Vital Surveillances: Trends of Mortality in End-Stage Liver Disease — China, 2008–2020

End-stage liver disease (ESLD), a severe stage of chronic liver disease, represents a significant global public health challenge due to its high mortality rate (1-2). Notably, liver cancer and decompensated cirrhosis represent a substantial proportion of ESLD cases. In 2020, liver cancer was the second most common cause of cancer-related deaths in China, accounting for nearly half of liver cancer fatalities worldwide (3). Additionally, cirrhosis and other chronic liver disorders constitute approximately 14.9% of global mortality, further emphasizing the severe public health impact of these conditions in China (4).

The prevalence and mortality rates of ESLD can significantly differ among various regions in China. Hence, understanding the current state and pattern of ESLD mortality, as well as its temporal trends, within China as a whole and its individual regions is of utmost importance. Such information can guide the formulation of intervention priorities and help reduce the worldwide disease burden of ESLD. In this study, we have gathered data from the Disease Surveillance Points (DSPs) system administered by the Chinese Center for Disease Control and Prevention (CDC) to analyze the mortality profile of ESLD in 2020. Additionally, we have examined the fluctuations in the annual mortality rates from 2008 to 2020, considering factors such as gender, age group, residential location, regional differences, and per capita gross domestic product (GDP).

Mortality data associated with ESLD, represented by deaths stemming from liver function decompensation triggered by liver cancer and cirrhosis, were procured from the DSPs system. The DSPs system, initiated by the Chinese government in 1978, has progressively expanded its geographical reach over the past four decades. In 2013, the coverage of the DSPs system broadened from 161 to 605 data points, encapsulating more than 324 million citizens of China (accounting for 24.3% of the national populace). Deaths that transpire within these surveillance points are consistently reported, and the associated cause of death is codified as per the International Classification of Diseases-10th Revision (ICD-10) by professionally trained staff positioned in local hospitals or CDC branches.

This research classifies the root cause of mortality as ESLD, associated with specific ICD-10 codes: C22 signifies liver cancer, as well as K70.2–K70.4 and K74–K74.6, which refer to cirrhosis. This study received approval from the Ethics Committee of the National Center for Chronic and Non-communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention (No. 202219).

In our analysis, we took into consideration five key sociodemographic factors: year of occurrence, place of residence, gender, age bracket, and geographical location. To categorize age, we used 13 groups: under 30 years, 30–34 years, 35–39 years, 40–44 years, 45–49 years, 50–54 years, 55–59 years, 60–64 years, 65–69 years, 70–74 years, 75–79 years, 80–84 years, and over 85 years. Geographical locations were segmented into seven regions, in line with the divisions provided by the National Statistics Bureau. These divisions include: North China (Beijing Municipality, Tianjin Municipality, Hebei Province, Shanxi Province, and Inner Mongolia Autonomous Region); Northeast China (Heilongjiang Province, Jilin Province, and Liaoning Province); East China (Shanghai Municipality, Jiangsu Province, Zhejiang Province, Anhui Province, Jiangxi Province, Shandong Province, and Fujian Province); Central China (Henan Province, Hubei Province, and Hunan Province); South China (Guangdong Province, Guangxi Autonomous Region, and Hainan Province); Southwest China [Chongqing Municipality, Sichuan Province, Guizhou Province, Yunnan Province, and Xizang Autonomous Region (Tibet)]; and Northwest China (Shaanxi Province, Gansu Province, Qinghai Province, Ningxia Autonomous Region, and Xinjiang Autonomous Region). Data pertaining to per capita GDP was acquired from the National Bureau of Statistics, with the information being accessed on January 8, 2022 (https://data.stats.gov.cn/).

Mortality rates are denoted as a count of deaths per 100,000 individuals. Using data derived from the 2010 Chinese census, the age-standardized mortality rate was computed (ASMRC) and aligned with Segi’s world standard population (ASMRW). Using Joinpoint Regression software, the average annual percentage change (AAPC) and its 95% confidence interval (CI) were estimated to scrutinize the mortality rate trends from 2008 to 2020. Subsequently, a Gaussian process regression was applied to examine the correlation between ASMRC and per capita GDP.

Statistical analysis was conducted in the Joinpoint Regression Program (version 4.9.0.0, Statistical Research and Applications Branch, National Cancer Institute, Bethesda, MD, USA) and R (version 4.1.1, R Foundation for Statistical Computing, Vienna, Austria), and all testing was two-tailed with statistical significance set at 0.05.

