Burden of liver cancer due to hepatitis C from 1990 to 2019 at the global, regional, and national levels

Background Liver cancer due to hepatitis C (LCDHC) is one of the leading causes of cancer-related deaths worldwide, and the burden of LCDHC is increasing. We aimed to report the burden of LCDHC at the global, regional, and national levels in 204 countries from 1990 to 2019, stratified by etiology, sex, age, and Sociodemographic Index. Methods Data on LCDHC were available from the Global Burden of Disease, Injuries, and Risk Factors (GBD) study 2019. Numbers and age-standardized mortality, incidence, and disability-adjusted life year (DALY) rates per 100,000 population were estimated through a systematic analysis of modeled data from the GBD 2019 study. The trends in the LCDHC burden were assessed using the annual percentage change. Results Globally, in 2019, there were 152,225 new cases, 141,810 deaths, and 2,878,024 DALYs due to LCDHC. From 1990 to 2019, the number of incidences, mortality, and DALY cases increased by 80.68%, 67.50%, and 37.20%, respectively. However, the age-standardized incidence, mortality, and DALY rate had a decreasing trend during this period. In 2019, the highest age-standardized incidence rates (ASIRs) of LCDHC were found in high-income Asia Pacific, North Africa and the Middle East, and Central Asia. At the regional level, Mongolia, Egypt, and Japan had the three highest ASIRs in 2019. The incidence rates of LCDHC were higher in men and increased with age, with a peak incidence in the 95+ age group for women and the 85–89 age group for men in 2019. A nonlinear association was found between the age-standardized rates of LCDHC and sociodemographic index values at the regional and national levels. Conclusions Although the age-standardized rates of LCDHC have decreased, the absolute numbers of incident cases, deaths, and DALYs have increased, indicating that LCDHC remains a significant global burden. In addition, the burden of LCDHC varies geographically. Male and older adult/s individuals have a higher burden of LCDHC. Our findings provide insight into the global burden trend of LCDHC. Policymakers should establish appropriate methods to achieve the HCV elimination target by 2030 and reducing the burden of LCDHC.


Introduction
According to GLOBOCAN-2020 estimates, liver cancer is the sixth most diagnosed cancer and the third leading cause of cancerrelated deaths worldwide, with 905,700 new cases and 830,200 deaths in 2020 (1).Primary liver cancer mainly includes three pathological types including hepatocellular carcinoma, intrahepatic cholangiocarcinoma, and mixed hepatocellular carcinoma and cholangiocarcinoma.Of total primary liver cancer, hepatocellular carcinoma accounts f or 75%-85%, and intrahepatic cholangiocarcinoma accounts for 10%-15% (2).The main risk factors of liver cancer include prolonged infections caused by hepatitis A virus, hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus, and hepatitis E virus, as well as alcoholic cirrhosis, obesity/type 2 diabetes, autoimmune hepatitis, nonalcoholic steatohepatitis, consumption of aflatoxin B1contaminated food, and various dietary exposures (3)(4)(5).The probability of developing liver cancer during an individual's lifespan can vary widely based on several factors.These factors include personal health, lifestyle choices, genetics, and exposure to risk factors.The treatment of liver cancer includes surgical resection, microwave or radiofrequency ablation, radiation therapy, transarterial embolization, immunotherapy, multitargeted tyrosine kinase inhibitors, and liver transplantation.However, liver cancer is often detected at middle and advanced stages during the diagnosis, rendering surgical options unfeasible (6,7).The efficacy of systemic therapies for advanced stages of liver cancer is still limited, with an overall 5-year survival rate of only 10% (2).Despite efforts to prevent liver cancer, its burden still exhibits an increasing trend (2,6,8).
HBV and HCV infections are known as the primary risk factors for liver cancer.However, most previous studies have mainly focused on HBV, with little epidemiological research conducted on HCV.HCV comprises six primary genotypes and has shown region variations: four of them are prevalent in low-income countries, whereas genotype-1 predominates in middle-income and high-income countries.HCV can lead to both acute and chronic hepatitis, liver cirrhosis, and liver cancer.The progression from HCV infection to the development of liver cancer is characterized by a gradual, protracted process that spans over 20-40 years in affected patients (9).Globally, in 2021, it was estimated that approximately 58 million people were living with chronic HCV infections (10).In the United States, the number of hepatocellular carcinoma cases due to HCV increased by 130% during 1990-1999 and 2000-2009 (11).Furthermore, it was reported that approximately 0.14 million deaths were attributable to liver cancer due to hepatitis C (LCDHC) in 2019 (4).Despite the burden of LCDHC based on regional and national factors being documented, comprehensive information on its epidemiology and burden, including the incidence, mortality, and disability-adjusted life years (DALYs), is lacking at the global, regional, and national levels.Therefore, there is an urgent need to gain a deeper understanding of LCDHC and allocate adequate resources for disease management and prevention.
In this study, we aimed to provide comprehensive and comparable information on the burden of LCDHC.To achieve this, we analyzed data from the Global Burden of Disease (GBD) 2019 study for global, regional, and national incidence, mortalities, and DALYs, which were presented as both numbers and agestandardized rates (ASRs), stratified by sex, age, and sociodemographic index (SDI).Our findings can be of valuable assistance to policymakers aiming to formulate strategies for addressing the challenges posed by LCDHC.

