Epidemic characteristics, spatiotemporal pattern, and etiologic factors of liver cancer burden in China from 2010 to 2016: A retrospective analysis

doi:10.21203/rs.3.rs-4725208/v1

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Research Article

Epidemic characteristics, spatiotemporal pattern, and etiologic factors of liver cancer burden in China from 2010 to 2016: A retrospective analysis

https://doi.org/10.21203/rs.3.rs-4725208/v1

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Background

With the rising prevalence of obesity, increasing alcohol consumption and the advances in hepatitis virus treatment, liver cancer epidemiology gradually changes. However, the impact of these changes on liver cancer burden in China remains unclear. This study aimed to assess temporal trends in liver cancer burden across the whole country and 33 province-level administrative regions and the contributions of various liver cancer etiologies in China from 2010 to 2016.

Methods

The age-standardized incidence/death rate for liver cancer from 2010 to 2016 was evaluated according to sex, age, and etiology using data from the 2016 Global Burden of Disease study. The liver cancer-related age-standardized rates in the 33 province-level administrative regions of China were obtained from the National Central Cancer Registry.

Results

From 2010 to 2016, there were 25% and 22% increase in liver cancer incidence and death respectively, while the age-standardized incidence/death rate remained stable. South China, especially rural South, had the highest incidence and death rate of liver cancer in the whole country. The proportion of alcohol and non-alcoholic steatohepatitis-associated liver cancer incidence and death increased, whereas that of HBV-associated liver cancer incidence and death decreased from 2010 to 2016. Non-alcoholic steatohepatitis was the only etiology with an increase in liver cancer incidence rate, and alcohol showed the fast-growing incidence of liver cancer in some age groups.

Conclusions

Urgent measures are required at a national level to tackle the underlying metabolic risk factors and slow down the rising burden of non-alcoholic steatohepatitis -induced liver cancer.

Liver cancer burden

epidemiology

nonalcoholic steatohepatitis

alcohol

hepatitis virus.

Liver cancer remains a global public health concern as the sixth-most frequent cancer and the fourth-leading cause of cancer-related death worldwide [1]. According to GLOBOCAN 2020, the global incidence of liver cancer was estimated to be as high as 0.9 million, with the highest incidence observed in East Asia and Africa [1, 2]. China is the region most affected by liver cancer globally, accounting for > 50% of newly diagnosed cases and deaths, despite accounting for only 19% of the global population [3, 4]. Recently, because of the control of hepatitis B and C virus (HBV and HCV) infection, a decreasing trend in incidence was observed in several global regions, including China [5]. However, the incidence of liver cancer due to metabolic and other causes has alarmingly risen in various countries [6–8]. In addition, liver cancer is a lethal malignant disease, considering the disappointing results of systematic treatments and the limitations of new approaches. According to the National Cancer Institute’s Surveillance, Epidemiology, and End Results program, the overall five-year relative survival rate is 20% for liver cancer, 35% for localized stage, 12% for regional stage, and 3% for distant stage [9]. Over 0.8 million deaths were caused by liver cancer worldwide in 2020 [9] despite many public health efforts being undertaken to address this problem.

The underlying etiological factors of liver cancer have been widely identified, including HBV and HCV infection, alcohol intake, nonalcoholic steatohepatitis (NASH), and other causes [10, 11]. The incidence of liver cancer is largely determined by the prevalence of risk factors across different countries and has changed over recent decades. Owing to vaccination coverage for HBV, enactment of the Blood Donation Law, and widespread availability of antiviral therapy, the burden of HBV- or HCV-associated liver cancer has significantly decreased both in China and worldwide, especially among young adults. However, the growing economy has fueled an increase in the global per capita consumption of alcohol, which has increased the burden of alcohol-induced liver cancer [12]. The prevalence of NASH has also increased along with the surge in obesity and diabetes, producing an increase in NASH-induced liver cancer in various regions, including the United States, Europe, and Asia. However, recent data is lacking from China.

