studies covering 50 countries. A statistical model was constructed to extrapolate empirical data to countries without prevalence data. Country-specific numbers of liver cancer cases attributable to HBV and HCV were calculated using data from GLOBOCAN 2012. Globally, 770 000 cases of liver cancer occurred worldwide in 2012 of which 56% (95%CI: 52–60) were attributable to HBV and 20% (95%CI: 18–22) to HCV. Currently, HBV causes approximately 2/3 cases of liver cancer in less developed countries but 1/4 cases in more developed countries and shows a much higher degree of geographical aggregation in Eastern Asia and sub-Saharan Africa than HCV. These estimates help set priorities for liver cancer prevention. High-coverage HBV vaccination will be transformational in HBV-endemic countries but the prevention of HCV transmission and the treatment of chronic carriers of both viruses requires new scalable solutions. This article is protected by copyright. All rights reserved.
Integration of hepatitis B vaccination into national immunization programs has resulted in substantial reductions of hepatitis B virus (HBV) transmission in previously high endemic countries. The key strategy for control of the HBV epidemic is birth dose and infant vaccination. Additional measures include use of hepatitis B immunoglobulin (HBIG) and diagnosis of mothers at high risk of transmitting HBV and use of antiviral agents during pregnancy to decrease maternal DNA concentrations to undetectable concentrations. Despite the substantial decrease in HBV cases since vaccination introduction, implementation of birth dose vaccination in low-income and middle-income countries and vaccination of high-risk adults remain challenging.
Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer and is a significant cause of morbidity and mortality, especially in patients with chronic liver disease. As a reflection of geographical variations in India, there is significant variation in the prevalence and etiological factors of HCC. In contrast to previous studies reporting viral hepatitis as the most common etiology, recent data indicates a changing etiological pattern of cirrhosis and HCC, with alcohol and metabolic dysfunction-associated steatotic liver disease (MASLD) emerging as the foremost causes. Thus, there was a need for an updated review of the current literature and databases for the changing epidemiology and etiological spectrum of HCC in India. The review included data primarily from the National Cancer Registry Program and the Global Burden of Diseases, Injuries, and Risk Factors Study, with the inclusion of other studies from India. The highlights of the present review are summarized in the following lines. Although the current incidence (2.15 per 100000), prevalence (2.27 per 100,000), and mortality (2.21 per 100000) rate of HCC in India remain lower compared to the global data, the annual rates of change in these parameters are higher in India. Among Indians, the present incidence, prevalence, and mortality related to HCC is higher in males, while the annual rate of change is higher in females. The Northeast states have higher incidence, prevalence, and mortality related to HCC, but the Western states of Gujarat, Maharashtra, Goa, and Kerala are emerging as newer hotspots with higher annual rates of change in incidence, prevalence, and mortality. The incidence of HCC related to Hepatitis B is on a downtrend, while those related to alcohol and MASLD are rising. Public health initiatives, awareness campaigns, and focused treatments are all necessary to combat these changes, particularly in areas with high incidence rates.
Background
Recent studies from both India and outside India have shown a change in the etiological profile of hepatocellular carcinoma (HCC). We aimed to analyze the etiological spectrum and changing trends of HCC etiology in India using a systematic review of current literature and meta-analysis.
Methods
Electronic databases of Pubmed/Medline, Scopus, and Embase were searched from inception to July 2023 for studies reporting the data on the etiology of HCC from India. The pooled proportions with 95% confidence interval were calculated using summative statistics.
Results
A total of 60 studies (n = 12327) were included in the final analysis. The pooled proportions of HCC cases with at least one positive and negative viral marker were 56.0 (49.5 – 62.6) and 43.1% (36.5 – 49.8), respectively. The pooled proportion of HCC cases with positive hepatitis B virus (HBV) markers was 41.0 (35.8 – 46.1), while those with positive markers for hepatitis C virus (HCV) were 20.3 (17.0 – 23.6). The pooled proportion of cases with HCC with significant alcohol intake was 19.0% (15.6 – 22.4), and those related to non-alcoholic fatty liver disease (NAFLD) were 16.9% (12.1 – 21.7). Around 7.9% (5.8 – 10.0) of the cases had HCC with multiple etiologies. Subgroup analysis showed a significant variation with the location of the study based on zone. Meta-regression analysis based on publication year (1990-2023) showed a significant reduction in the proportion of cases with HBV and an increase in cases with NAFLD. In contrast, the proportion of cases with HCV and alcohol did not change significantly.