Overview and data source
The GBD 2019 study led by the Institute of Health Metrics and Evaluation was the largest and most comprehensive study of this type.The most recent update in 2019 analyzed epidemiological levels of 369 diseases and injuries, 282 causes of death, and 84 risk factors in 204 countries and territories, 21 regions, and 7 superregions from 1990 to 2019 (12).
The GBD database is categorized by etiology, age, sex, country, and SDI.It classifies regions into five SDI categories: low, lowmiddle, middle, high-middle, and high.In addition, the 21 GBD regions are classified based on their geographical location.The SDI was calculated by synthesizing the gross domestic product, the educational level of people younger than 25 years, and the years of education of people older than 15 years.The index ranges from 0 (lowest) to 1 (highest) level (12).Data on incidence, deaths, DALYs, age-standardized incidence rate (ASIR), age-standardized mortality rate (ASMR), and age-standardized DALY rate (ASDR) were obtained from the Global Health Data Exchange query tool (http://gbdx.healthdata.org/gbd-results-tool)for global, regional, country, age, sex, and SDI levels, including information on LCDHC.

Statistical analysis
To quantify trends in the global burden of LCDHC, the percentage change values of ASIR, ASMR, and ASDR were used.Positive or negative percentage change values were used to determine increasing or decreasing trends in the burden of LCDHC, respectively.The 95% uncertainty intervals (UIs) were determined as the 2.5th and 97.5th centiles of the ordered draws.All statistics were generated using R software version 3.6.3,and visualization was performed using the "ggplot2" package.Sex differences were analyzed using an unpaired t test, with statistical significance defined as a P value <0.05.S2).

National burden of LCDHC
At the national level, the ASIR of LCDHC varied from 0.   S1, Figure 3C).
The ASMR of LCDHC varied from 0.12 to 40.The global incidence cases (A) and ASIR (B) of liver cancer due to hepatitis C per 100,000 population in 2019, and the relative change in ASIR of liver cancer due to hepatitis C between 1990 and 2017 (C), stratified by country and territory.ASIR, age-standardized incidence rate.