In 2020, the DSPs system reported a total of 102,067 ESLD-related deaths: 86,692 due to liver cancer and 15,375 attributed to cirrhosis. The average age at death for ESLD was 63.37 years, with liver cancer at 63.57 years and cirrhosis at 62.32 years. The crude mortality rate for ESLD was calculated at 30.08 deaths per 100,000 people, while liver cancer and cirrhosis had rates of 25.57 deaths and 4.51 deaths per 100,000 people, respectively.

Examining the data for each ESLD (liver cancer or cirrhosis), males consistently demonstrated higher age-standardized mortality rates (ASMRC and ASMRW) than females, especially in rural regions. Furthermore, individuals residing in rural locations recorded higher age-standardized mortality rates compared to their urban counterparts.

Upon stratification by region, consistent sex differences in ASMRC and ASMRW persisted due to ESLD, while differences due to residential location experienced slight variations. Specifically, ASMRC and ASMRW were observed to be higher in urban areas compared to rural regions in the North, Northeast, East, and Central regions of China (Supplementary Table S1).

Table 1 displays the geographical distribution of ASMRC of ESLD, inclusive of its individual components (liver cancer and cirrhosis) across China in 2020. While South China recorded the highest ASMRC of liver cancer (26.86 deaths per 100,000 people), the lowest observed ASMRC of liver cancer was in North China (16.44/13.29 deaths per 100,000 people). In contrast, Southwest China experienced the highest ASMRC of cirrhosis (7.14 deaths per 100,000 people). East China had the smallest occurrence, with an ASMRC of merely 2.11 deaths per 100,000 people.

Both in 2008 and 2020, a consistent increase was observed in the age-specific ESLD mortality rates. However, the rate of increase in 2020 was less significant than that in 2008. This trend remained consistent even after accounting for variables such as residential location, sex, and region (Figure 1).

Figure 1. 

Trends in mortality rates for end-stage liver disease, liver cancer, and cirrhosis in 2008 and 2020. Among age groups based on all population (A) residential location (urban or rural, B–C), sex (male or female, D–E), and region (North, Northeast, East, Central, South, Southwest, or Northwest China (F–L).

Abbreviation: ASMRC=age-standardized mortality rates adjusted by the Chinese standard population.

In 2008, the mortality rate for ESLD in China was significantly high, with a crude rate of 35.92 deaths per 100,000 individuals. From 2008 to 2020, the general ASMRC for ESLD in China exhibited a downward trajectory. This decline remained consistent upon stratification by gender and location (Figure 2, Supplementary Table S2).

Figure 2. 

Trends in the ASMRC for end-stage liver disease, liver cancer, and cirrhosis from 2008 to 2020, broken down by all population (A), residential location (urban or rural, B–C), sex (male or female, D–E), and region (North, Northeast, East, Central, South, Southwest, or Northwest China, F–L).

ASMRC: age-standardized mortality rates, adjusted in accordance with the Chinese standard population

From 2008 to 2020, the AAPC in ASMRC of ESLD, stratified by gender or residential location, showed no variability. However, in urban regions, the AAPC in ASMRC of cirrhosis was higher than that linked to liver cancer (AAPC in ASMRC: AAPC=−5.2, 95% CI: −5.9, −4.4 versus AAPC=−3.3, 95% CI: −4.2, −2.5). This trend continued when data was stratified by gender, for both males and females (Supplementary Table S2).

Upon examining the data by region, there was a consistent decreasing trend in the ASMRC of ESLD from 2008 to 2020 (Figure 2). Throughout this time frame, liver cancer demonstrated a greater AAPC of ASMRC in Northern, Northeastern, Southern, and Southwestern China, while cirrhosis had a higher AAPC of ASMRC in Northeastern and Southwestern China. Additionally, when compared to liver cancer, cirrhosis exhibited a higher AAPC of ASMRC in Northeastern and Eastern China (Figure 2, Supplementary Table S3).

From 2008 to 2020, there was a noticeable downward trend in the ASMRC of ESLD, which corresponded with an increase in per capita GDP (Figure 3A–C). The lowest ASMRC of cirrhosis was observed when the per capita GDP exceeded 8,000 CNY, after which it appeared to stabilize (Figure 3C). When analyzed on a provincial-level administrative division (PLAD) basis, Guangdong — a province credited with a high per capita GDP — demonstrated the most significant reduction in the ASMRC of liver cancer. Conversely, the greatest decrease in the ASMRC of cirrhosis was recorded in Sichuan Province. Generally, the data insinuates that provinces with higher per capita GDP tend to manifest lower ASMRC of ESLD (Figure 3A–C).

Figure 3. 

Age-standardized mortality rates for end-stage liver diseases stratified by per capita GDP in China from 2008 to 2020. (A) End-stage liver disease, (B) Liver cancer and (C) Cirrhosis.

Abbreviation: GDP=gross domestic product; CNY=Chinese Yuan.