Conclusion
Viral hepatitis is the most common etiology of HCC in India, predominantly HBV. The proportions of cases with HCC related to NAFLD are increasing, and those related to HBV are declining
Cirrhosis is an important cause of morbidity and mortality in people with chronic liver disease worldwide. In 2019, cirrhosis was associated with 2.4% of global deaths. Owing to the rising prevalence of obesity and increased alcohol consumption on the one hand, and improvements in the management of hepatitis B virus and hepatitis C virus infections on the other, the epidemiology and burden of cirrhosis are changing. In this Review, we highlight global trends in the epidemiology of cirrhosis, discuss the contributions of various aetiologies of liver disease, examine projections for the burden of cirrhosis, and suggest future directions to tackle this condition. Although viral hepatitis remains the leading cause of cirrhosis worldwide, the prevalence of non-alcoholic fatty liver disease (NAFLD) and alcohol-associated cirrhosis are rising in several regions of the world. The global number of deaths from cirrhosis increased between 2012 and 2017, but age-standardized death rates (ASDRs) declined. However, the ASDR for NAFLD-associated cirrhosis increased over this period, whereas ASDRs for other aetiologies of cirrhosis declined. The number of deaths from cirrhosis is projected to increase in the next decade. For these reasons, greater efforts are required to facilitate primary prevention, early detection and treatment of liver disease, and to improve access to care.
Background & Aim
Nonalcoholic fatty liver disease (NAFLD) has become a major cause of chronic liver disease (CLD) worldwide. Our aim was to assess the burden of liver complications (LC, cirrhosis and liver cancer) related to NAFLD (LC-NAFLD) between 2009-2019 in Asia, Middle East and Northern Africa (MENA) regions.
Methods
We used Global Burden of Disease data to assess incidence, mortality, and disability-adjusted-life-years (DALYs) for LC-NAFLD from Asia and MENA regions. Annual percentage change in rates were computed by Joinpoint Regression model. Associations of LC-NAFLD with low physical activity, diet and metabolic risks were determined by partial Spearman correlation coefficients (ρ).
Results
Globally in 2019, there were 170.000 incident cases of LC-NAFLD, accounting for 6.6% of LC incident cases from all chronic liver diseases (CLDs). There were 168,969 deaths related to LC-NAFLD, accounting for 8.6% of LC deaths from all CLDs. Among global incident and death of LC-NAFLD, 48.3% and 46.2% occurred in Asia, 8.9% and 8.6% in MENA. There were 2.08 million DALYs in Asia and 340.000 DALYs in MENA. From 2009 to 2019, regions in Asia and MENA experienced a rise in DALY of LC-NAFLD (compared to LC from other CLDs), ranging from South Asia (APC=+2.12% vs. -0.94%) to high-income Asia Pacific (APC=-0.07%, p=0.646 vs. -0.97%). In Asia, DALY of NAFLD was significantly correlated with dietary risks [(95% CI: 0.280-0.763, p=0.004)], metabolic risks [(0.341-0.790, p<0.001)] and tobacco use [(0.134-0.691, p=0.007)]. In MENA, low physical activity [(0.557-0.918, p<0.001)], metabolic risks [(0.432-0.888, p=0.001)], and dietary risks [(0.315-0.855, p=0.001)] correlated with DALY.
Conclusions
NAFLD is posing a substantial burden in Asia and MENA. About half of the global burden of LC-NAFLD is accounted by these regions.
Lay Summary
Nonalcoholic fatty liver disease (NAFLD) has emerged as one of the most common causes of chronic liver disease worldwide. We used Global Burden of Disease data to assess incidence, mortality, and disability-adjusted-life-years (DALYs) from LC-NAFLD in Asia and MENA regions. NAFLD is poised to be responsible for a substantial liver disease burden in Asia and MENA regions of the world. Regional and global policies are needed to address the increasing burden of complications of NAFLD.