Burden of LCDHC by age and sex
Globally, the incidence rates of LCDHC were higher in men and increased with age, with a peak incidence in the 95+ age group for women and the 85-89 age group for men in 2019.The number of incident cases increased with age and peaked in the 70-74 age group for men and the 75-79 age group for women in 2019, followed by a decreasing trend (Figure 4).Before the age of 70-74 years, incidence rates were higher in men than in women, but after this age, the incidence rate in women surpassed that of men.No statistically significant difference was found in the incidence rates between men and women in any age group (Figure 4).The pattern of DALYs due to LCDHC by sex and age group was similar to that of incidence (Additional file 2: Figure S13).
There was no statistically significant difference found in the mortality rates of LCDHC between men and women in any age group.In 2019, the global mortality rates of liver cancer were higher in men and increased with age for both women and men.The number of death cases increased with age and peaked in the 70-74 age group for men and the 80-84 age group for women in 2019, followed by a decrease in the mortality rates of LCDHC.Before the age of 80-84 years, the mortality rates of LCDHC were higher in men than in women, but after this age group, the mortality rate in women surpassed that of men (Additional file 2: Figure S14).

Burden of LCDHC by sociodemographic index
At the regional level, a positive association was observed between the ASDR of LCDHC and the SDI from 1990 to 2019.The lowest ASDR was observed at an SDI of approximately 0.569, with an overall increasing trend observed with increasing SDI value.From 1990 to 2019, the observed burden was higher than the Global number and rates of incidence for liver cancer due to hepatitis C per 100,000 population, stratified by age and sex in 2019.Shading indicates the 95%UIs for the incidence rate.UIs, uncertainty intervals.
expected level based on SDI in high-income Asia Pacific, East Asia, North Africa and the Middle East, Global, Southern Sub-Saharan Africa, and Central Asia.By contrast, Andean Latin America, Tropical Latin America, Western Europe, South Asia, the Caribbean, Central Europe, Eastern Europe, high-income North America, Australasia, and Central Latin America were below the expected level based on the SDI in all years (Figure 5).The association between incidence, death, and SDI is described in the additional file (Additional file 2: Figures S15, S16).
At the national level, there was a nonlinear association between the ASDR of LCDHC and SDI in 2019.The expected values exhibited a slight increase and then decreasing and increasing trends in the SDI.The burden due to LCDHC was higher than the expected levels based on SDI in countries such as Mongolia, Egypt, and Honduras, whereas in countries such as Barbuda, Niger, and Cameroon, the burden was much lower than the expected levels (Figure 6).The ASIR and ASMR exhibited a similar pattern with ASDR (Additional file 2: Figures S17, S18).