The disease burden of liver cancer has decreased in China over the past few decades in terms of incidence, mortality, and disability-adjusted life years (DALYs) [1, 12, 13]. Studies have reported that the incidence rate of liver cancer has decreased by > 2% per year in both males and females over recent decades, especially in the younger generation, particularly for those < 40 years of age, who showed a faster downward trend [14]. Moreover, the incidence and mortality of liver cancer declined significantly in both urban and rural areas but were more pronounced in rural areas of China [15]. However, since 1990, studies on liver cancer epidemiology in China have largely focused on certain regions- or etiology-specific data [16, 17], and an updated comparative picture of the national liver cancer burden in China remains limited. Herein, we used liver cancer incidence, mortality, and DALYs data from the Global Burden of Disease (GBD) study in the general population according to sex, age, and etiology for the 2010–2016 period at the national level. Additionally, data on liver cancer in 33 provinces of China from the Chinese Center for Disease Control and Prevention were used to obtain an overview of the liver cancer burden in different regions of China. We aimed to report temporal trends in liver cancer burden throughout China and 33 province-level administrative regions, and the contributions of various liver cancer etiologic factors in China from 2010 to 2016. This study provides valuable insights for evidence-based healthcare planning and resource distribution for liver cancer control and prevention in China.

2.1. Data sources

Whole country data of this study were obtained from the GBD 2016 study, a systematic effort to estimate the burden of 328 diseases and 84 risk factors in 195 countries/territories. Annual frequencies and age-standardized rates (ASRs) of liver cancer-related incidence, mortality, and DALYs from 1990 to 2016 by sex, age, region, and country were obtained from an online data source, the Global Health Data Exchange (GHDx) query tool (http://ghdx.healthdat.com/gbd-results-tool), which is maintained by an ongoing multinational collaboration and coordinated by the Institute for Health Metrics and Evaluation [18]. To obtain regional-level data for China, 33 province-level administrative regions of China (including two Special Administrative Regions) were analyzed in this study. The 2016 data for two Special Administrative Regions (Hong Kong and Macao) were obtained from the Hong Kong Cancer Registry and Health Bureau of Statistics of Macao. The ASRs of liver cancer-related incidence and mortality in 31 provinces (including autonomous regions and municipalities) were obtained from the National Central Cancer Registry (NCCR), which collected registration data from 2016 from 487 cancer registries (after data quality control), of which 200 registries were from rural areas and 287 were from urban areas. The population covered by these cancer registries was 381,565,422 (193,632,323 males and 187,933,099 females), accounting for 27.6% of the national population as of the end of 2016.

2.2. Estimates of disease burden

The general methods used for the GBD 2016 are described in previous studies [10, 18]. Briefly, various data from different sources, including the vital registration system and cancer registry incidence data, were transformed to generate cause-specific mortality estimates using the Cause of Death Ensemble Model (CODEm). The incidence was estimated by dividing the mortality estimates by the mortality-to-incidence ratios. DALYs were calculated as the sum of the years of life lost and years lived with disability. All ICD9 and ICD10 codes pertaining to primary liver cancer were included in the estimates. The GBD provides a simple quality assessment from 0 to 5 to assess the quality of the data provided by each country.

To determine the proportion of liver cancer cases due to the five etiological groups included in GBD (HBV, HCV, alcohol, NASH, and other causes), a systematic literature search was performed in PubMed. Only population-based studies that provided data on the contribution of liver cancer etiologic factors were included. Search terms used in the systematic review for liver cancer etiology were “liver neoplasmas”[All Fields] OR "HCC"[All Fields] OR "liver cancer"[All Fields] OR "Carcinoma, Hepatocellular"[Mesh]) AND (("hepatitis B"[All Fields] OR "Hepatitis B"[Mesh] OR "Hepatitis B virus"[Mesh] OR"Hepatitis B Antibodies"[Mesh] OR "Hepatitis B Antigens"[Mesh]) OR ("hepatitis C"[All Fields] OR "Hepatitis C"[Mesh] OR "hepatitis C antibodies"[MESH] OR "Hepatitis C Antigens"[Mesh] OR "Hepacivirus"[Mesh]) OR ("alcohol"[All Fields] OR "Alcohol Drinking"[Mesh] OR "Alcohol-Related Disorders"[Mesh] OR "Alcoholism"[Mesh] OR "Alcohol-Induced Disorders"[Mesh])) NOT (animals[MeSH] NOT humans[MeSH]. Cases where the etiology was described as “unknown”, “idiopathic”, or “cryptogenic” were included in the “other causes” group. Other etiologies of liver disease, such as hemochromatosis, Wilson’s disease, autoimmune hepatitis, were also included in the “other causes” category. The proportion data found through the systematic literature review were used as input for five separate Dismod-MR2.1 models to determine the proportion of liver cancer due to the five subgroups for all locations, both sexes, and all age groups. When multiple risk factors were reported in individual patients, they were assigned in proportion to the individual risk factors. These estimated proportions were used to split the overall liver cancer estimates into those for the respective liver cancer etiologies. The proportion models were run independently of each other, and the final proportion models were consequently scaled to sum up to 100% for each age, sex, year, and location by dividing each proportion by the sum of the five models.