Background & Aims
There were an estimated 4.8 million new cases of gastrointestinal (GI) cancers and 3.4 million related deaths, worldwide, in 2018. GI cancers account for 26% of the global cancer incidence and 35% of all cancer-related deaths. We investigated the global burden from the 5 major GI cancers as well as geographic and temporal trends in cancer-specific incidence and mortality.
Methods
Data on primary cancers of the esophagus, stomach, colorectum, liver, and pancreas were extracted from the GLOBOCAN database for the year 2018, as well as from the Cancer Incidence in 5 Continents series, and the World Health Organization mortality database from 1960 onward. Age-standardized incidence and mortality rates were calculated by sex, country, and level of human development.
Results
We observed geographic and temporal variations in incidence and mortality for all 5 types of GI cancers. Esophageal, gastric, and liver cancers were more common in Asia than in other parts of the world, whereas of the burden from colorectal and pancreatic cancers was highest in Europe and North America. There was a uniform decrease in gastric cancer incidence but an increasing incidence of colorectal cancer in formerly low-incidence regions over the studied time period. We found slight increases in incidence of liver and pancreatic cancer in some high-income regions.
Conclusions
Although the incidence of some GI cancer types has decreased, this group of malignancies continues to pose major challenges to public health. Primary and secondary prevention measures are important for controlling these malignancies—most importantly reducing consumption of tobacco and alcohol, obesity control, immunizing populations against hepatitis B virus infection, and screening for colorectal cancer.
Background & aims:
Biopsy-confirmed liver fibrosis is a prognostic factor for patients with non-alcoholic fatty liver disease (NAFLD). We performed a systematic review to quantify the prognostic value of fibrosis stage in patients with NAFLD and the subgroup of patients with non-alcoholic steatohepatitis (NASH) and to assess the evidence that change in fibrosis stage is a surrogate endpoint.
Methods:
We searched the MEDLINE, EMBASE, Cochrane Library, and trial registry databases through August 2018 for prospective or retrospective cohort studies of liver-related clinical events and outcomes in adults with NAFLD or NASH. We collected data on mortality (all-cause and liver-related) and morbidity (cirrhosis, liver cancer, and all liver-related events) by stage of fibrosis, determined by biopsy, for patients with NAFLD or NASH. Using fibrosis stage 0 as a reference population, we calculated fibrosis stage-specific relative risk (RR) and 95% CI values for mortality and morbidities. We performed fixed-effect and random-effect model meta-analyses. Meta-regression was used to examine associations among study design (prospective vs retrospective cohort), overall risk of bias (medium or high), and mean duration of follow up (in years).
Results:
Our meta-analysis included 13 studies, comprising 4428 patients with NAFLD; 2875 of these were reported to have NASH. Compared to no fibrosis (stage 0), unadjusted risk increased with increasing stage of fibrosis (stage 0 vs 4): all-cause mortality RR, 3.42 (95% CI, 2.63-4.46); liver-related mortality RR, 11.13 (95% CI, 4.15-29.84); liver transplantation RR, 5.42 (95% CI, 1.05-27.89), and liver-related events RR, 12.78 (95% CI, 6.85-23.85). The magnitude of RR did not differ significantly following adjustment for confounders including age or sex in the subgroup of NAFLD patients with NASH. Three studies examined the effects of increasing fibrosis on quality of life had inconsistent findings.
Conclusions:
In a systematic review and meta-analysis, we found biopsy-confirmed fibrosis to be associated with risk of mortality and liver-related morbidity in patients with NAFLD, with and without adjustment for confounding factors and in patients with reported NASH. Further studies are needed to assess the association between fibrosis stage and patient quality of life and establish that change in liver fibrosis stage is a valid endpoint for use in clinical trials.
Background
Although direct-acting antivirals have been used extensively to treat patients with chronic hepatitis C virus (HCV) infection, their clinical effectiveness has not been well reported. We compared the incidence of death, hepatocellular carcinoma, and decompensated cirrhosis between patients treated with direct-acting antivirals and those untreated, in the French ANRS CO22 Hepather cohort.