Discussion
In the present study, we reported the incidence, mortality, and DALY numbers and ASRs of LCDHC at the global, regional, and national levels over 30 years from 1990 to 2019 based on the GBD 2019 study.In 2019, there were 152,225 incident cases, 141,810 mortality cases, and 2,878,024 DALY cases, and these numbers increased from 1990 to 2019.The ASRs for incidences, mortalities, and DALYs exhibited a global upward trend during this period.To the best of our knowledge, this study presents the first assessment of the correlation between the ASR and the SDI in 21 GBD regions and 204 countries.We found that the ASDR of LCDHC increased with increasing SDI in terms of region, whereas there was no correlation between ASDR and SDI in terms of countries.
Previous studies reported that hepatitis B and hepatitis C are the leading causes of liver cancer (4), with hepatitis B responsible for approximately 41% of liver cancer deaths and hepatitis C for 28.5% in 2019 (4).However, the proportion of liver cancer deaths attributed to these viruses was only 18.7% in 2016 (13).The incidence of hepatitis B-related liver cancer has decreased somewhat in recent years because of the widespread use of hepatitis B vaccines worldwide (14, 15), but the incidence of hepatitis C-related liver cancer has been increasing because of a lack of effective vaccines (16,17).The burden of acute hepatitis B has been decreasing, whereas that of acute hepatitis C has remained stable from 1990 to 2019 (17).As a result, hepatitis C has become one of the most significant causes of liver cancer (13,18).Understanding the burden of liver cancer due to hepatitis C infection may help reduce the overall burden of the disease.Our study found that the number of incident cases due to LCDHC increased, whereas the ASIR of LCDHC decreased from 1990 to 2019, consistent with previous research (4).The highest agestandardized incidence rates of liver cancer due to chronic hepatitis C infection in 2019 were observed in high-income regions of the Asia Pacific, North Africa and the Middle East, and Central Asia, and these regions also exhibited the greatest increasing trends in the ASIR of LCDHC from 1990 to 2019.However, in 2017, Central Asia, high-income Asia Pacific, and East Asia had the highest ASIR (19).HCV is the leading cause of primary liver cancer in the high SDI regions, with liver cancer due to chronic hepatitis C infection accounting for 43% and 41.4% of the total liver cancer deaths and incident cases, respectively, in these regions (19).
Our investigation reveals that certain high-income regions, such as Japan, had a higher ASIR of LCDHC than most countries.Despite having more resources, including financial resources, healthcare infrastructure, and medical technology, high-income countries are not immune to the burden of HCV infection and LCDHC.Effective screening and early detection programs for LCDHC can help reduce the incidence of LCDHC.However, only 9 of 45 high-income countries are expected to achieve the HCV elimination goal by 2030, with 30 of these countries projected to reach the goal after 2050 (20).Notably, the three countries with the highest ASIR of LCDHC in 2017 were Mongolia, Egypt, and Japan (19).In 2019, the same countries continued to have the highest ASIR of LCDHC, indicating that the burden of LCDHC is not limited to developed countries and that developing countries also have a high incidence of this disease.Consequently, it is imperative to allocate more resources and implement preventative measures aimed at reducing the burden of LCDHC in these regions.Unsafe injections, shared injection apparatuses, blood transfusions, and mother-to-child transmission remain the primary modes of HCV transmission, whereas vertical transmission is the primary route of infection in children (21,22).
According to a previous study, approximately 5% of HCV-infected individuals (315,000 people) were infected through unsafe injections in 2015 (23).Preventing the reuse of syringes can significantly reduce the incidence of HCV infections caused by unsafe injections (24).In addition, dental procedures, tattoos, and manicure and pedicure services are high-risk factors for HCV infection (25,26).Therefore, preventing the widespread transmission of HCV among high-risk individuals is an important strategy to reduce the burden of LCDHC.To date, no effective vaccine exists to prevent HCV infection.Although directacting antiviral agent regimens were introduced in 2014 and can cure more than 90% of HCV patients, high costs, drug resistance, and reinfection rates are still significant obstacles to achieving this goal (27,28).Therefore, many HCV patients lack efficacy treatment and then progress to liver cancer.With the improvement in the world's medical health standards and the popularization of HCV health knowledge, the detection rate of LCDHC has increased, which has led to a decrease in ASIR.Nonetheless, the development of an effective HCV vaccine is imperative to achieving the goal of HCV elimination by 2030 (29).
The burden of LCDHC exhibits variations across different age groups and sex.The incidence rates of LCDHC were generally higher in men than women, with this trend continuing until the age of 85-89 age group.The reason why the rates are higher in men than women may be as follows: men are more likely to engage in high-risk behaviors that can lead to HCV infection, such as injection drug use or unprotected sex with multiple partners.Men are also more likely to have jobs that expose them to blood and bodily fluids, such as healthcare workers or emergency responders ASDR of liver cancer due to hepatitis C in 204 countries and territories and SDI in 2019.The black line indicates the expected values based on sociodemographic index and disease rates in all locations.DALYs, disability-adjusted life years; SDI, sociodemographic index; ASDR, agestandardized DALY rate.(30).Hormonal differences between men and women may also play a role, as estrogen has been shown to have a protective effect against liver cancer, with women generally having higher estrogen levels than men (31).Moreover, studies have suggested that testosterone may promote the growth of hepatocellular carcinoma cells, which could also contribute to the sex disparity in HCV-related hepatocellular carcinoma incidence (32).In 2017, the highest burden of liver cancer was found in the above 50 age group, and liver cancer due to hepatitis C and alcohol use contributes to approximately 95% of the proportions (19).In our study, we found that the number of incident cases was high in those aged 50-89 years.The findings of our study indicate that screening for HCV is recommended for older individuals to facilitate early detection of the infection and prompt initiation of treatment.HCV-infected older individuals should receive timely and effective treatment to decrease the risk of developing liver cancer.Furthermore, routine monitoring of liver function and early detection of any signs of liver cancer should be conducted regularly in older people with HCV.
Previous studies have investigated the relationship between incidence, death, and DALYs with the SDI of countries and regions for liver cancer.However, this study is the first to examine the correlation between the burden of LCDHC and the SDI of regions and countries as regards incidence, death, and DALYs.Our findings reveal a positive association between the burden of LCDHC and SDI values from 1990 to 2019.Moreover, a nonlinear association was found between the burden of LCDHC and the SDI value of countries in 2019.Although there is a general association between the burden of LCDHC and SDI, it should not be considered in isolation.The burden of LCDHC is not limited to developed or less-developed regions or countries, and a relatively high burden of LCDHC was observed in regions or countries with a range of SDI values.Furthermore, to assess the effectiveness of prevention programs, the observed value and expected levels in each country and region should be compared.It is crucial to consider other factors such as the prevalence of hepatitis C infection, accessibility to healthcare and screening programs, the availability of effective treatment options, demographics, lifestyle factors, and socioeconomic and environmental factors.
In the present study, we analyzed data from 204 countries and territories from 1990 to 2019 to provide a high-quality assessment of global and regional burdens and trends for LCDHC.However, some limitations should be considered.First, this study was a secondary analysis of data from the GBD study, and as with many GBD studies, the accuracy and reliability of estimates largely depend on the quality and quantity of input data used for modeling.Second, some HCV infections may occur simultaneously with other liver diseases such as HBV infection (25,33,34), alcoholic liver disease (35), or diabetes (36), making it difficult to determine the true cause of liver cancer, consequently leading to potential data distortion.Third, the effects of prevention and management strategies in different countries were not taken into account, and significant variations may exist between low-to middle-income countries and high-income countries.