The methods used for the NCCR data have been described in previous studies [19, 20]. Cancer incidence and mortality rates stratified by age (0-, 1–4, 5–84 by 5 years, and 85 + years), sex (male/female), area (urban/rural), and region (seven administrative regions: North, Northeast, East, Central, South, Southwest, and Northwest) were calculated using pooled qualified cancer registry data. A registry was classified as rural when located in a county, and as urban registry was classified when located in a city. Classification of the seven administrative regions was based on the National Bureau of Statistics.

2.3. Statistical analysis

Standardization is necessary when comparing several populations with different age structures or the same population over time, where the age profiles change accordingly. The ASRs (per 100,000 population) were calculated by summing the products of the ASR and the number of persons in the same age groups of the chosen reference standard population and then dividing by the sum of the standard population weights. The annual percentage change (APC) in ASRs was estimated to quantify trends within a specific time interval. A 95% uncertainty interval (obtained) for each quantity was exhibited at the same time. The natural logarithm of ASRs is assumed to fit a linear regression model, Y = α + βX + ε, where Y is equal to the natural logarithm of age-standardized rates, α is a constant, β indicates positive or negative changing trends, X refers to the calendar year, and ε is the error. Therefore, estimated APCs = 100 × (e^β − 1). An increasing trend was considered when the APC and lower boundary of the 95% confidence interval (CI) were both positive. Conversely, when the APC and upper boundary were negative, a decreasing trend was observed. Otherwise, the ASR was deemed stable over time. All statistical analyses were performed using R, and a p-value of < 0.05 was considered significant.

3.1. Liver cancer burden in China, 2016

In 2016, 189,296 incident cases (95% uncertainty interval [UI] 171,330 − 209,173), 172,587 deaths (95% UI 149,454 − 197,473), and 4.9 million (95% UI 4.2–5.7 million) DALYs occurred in China due to liver cancer (Tables 1, 2 and S1). In 2016, the estimated age-standardized incident rate (ASIR), age-standardized death rate (ASDR), and age-standardized DALYs (ASDALYs) of liver cancer were 10.16 per 100,000 (95% UI 9.24–11.2), 9.41 per 100,000 (95% UI 8.21–10.71), and 262.69 per 100,000 (95% UI 226.36–300.90), respectively (Tables 1, 2 and S1). From 2010 to 2016, liver cancer incidence, liver cancer deaths, and DALYs increased by 25%, 22%, and 18%, respectively. Over this period, the estimated annual percentage changes (APCs) of the ASIR, ASDR and ASDALYs were stable, with APCs of 0.08% (95% CI − 0.12–0.32), 0.01% (95% CI − 0.17–0.22), and 0.03% (95% CI − 0.17–0.25), respectively (Tables 1, 2 and S1).