Methods
We did a prospective study in adult patients with chronic HCV infection enrolled from 32 expert hepatology centres in France. We excluded patients with chronic hepatitis B, those with a history of decompensated cirrhosis, hepatocellular carcinoma, or liver transplantation, and patients who were treated with interferon-ribavirin with or without first-generation protease inhibitors. Co-primary study outcomes were incidence of all-cause mortality, hepatocellular carcinoma, and decompensated cirrhosis. The association between direct-acting antivirals and these outcomes was quantified using time-dependent Cox proportional hazards models. This study is registered with ClinicalTrials.gov, number NCT01953458.
Findings
Between Aug 6, 2012, and Dec 31, 2015, 10 166 patients were eligible for the study. 9895 (97%) patients had available follow-up information and were included in analyses. Median follow-up was 33·4 months (IQR 24·0–40·7). Treatment with direct-acting antivirals was initiated during follow-up in 7344 patients, and 2551 patients remained untreated at the final follow-up visit. During follow-up, 218 patients died (129 treated, 89 untreated), 258 reported hepatocellular carcinoma (187 treated, 71 untreated), and 106 had decompensated cirrhosis (74 treated, 32 untreated). Exposure to direct-acting antivirals was associated with increased risk for hepatocellular carcinoma (unadjusted hazard ratio [HR] 2·77, 95% CI 2·07–3·71) and decompensated cirrhosis (3·83, 2·29–6·42). After adjustment for variables (age, sex, body-mass index, geographical origin, infection route, fibrosis score, HCV treatment-naive, HCV genotype, alcohol consumption, diabetes, arterial hypertension, biological variables, and model for end-stage liver disease score in patients with cirrhosis), exposure to direct-acting antivirals was associated with a decrease in all-cause mortality (adjusted HR 0·48, 95% CI 0·33–0·70) and hepatocellular carcinoma (0·66, 0·46–0·93), and was not associated with decompensated cirrhosis (1·14, 0·57–2·27).
Interpretation
Treatment with direct-acting antivirals is associated with reduced risk for mortality and hepatocellular carcinoma and should be considered in all patients with chronic HCV infection.
Funding
INSERM-ANRS (France Recherche Nord & Sud Sida-HIV Hépatites), ANR (Agence Nationale de la Recherche), DGS (Direction Générale de la Santé), MSD, Janssen, Gilead, AbbVie, Bristol-Myers Squibb, and Roche.
This article provides a status report on the global burden of cancer worldwide using the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer, with a focus on geographic variability across 20 world regions. There will be an estimated 18.1 million new cancer cases (17.0 million excluding nonmelanoma skin cancer) and 9.6 million cancer deaths (9.5 million excluding nonmelanoma skin cancer) in 2018. In both sexes combined, lung cancer is the most commonly diagnosed cancer (11.6% of the total cases) and the leading cause of cancer death (18.4% of the total cancer deaths), closely followed by female breast cancer (11.6%), prostate cancer (7.1%), and colorectal cancer (6.1%) for incidence and colorectal cancer (9.2%), stomach cancer (8.2%), and liver cancer (8.2%) for mortality. Lung cancer is the most frequent cancer and the leading cause of cancer death among males, followed by prostate and colorectal cancer (for incidence) and liver and stomach cancer (for mortality). Among females, breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death, followed by colorectal and lung cancer (for incidence), and vice versa (for mortality); cervical cancer ranks fourth for both incidence and mortality. The most frequently diagnosed cancer and the leading cause of cancer death, however, substantially vary across countries and within each country depending on the degree of economic development and associated social and life style factors. It is noteworthy that high‐quality cancer registry data, the basis for planning and implementing evidence‐based cancer control programs, are not available in most low‐ and middle‐income countries. The Global Initiative for Cancer Registry Development is an international partnership that supports better estimation, as well as the collection and use of local data, to prioritize and evaluate national cancer control efforts. CA: A Cancer Journal for Clinicians 2018;0:1‐31. © 2018 American Cancer Society
Background:
While hepatitis B and C have been the main drivers of hepatocellular carcinoma (HCC), non-alcoholic steatohepatitis (NASH) has recently become an important cause of HCC. The aim of this study was to assess the causes of HCC among liver transplant (LT) candidates in the U.S.