This study reveals a significant decrease in the mortality rates associated with liver cancer and cirrhosis between 2008 and 2020, likely due to the effective management of chronic viral hepatitis, inclusive of both hepatitis B and C. Since 1992, China has instituted a policy mandating neonatal hepatitis B vaccinations (5). Furthermore, in 2009, a nationwide “catch-up” hepatitis B vaccination initiative for children aged between 8 and 15 was commenced (6). These collective strategies resulted in a substantial decrease in the rate of hepatitis B surface antigen (HBsAg) positivity. Moreover, national guidelines endorsed the use of first-line antiviral medicines, including pegylated interferon, entecavir, and tenofovir (7). Consequently, the proportion of chronic hepatitis B (CHB) patients receiving antiviral therapy increased from 13.5% in 2003 to 79.7% in 2016 (8). Concerning chronic hepatitis C (CHC), the implementation of direct-acting antiviral agents (DAAs) drastically lessened the burden of hepatitis C virus (HCV) infection in China. Specifically, the population with viremic HCV in China declined by around 536,000 from 2015 to 2020 (9). Collectively, these initiatives have reduced the mortality rates of liver cancer and cirrhosis associated with chronic viral hepatitis. A smaller decrease in mortality due to ESLD was observed in rural areas compared to urban areas — a correlation to the easier access in urban areas to timely treatment for chronic viral hepatitis, cirrhosis, and liver cancer (10).

From 2008 to 2020, decreases were observed in the mortality rates of ESLD, liver cancer, and cirrhosis concurrent with increases in per capita GDP. This trend aligns with prior research, which demonstrated a negative correlation between the Sociodemographic Index (SDI) values and the age-standardized mortality rates of cirrhosis and other chronic liver diseases (11). It’s possible that the decline in mortality rates could be attributed to improvements in sanitation, healthcare conditions, and the increased public awareness of medical treatment, all potentially facilitated by the rise in per capita GDP.

Hepatitis B virus (HBV) and HCV continue to be predominant contributors to cirrhosis and liver cancer mortality rates in China (12-13). As indicated by the GBD data of 2017, liver-related deaths (including liver cancer and cirrhosis) totalled 0.61 million in East Asia, 0.34 million in South Asia, 0.25 million in Southeast Asia, 0.12 million in Western Europe, and 0.1 million in the Middle East and North Africa (MENA) (14). In 2020, the death toll related to ESLD remained significantly high in China. This was consistent with the results from a data study on the burden of all cancers (15). First, despite the implementation of the neonatal hepatitis B vaccination program leading to a noticeable decline in HBV incidence and transmission, the prevalence of hepatitis B in China remains high due to an extensive population, approximately 84 million, living with CHB (8). Particularly in women of reproductive age, the prevalence of HBsAg persists between 5%–6% with the continuing risk being mother-to-child transmission. This poses a substantial challenge in advancing diagnostic coverage, eradicating HBV infection, and lessening ESLD mortality resulting from CHB. Second, while DAA treatment has proven to achieve a higher curative rate in patients suffering from CHC (16), the actual diagnostic rate of Hepatitis C in China stands only at 2.1% (17). Owing to this low diagnostic rate, fewer CHC patients avail antiviral therapy, leading to higher incidences of HCV-related ESLD.

Our study faced several limitations. First, due to data unavailability in the DSPs system, we were unable to analyze morbidity and mortality data concerning specific etiologies of ESLD. Second, our study did not investigate fatalities resulting from other potential causes such as type 2 diabetes mellitus, which may have contributed to incompleteness in the report. Third, a significant challenge associated with the DSP data is the under-reporting of deaths, with higher rates observed in the west compared to the east and central regions, and rural areas more so than urban ones. This could potentially result in an underestimation of the overall mortality burden of ESLD, given that higher death rates were seen in rural areas and the west region. Despite these caveats, our study offers important insights into the mortality burden and shifting trends of ESLD, as well as disparities in mortality between liver cancer and cirrhosis. These findings enable the identification of high-risk populations and the development of preventive strategies, guiding future etiological studies on ESLD in China.

In sum, the last decade has witnessed a substantial decline in ESLD mortality rates in China, which can be largely attributed to the implementation of the HBV vaccine and treatment for chronic viral hepatitis. Nevertheless, the mortality burden of ESLD remains substantial. As such, future research efforts and healthcare initiatives should prioritize the exploration of antiviral therapy for adults diagnosed with viral hepatitis and preventative measures against HBV infection across all demographics, with the goal of further reducing ESLD mortality.

Prof. Rao HY has received speaking fees from Bristol-Myers Squibb, Gilead, and AbbVie. The other authors declared no conflicts of interest.