Table 1

Incident cases and age-standardized incidence rates of liver cancer in 2010 and 2016 and the temporal trend of age-standardized incident rates from 2010 to 2016
	2010		2016
	No. incident cases (95% UI)	ASIR per 100,000 (95% UI)	No. incident cases (95% UI)	ASIR per 100,000 (95% UI)	Annual percentage change of ASIR (95% CI)
China	151,873 (137,015–168,534)	9.68 (8.76–10.74)	189,296 (171,330 − 209,173)	10.16 (9.24–11.20)	0.08 (-0.12 to 0.32)
Etiology
Alcohol	11,853 (9,160 − 15,030)	0.76 (0.59–0.96)	16,612 (12,703 − 21,099)	0.88 (0.69–1.11)	0.21 (-0.01 to 0.48)
Hepatitis B	101,411 (89,731 − 114,562)	6.24 (5.53–7.02)	123,156 (108,220 − 139,247)	6.46 (5.69–7.28)	0.06 (-0.15 to 0.33)
Hepatitis C	23,115 (20,017–26,384)	1.65 (1.43–1.89)	29,692 (25,403 − 33,765)	1.71 (1.47–1.94)	0.06 (-0.11 to 0.25)
NASH	6,269 (5,183-7,488)	0.42 (0.35–0.50)	8,691 (7,188 − 10,367)	0.48 (0.40–0.57)	0.20 (0.01 to 0.41)
Other causes	9,222 (7,862 − 10,910)	0.61 (0.53–0.72)	11,143 (9,334 − 13,164)	0.63 (0.54–0.74)	0.05 (-0.12 to 0.24)
Age
0–9 years	297 (245–369)	0.21 (0.17–0.26)	327 (262–395)	0.22 (0.18–0.27)	0.03 (-0.22 to 0.20)
10–24 years	1,482 (1,302-1,791)	0.47 (0.42–0.57)	1,109 (996-1,283)	0.45 (0.40–0.52)	-0.02 (-0.18 to 0.22)
25–29 years	1,377 (1,209-1,664)	1.32 (1.16–1.59)	1,851 (1,661-2,070)	1.42 (1.27–1.59)	0.15 (-0.11 to 0.44)
30–34 years	3,105 (2,706-3,705)	3.09 (2.69–3.69)	3,449 (3,099 − 3,861)	3.13 (2.82–3.51)	0.09 (-0.14 to 0.37)
35–39 years	6,941 (6,111-8,010)	5.68 (5.00-6.56)	6,003 (5,325-6,795)	6.09 (5.40–6.89)	0.18 (-0.08 to 0.50)
40–44 years	12,235 (10,757 − 14,138)	9.49 (8.35–10.97)	12,641 (11,159 − 14,363)	10.95 (9.67–12.44)	0.24 (-0.04 to 0.62)
45–49 years	15,342 (13,322 − 17,716)	14.09 (12.23–16.27)	19,462 (16,920 − 22,192)	15.42 (13.41–17.59)	0.10 (-0.19 to 0.47)
50–54 years	14,958 (13,308 − 16,791)	18.46 (16.43–20.72)	22,427 (19,612 − 25,752)	19.50 (17.05–22.39)	0.12 (-0.13 to 0.44)
55–59 years	20,569 (18,300 − 23,076)	24.76 (22.03–27.78)	20,389 (18,023 − 22,930)	26.27 (23.22–29.55)	0.10 (-0.15 to 0.42)
60–79 years	63,680 (57,785 − 70,272)	39.88 (36.18-44.00)	85,761 (77,994 − 94,249)	41.07 (37.35–45.41)	0.06 (-0.13 to 0.28)
80 + years	11,882 (10,695 − 13,085)	60.90 (54.82–67.06)	15,873 (14,266 − 17,182)	59.69 (53.65–64.62)	-0.01 (-0.14 to 0.13)
ASIR, age-standardized incidence rate; NASH, nonalcoholic steatohepatitis