Methods:
The Scientific Registry of Transplant Recipients (2002-2016) was used to estimate the trends in prevalence of HCC in LT candidates with the most common types of chronic liver disease: alcoholic liver disease (ALD), chronic hepatitis B (CHB), chronic hepatitis C, and NASH.
Results:
158,347 adult LT candidates were included. Of these, 26,121 (16.5%) had HCC; this proportion increased from 6.4% (2002) to 23.0% (2016) (trend p<0.0001). Over the study period, CHC remained the most common etiology for HCC (65%). The proportions of HCC accounted for by CHC and ALD remained stable (both trend p>0.10), the proportion of CHB decreased 3.1-fold (p<0.0001), while the proportion of NASH in HCC increased 7.7-fold (from 2.1% to 16.2%, p<0.0001). Furthermore, since 2002, the prevalence of HCC in LT candidates with NASH increased 11.8-fold, while this rate increased 6.0-fold in CHB, 3.4-fold in ALD and 2.3-fold in CHC (all p<0.0001); the increasing trend in NASH was steeper than that for any other etiology (p<0.0001 in a trend regression model). The proportion of LT candidates with HCC who were ultimately transplanted or died while waiting did not differ between etiologies (p>0.05).
Conclusions:
Non-alcoholic steatohepatitis is the most rapidly growing cause of HCC among U.S. patients listed for liver transplantation.
On the global scale, hepatitis B virus (HBV) infection is the main cause of hepatocellular carcinoma (HCC) especially in regions of Asia where HBV infection is endemic. Epidemiological studies show that the incidence of inflammation-driven HCC in males is three times as high as in females. Recent studies suggest that sex hormones have a crucial role in the pathogenesis and development of HBV-induced HCC. We found that the estrogen/androgen signaling pathway is associated with decreased/increased transcription and replication of HBV genes and can promote the development of HBV infections by up/downregulating HBV RNA transcription and inflammatory cytokines levels, which in turn slow down the progression of HBV-induced HCC. Additionally, sex hormones can also affect HBV-related HCC by inducing epigenetic changes. The evidence that both morphology and function of the human liver are affected by sex hormones was found over 60 years ago. However, the underlying molecular mechanism largely remains to be elucidated. This review focuses mainly on the molecular mechanisms behind the sex difference in HCC associated with HBV and other factors. In addition, several potential treatment and therapeutic strategies for inflammation-driven HCC will be introduced in this review.
Background:
Around half of input data in the global burden of disease cancer collaboration (GBDCC) and GLOBOCAN projects come from low quality sources, mainly from developing countries. This may lead to loss of precision in estimates. Our question was: Are the absolute values and trends of the GBDCC and GLOBOCAN estimates for lung cancer (LC) in Iran consistent with available statistics?.
Materials and methods:
Incidence and mortality statistics were extracted from national reports (N.IRs and N.MRs) and GBDCC (GBDincidence and mortality) and GLOBOCAN databases for 19902013 where available. Trends were analyzed and absolute values and annual percentage changes (APCs) were estimated and compared. Incompleteness of case ascertainment at the Iranian national cancer registry and Iranian national civil registration was assessed for better understanding.
Results:
Trends of N.IRs were significantly rising for males (APC: 19.4; 95% CI: 12.526.7) and females (23.2; 16.030.8). Trends of GBDincidence were stable for males (0.2; 1.51.1) and females (1.0; 2.30.4). Absolute N.IRs were less than GBDincidence steadily except for 2009. Trend of N.MRs was increasing up to 2004, but stable thereafter. Trends of GBDmortality were also stable. Absolute N.MRs were less than GBDmortality for years up to 2003 and more than GBDmortality since 2005. The estimates of GLOBOCAN were more than N.IRs and N.MRs.
Conclusions:
The GBDCC and GLOBOCAN values for LC in Iran are underestimates. Generation of data quality indices to present along with country specific estimates is highly recommended.