Conclusion
Although the ASR of LCDHC has been decreasing, the absolute numbers of incident cases, mortality, and DALYs have increased, indicating that LCDHC remains a significant global burden.Geographically, the burden of LCDHC exhibits significant variations, with high-income Asia Pacific, North Africa and the Middle East, and Central Asia having the highest burden among the 21 GBD regions.Furthermore, male and older individuals have a higher burden of LCDHC.Our findings provide insight into the global burden trend of LCDHC and could assist policymakers in establishing appropriate methods for achieving the HCV elimination target by 2030 and reducing the burden of LCDHC.It is crucial to focus on these burden trends, particularly as the number of LCDHC cases and the aging population continue to rise.

2 ASIR
FIGURE 1 (A) Incidence number, (C) ASIR, (E) number of deaths, and (G) ASMR are illustrated for liver cancer due to hepatitis C at the global and regional levels from 1990 to 2019.(B) Incidence number, (D) ASIR, (F) number of deaths, and (H) ASMR of liver cancer due to hepatitis C at the global level in 1990 and 2019.SDI, sociodemographic index; ASIR, age-standardized incidence rate; ASMR, age-standardized mortality rate.

FIGURE 5
FIGURE 5 Trends in ASDR of liver cancer due to hepatitis C across 21 Global Burden of Disease study regions are illustrated by sociodemographic index (SDI) for both sexes combined from 1990 to 2019.The black line indicates expected values.DALYs, disability-adjusted life years; SDI, sociodemographic index; ASDR, age-standardized DALY rate.

TABLE 1
Mortality, incident cases, and disability-adjusted life years (DALYs) for liver cancer due to hepatitis C in 2019 and percentage change in age-standardized rates (ASRs) per 100,000 population from 1990 to 2019 by Global Burden of Disease regions., age-standardize incidence rate; ASMR, age-standardize mortality rate; ASDR, age-standardize DALYs rate. ASIR addition, the ASDR of LCDHC in 2019 ranged from 2.45 to 752.55 per 100,000 population.The highest rates were found in Mongolia (752.55 [95%UI 511.89 to 1,044.07]),Egypt (333.