Table 2

Deaths and age-standardized death rates of liver cancer in 2010 and 2016 and the temporal trend of age-standardized death rates from 2010 to 2016
	2010		2016
	No. deaths (95% UI)	ASDR per 100,000 (95% UI)	No. deaths (95% UI)	ASDR per 100,000 (95% UI)	Annual percentage change of ASDR (95% CI)
China	141,706 (128,396 − 157,119)	9.28 (8.42–10.27)	172,587 (149,454 − 197,473)	9.41 (8.21–10.71)	0.01 (-0.17 to 0.22)
Etiology
Alcohol	11,278 (8,798 − 14,535)	0.74 (0.58–0.95)	15,439 (11,870 − 20,082)	0.83 (0.64–1.06)	0.15 (-0.06 to 0.38)
Hepatitis B	92,455 (82,477 − 104,945)	5.79 (5.17–6.57)	109,285 (92,021–127,730)	5.78 (4.88–6.73)	-0.01 (-0.21 to 0.23)
Hepatitis C	23,364 (20,050 − 26,641)	1.74 (1.51–1.98)	29,452 (24,843 − 34,705)	1.75 (1.48–2.05)	0.01 (-0.14 to 0.18)
NASH	6,117 (5,061 − 7,247)	0.43 (0.35–0.51)	8,324 (6,773 − 10,108)	0.47 (0.39–0.57)	0.13 (-0.04 to 0.32)
Other causes	8,490 (7,213 − 10,019)	0.58 (0.50–0.67)	10,085 (8,426 − 12,160)	0.58 (0.49–0.68)	-0.01 (-0.16 to 0.16)
Age
0–9 years	293 (259–337)	0.21 (0.18–0.24)	313 (250–361)	0.21 (0.17–0.24)	-0.11 (-0.32 to 0.11)
10–24 years	901 (795-1,082)	0.29 (0.25–0.35)	641 (558–740)	0.26 (0.23–0.30)	-0.08 (-0.25 to 0.12)
25–29 years	960 (850-1,149)	0.92 (0.81–1.10)	1,232 (1,073 − 1,402)	0.94 (0.82–1.08)	0.05 (-0.17 to 0.31)
30–34 years	2,408 (2,112-2,869)	2.40 (2.10–2.86)	2,540 (2,205-2,914)	2.31 (2.00-2.65)	-0.01 (-0.20 to 0.27)
35–39 years	5,656 (5,015 − 6,558)	4.63 (4.11–5.37)	4,606 (3,910-5,402)	4.67 (3.96–5.48)	0.08 (-0.17 to 0.36)
40–44 years	10,263 (9,071 − 11,796)	7.96 (7.04–9.15)	9,994 (8,393 − 11,725)	8.66 (7.27–10.16)	0.13 (-0.13 to 0.44)
45–49 years	12,899 (11,197 − 14,841)	11.84 (10.28–13.63)	15,976 (13,243 − 19,109)	12.66 (10.49–15.14)	0.03 (-0.24 to 0.35)
50–54 years	12,763 (11,402 − 14,422)	15.75 (14.07–17.80)	18,637 (15,605 − 22,157)	16.20 (13.57–19.26)	0.06 (-0.19 to 0.36)
55–59 years	18,054 (16,149 − 20,256)	21.74 (19.44–24.39)	17,485 (14,666 − 20,504)	22.53 (18.90-26.42)	0.05 (-0.18 to 0.32)
60–79 years	63,203 (57,475 − 69,613)	39.58 (35.99–43.59)	82,599 (72,076–94,387)	39.56 (34.52–45.20)	-0.01 (-0.16 to 0.19)
80 + years	14,300 (12,804 − 15,726)	73.29 (65.62–80.59)	18,559 (16,447 − 20,423)	69.80 (61.85–76.81)	-0.06 (-0.17 to 0.07)
ASDR, age-standardized death rate; NASH, nonalcoholic steatohepatitis

3.2. Burden of liver cancer in seven administrative regions of China in 2016

The estimated frequencies of liver cancer incidence and death rates (ASIRs and ASDRs) in different administrative regions are summarized in Table 3 and shown in Fig. 1. South China has the highest incidence and death rates of liver cancer in the country. Specifically, South China had the highest ASIR (26.1 per 100,000) of liver cancer, followed by Southwest China (19.2 per 100,000) and Northeast China (18.6 per 100,000) in 2016 (Table 3 and Fig. 1a). Similarly, South China had the highest ASDR (22.3 per 100,000) for liver cancer, followed by Southwest China (17.1 per 100,000), and Central China (15.7 per 100,000) (Table 3 and Fig. 1b). North China had the lowest incidence and death rates of liver cancer (12.5 and 10.5 per 100,000 people, respectively) (Fig. 1c) in the whole country in 2016.