Background and aim:
NAFLD is a major cause of liver disease worldwide. We estimated the global prevalence, incidence, progression and outcomes of NAFLD and NASH.
Methods:
Pubmed/MEDLINE were searched from 1989-2015 for terms involving epidemiology and progression of NAFLD.
Exclusions:
selected groups (only morbidly obese or diabetics or pediatric), no data on alcohol consumption or other liver diseases. Incidence of HCC, cirrhosis, overall mortality and liver-related mortality were determined. NASH required histologic criteria. All studies were reviewed by 3 independent investigators. Analysis was stratified by region, diagnostic technique, biopsy indication and study population. We used random-effects models to provide point estimates (95% CI) of prevalence, incidence, mortality and incidence rate ratios, and meta-regression with sub-group analysis to account for heterogeneity.
Results:
Out of 729 studies, 86 were included with a sample size of 8,515,431 from 22 countries. Global prevalence of NAFLD is 25.24% (22.10-28.65) with highest prevalence in Middle East and South America and lowest in Africa. Metabolic comorbidities associated with NAFLD included obesity [51.34% (41.38-61.20)], type 2 diabetes [22.51% (17.92-27.89)], hyperlipidemia [69.16% (49.91-83.46%)], hypertension [(39.34% (33.15-45.88)]] and metabolic syndrome [42.54% (30.06-56.05)] . Fibrosis progression proportion, measured in Brunt's score, and mean annual rate of progression in NASH were 40.76% (34.69-47.13) and 0.09 (0.06-0.12). HCC incidence among NAFLD patients was 0.44/1000 person-years (0.29-0.66). Liver-specific mortality and overall mortality among NAFLD and NASH were 0.77/1000 person-years (0.33-1.77) and 11.77/1000 person-years (7.10-19.53), 15.44/1000 person-years (11.72-20.34) and 25.56/1000 person-years (6.29-103.80). Incidence Risk Ratios for liver-specific and overall mortality for NAFLD were 1.94 (1.28-2.92) and 1.05 (0.70-1.56).
Conclusions:
As the global epidemic of obesity fuels metabolic conditions, the clinical and economic burden of NAFLD will become enormous.f This article is protected by copyright. All rights reserved.
Background and aims:
The risk of development of hepatocellular carcinoma (HCC) in hepatitis B virus (HBV) and hepatitis C virus (HCV) infection is well established and is being recognized increasingly in non-alcoholic steatohepatitis (NASH)-related cirrhosis. This study aimed to assess the risk of development of HCC in patients with NASH-related cirrhosis.
Methods:
From January 2010 to October 2011, we prospectively enrolled 585 patients with liver cirrhosis (men:women ratio 4.4:1, mean age 50.1 +/- 6.1 years, aetiology HBV 19%, HCV 14.2%, NASH-related 7%, cryptogenic cirrhosis 17.8%, already diagnosed cirrhosis 48.2%, and the remaining were newly diagnosed cases). The cumulative follow-up was for 5.9 +/- 0.5, 6.1 + 0.8 and 6.8 + 1.2 years for HBV, HCV and NASH-related cirrhosis, respectively. Patients with advanced cirrhosis, Child class C and associated comorbid conditions where survival was < 1 year were excluded from the study. The remaining patients were followed up 6-monthly with ultrasound examination and alpha-fetoprotein (AFP) test. Patients suspected of HCC underwent triple-phase computed tomography (CT) scan and liver biopsy was done to confirm the diagnosis.
Results:
A total of 54 patients developed HCC, of which 26 had HBV, 14 had HCV, 9 had- cryptogenic and 6 had- NASH-related cirrhosis. The annual rate of development of HCC was 1.5%, 3.6%, 0.6% and 0.46 in HBV, HCV, cryptogenic and NASH-related cirrhosis, respectively.
Conclusions:
The incidence of HCC was highest in HCV and lowest in NASH-related cirrhosis. These figures suggest an intermediate risk of development of HCC when compared to western countries and Japan.