Table 3

Age-standardized incident rate (ASIR) and age-standardized death rate (ASDR) of liver cancer by geographic areas covered by 487 cancer, 2010 and 2016 (1/10⁵)
All areas
Geographic areas	ASIR per 100,000 in 2010	ASIR per 100,000 in 2010	ASIR per 100,000 in 2016	ASDR per 100,000 in 2016
All areas	19.8	17.5	17.7	15.2
North	15.2	13.2	12.5	10.5
Northeast	18.8	16.9	18.6	15.7
East	21.2	18.8	16.6	14.3
Central	22.0	18.7	18.5	15.8
South	26.1	23.5	26.1	22.3
Southwest	22.5	19.8	19.2	17.1
Northwest	18.5	14.5	18.1	14.5
Urban
North	11.5	10.5	10.5	9.0
Northeast	16.3	15	15.9	13.4
East	18.5	16.3	15.4	13.1
Central	19.3	17.5	15.9	13.7
South	21.1	21.0	24.1	20.1
Southwest	19.7	17.5	18.0	16.2
Northwest	17.5	11.5	17.3	13.9
Rural
North	20.0	17.9	14.6	12.0
Northeast	23.8	22.7	24.8	21.0
East	22.7	20.9	17.7	15.4
Central	22.6	18.9	20.3	17.3
South	40.0	38.0	30.0	26.6
Southwest	29.9	27.8	20.4	17.9
Northwest	25.4	22.8	20.9	16.3
ASIR, Age-standardized incident rate; ASDR: age-standardized death rate

3.3. Burden of liver cancer classified by area (urban and rural) in China, 2016

The ASIR and ASDR of liver cancer in the urban and rural areas of the seven administrative regions are summarized in Table 3. Generally, the ASIR and ASDR for liver cancer in rural China were higher than those in urban China (19.3 vs 16.3 and 16.6 vs 13.9 per 100,000, respectively) (Table 3, Fig. 1d and 1e). Similarly, the rural areas in each administrative region had higher incidence and death rates than the urban areas in that region.

The highest ASIR and ASDR of liver cancer in 2016 occurred in southern rural areas (30.0 and 26.6 per 100,000 people, respectively), followed by northeastern rural areas (24.8 and 21 per 100,000 people, respectively). Notably, southern urban areas also had a high ASIR (24.1 peer 100,000) and ASDR (20.1 per 100,000) for liver cancer in 2016. North China, in both urban and rural areas, had the lowest incidence and death rates of liver cancer in the entire country (10.5 and 9.0 per 100,000, respectively) (Table 3, Fig. 1d and 1e).

Liver cancer incidence and death rates in rural and urban areas by sex and age were analyzed simultaneously. Generally, the ASIR and ASDR for liver cancer were higher in males than in females in both rural and urban areas. Specifically, the ASIR by Chinese standard population (ASR China) and World Segi population (ASR World) were 25.3% and 24.88% for males compared with 7.93% and 7.84% for females in urban China, and 29.48% and 28.79% for males compared with 9.80% and 9.72% for females in rural China, respectively. The ASDR by ASR China and ASR World were 21.61% and 21.32% for males compared with 6.70% and 6.61% for females in urban China and 25.5% and 24.97% for males compared with 8.26% and 8.19% for females in rural China. The age-specific incidence and mortality rate of liver cancer usually increased with age and were consistently high among older populations, regardless of the group, men or female, or urban or rural areas.

3.4. Trends in etiology of liver cancer

The frequencies of incident cases and deaths, ASIRs, ASDRs, and DALYs according to liver cancer etiology are summarized in Tables 1, 2, and S1. In 2010, 101,411 liver cancer cases were caused by hepatitis B, 23,115 by HCV, 11,853 by alcohol consumption, 9,222 by other causes, and 6,269 by NASH (Fig. 2a). In 2010, HBV accounted for 67% of liver cancer incidence in China, followed by HCV (15%), alcohol (7.8%), other causes (6.1%), and NASH (4.1%) (Fig. 2b). In 2016, 123,156 liver cancer cases were caused by hepatitis B, 29,692 by HCV, 16,612 by alcohol consumption, 11,143 by other causes, and 8,691 by NASH (Fig. 2a). HBV accounted for 65% of the liver cancer incidence, followed by HCV (15%), alcohol (9%), other causes (6%), and NASH (5%) (Fig. 2b). The proportion of alcohol-, NASH-, and other cause-associated liver cancer incidence increased, whereas the proportion of HBV-associated liver cancer incidence decreased, and the proportion of HCV-associated liver cancer incidence remained stable from 2010 to 2016. Similarly, in 2010, 109,285 hepatitis B-induced liver cancer deaths, 29,452 HCV-related liver cancer deaths, 15,439 alcohol-induced liver cancer deaths, 10,085 other-cause-induced liver cancer deaths, and 8,324 NASH-induced liver cancer deaths were reported (Fig. 2c). HBV accounted for 65% of liver cancer deaths, followed by HCV (17%), alcohol consumption (8.0%), other causes (6.0%), and NASH (4%). HBV accounted for 63% of liver cancer deaths in 2016, followed by HCV (17%), alcohol (9%), other causes (6%), and NASH (5%) (Fig. 2d). From 2010 to 2016, the proportion of alcohol- and NASH-associated liver cancer deaths increased, that of HBV-associated liver cancer deaths decreased, and that of HCV- and other cause-associated liver cancer deaths remained stable (Fig. 2d).

The ASIRs, ASDRs, ASDALYs, and APCs in liver cancer rates stratified by etiology from 2010 to 2016 are summarized in Tables 1, 2, and S1, respectively. NASH was the only etiology with an increase in liver cancer ASIRs (APC 0.20%, 95% CI 0.01–0.41) from 2010 to 2016 (Fig. 2e). ASIRs for alcohol-, HBV-, HCV- and other cause-associated liver cancer remained stable, with APCs of 0.21% (95% CI − 0.01–0.48), 0.06% (95% CI − 0.15–0.33), 0.06% (95% CI − 0.11–0.25), and 0.05% (95% CI − 0.12–0.24), respectively (Fig. 2e). From 2010 to 2016, the ASDRs for the five etiology-related HCC cases remained stable in China (Table 2). Specifically, the ASDRs of liver cancer due to alcohol (APC: 0.15%, 95% CI − 0.06–0.38), NASH (APC: 0.13%, 95% CI − 0.04–0.32), HCV (APC: 0.11%, 95% CI − 0.014–0.18), HBV (APC: -0.01%, 95% CI − 0.21–0.23), and other causes (APC: −0.01%, 95% CI − 0.16–0.16) showed no significant changes from 2010 to 2016 (Table 2; Fig. 2f). Similarly, the liver cancer ASDALYs from 2010 to 2016 in China were statistically stable, specifically reflected in alcohol-related (APC: 0.15%, 95% CI − 0.06–0.40), NASH-related (APC 0.15%, 95% CI − 0.05–0.36), HBV-related (APC: 0.02%, 95% CI − 0.20–0.28), HCV-related (APC: 0.02%, 95% CI − 0.14–0.20) and other cause-related (APC: −0.02%, 95% CI − 0.17 − 0.15) liver cancer (Table S1).

3.5. Trends in the etiology of liver cancer stratified by age

The incidence, mortality, and DALY rates of liver cancer according to age are summarized in Tables 1, 2, and S1. In 2016, the incidence rate of liver cancer was < 1.0/100,000 for individuals aged < 25 years and increased with age. The highest incidence of liver cancer was observed in individuals aged > 80 years (59.69 per 100,000 individuals) (Table 1). Similar tendencies were observed in the mortality rates, which were consistently high in older populations. Specifically, the death rate of liver cancer was < 1.0/100,000 for those aged < 30 years, increased to > 10 per 100,000 population at 45 years, and peaked in the > 80-year age group (69.8 per 100,000 population) (Table 2). From 2010 to 2016, the incidence rates of liver cancer due to alcohol consumption and NASH increased in several age groups, with the highest APCs observed in the 40-44-year age group (0.32% and 0.34%, respectively), followed by those in the 35–39-year age group (0.24% and 0.27%, respectively) (Fig. 3a and b). The incidence of liver cancer due to HBV, HCV, and other causes remained stable in all age groups from 2010 to 2016 (Table S2). The death rates and DALYs rates of liver cancer due to these causes in each age group from 2010 to 2016 are shown in Tables S3 and S4, which indicate no significant differences during this period.