Hepatocellular carcinoma (HCC) is increasing in incidence and has a very high fatality rate. Cirrhosis due to chronic hepatitis B or hepatitis C is the leading risk factor for HCC. Global epidemiology of HCC is determined by the prevalence of dominant viral hepatitis and the age it is acquired in the underlying population. Upcoming risk factors include obesity, diabetes, and related nonalcoholic fatty liver disease. This review discusses the latest trends of HCC globally and in the United States. It also provides an evidence-based commentary on the risk factors and lists some of the preventive measures to reduce the incidence of HCC.
We investigated the relative etiological role of prior hepatitis B virus (HBV) infection and nonalcoholic fatty liver disease (NAFLD) in the development of non-B non-C, non-alcohol or specific cause-related hepatocellular carcinoma (NBNC-NA-NS HCC) in an HBV-endemic area of Korea.
A total of 329 patients with NBNC-NA-NS HCC were enrolled in this study. Prior HBV infection was defined as the presence of isolated IgG hepatitis B core antibody (anti-HBc), and NAFLD was diagnosed by the findings from the imaging in the absence of a history of excessive alcohol consumption.
Prior HBV infection was the most common cause of underlying liver disease (76.6%). Only 8.2% of the patients had NAFLD as the only risk factor and the same proportion of patients had evidence of both prior HBV infection and NAFLD. Patients without definitive causes accounted for 7.0% of the cases. During the past 10 years, the relative proportion of isolated IgG anti-HBc-positive HCC decreased significantly from 86.6% in 2001-2005 to 67.4% in 2006-2010 (p < 0.0001) and that of NAFLD-related HCC increased from 3.8% to 12.2% in the same period, respectively (p = 0.008). The mean age of NAFLD-related HCC patients (67.3 years) was significantly older than that of HCC patients related to prior HBV infection (61.2 years, p < 0.001).
NAFLD-related HCC increased significantly while HCC related to prior HBV infection decreased during the past 10 years in an HBV-endemic area of Korea; however, the relative etiological role of prior HBV infection was still greater than that of NAFLD in the development of NBNC-NA-NS HCC.
To gain a clearer understanding of the rate of progression to cirrhosis and its determinants in chronic hepatitis C virus (HCV) infection, a systematic review of published epidemiologic studies that incorporated assessment for cirrhosis has been undertaken. Inclusion criteria were more than 20 cases of chronic HCV infection, and information on either age of subjects or duration of infection. Of 145 studies examined, 57 fulfilled the inclusion criteria. Least-squares linear regression was employed to estimate rates of progression to cirrhosis, and to examine for factors associated with more rapid disease progression in 4 broad study categories: 1) liver clinic series (number of studies = 33); 2) posttransfusion cohorts (n = 5); 3) blood donor series (n = 10); and 4) community-based cohorts (n = 9). Estimates of progression to cirrhosis after 20 years of chronic HCV infection were 22% (95% CI, 18%-26%) for liver clinic series, 24% (11%-37%) for posttransfusion cohorts, 4% (1%-7%) for blood donor series, and 7% (4%-10%) for community-based cohorts. Factors that were associated with more rapid disease progression included older age at HCV infection, male gender, and heavy alcohol intake. Even after accounting for these factors, progression estimates were much higher for cross-sectional liver clinic series. Selection biases probably explain the higher estimates of disease progression in this group of studies. Community-based cohort studies are likely to provide a more representative basis for estimating disease progression at a population level. These suggest that for persons who acquire HCV infection in young adulthood, less than 10% are estimated to develop cirrhosis within 20 years.
Disability-Adjusted Life-Years (DALYs), and Healthy Life Expectancy (HALE) for 371 Diseases and Injuries in 204 Countries and Territories and 811 Subnational Locations, 1990-2021: A Systematic Analysis for the Global Burden of Disease Study 2021
GBD 2021 Diseases and Injuries Collaborators, "Global Incidence,
Prevalence, Years Lived With Disability (YLDs), Disability-Adjusted
Life-Years (DALYs), and Healthy Life Expectancy (HALE) for 371 Diseases and Injuries in 204 Countries and Territories and 811 Subnational
Locations, 1990-2021: A Systematic Analysis for the Global Burden of
Disease Study 2021," Lancet 403 (2024): 2133-2161.