Additionally, we investigated the proportion of liver cancer according to etiology in different age groups. As shown in Fig. 4a, HBV accounted for the highest frequency of liver cancer in each age group in 2016. The incidence rate of HBV-induced liver cancer increased and peaked in the 30–34-year age group (85%) and then decreased with age. However, the proportion of HCV- (37% in the > 80-year age group), alcohol- (11% in the 60–79-year age group), and NASH-induced liver cancer incidence (7.9% in the > 80-year age group) increased with age. Similar trends were observed for liver cancer mortality rate (Fig. 4b). From 2010 to 2016, the proportion of liver cancer due to HCV and HBV infection declined in each age group, whereas the proportion of liver cancer incidence due to alcohol consumption and NASH increased in each age group. Similar trends were observed in the proportion of liver cancer mortality due to these causes during the study period (Fig. 4b). The proportion of liver cancer mortality due to alcohol consumption and NASH increased in each age group from 2010 to 2016, whereas the proportion of liver cancer mortality due to HCV and HBV declined in each age group.

China is one of the countries most affected by liver cancer. As shown in previous studies, liver cancer was the only disease that had higher than expected age-standardized DALYs in all provinces of China, indicating the continuing serious impact of liver cancer in this country [5, 21]. The present study is the most comprehensive evaluation of the disease burden of liver cancer in China, demarcated by etiology, age, area, and region. Owing to the standardized method for estimating liver cancer metrics used in the GBD study, we could compare the incidence and mortality levels in China with those worldwide or compare the data at the provincial level in China. Using data from the 2016 GBD study, we determined that from 2010 to 2016, the incidence of liver cancer cases and number of liver cancer-related deaths increased by 25% and 22%, respectively, although significant changes occurred in the age-standardized incidence and death rates. The growth and aging of the Chinese population probably contributes to this disconnect in the temporal trends of frequency and age-standardized incidence or death rates. South China, an endemic area for liver cancer [22], had the highest incidence and death rates of liver cancer in 2016, which was probably attributed to the high hepatitis incidence rate, prevalence of liver fluke infestation, and damp and muggy environment in this region. Moreover, cancer incidence and mortality are higher in rural areas than in urban areas. This disparity was primarily attributed to period effects, mainly referring to the unequal medical levels and resources between urban and rural areas [23, 24]. Therefore, improving the medical level and resources in rural areas is essential, including reimbursing treatment for patients with chronic hepatitis, implementing annual cancer surveillance, and upgrading treatment quality in rural areas.

Although the ASIR and ASDR due to HBV-associated liver cancer remained stable from 2010 to 2016, the proportion of HBV-associated liver cancer incidence and deaths decreased in each age group. Moreover, a reduction in the ASIR of HBV-associated cirrhosis and other chronic liver diseases was observed in each age group from 2010 to 2016 in China, indicating a decreasing trend in the incidence of HBV-associated liver cancer in the following years. This decrease was likely because of the impact of successful vaccination, antiviral therapy, and aflatoxin reduction programs [25]. Similarly, no significant changes occurred in the ASIR and ASDR of HCV-associated liver cancer or in the proportion of HCV-associated liver cancer from 2010 to 2016. We observed an increase in the ASIR of HCV-related cirrhosis and other chronic liver diseases in the 25–49-year age group, especially with individuals aged 25–29 years. Despite the implementation of blood donor screening in 1993 and the availability of highly effective oral antiviral therapy [26–28], a high HCV prevalence persists among high-risk populations, including people who inject drugs, patients on hemodialysis, and patients coinfected with human immunodeficiency virus or HBV [29]. Moreover, major gaps remain in early disease diagnosis and linkage to care [30, 31]. Therefore, improvements are needed in infection control, disease screening, and treatment quality to achieve the elimination goal [29, 32].

NASH and alcohol consumption were the two etiological factors of liver cancer that increased in incidence and death rates in each age group from 2010 to 2016. NASH was the only etiology with an increase in the liver cancer incidence rate from 2010 to 2016, prominently in the 35–45 age group, driven by rapidly rising obesity rates [33, 34]. Moreover, the total burden related to nonalcoholic fatty liver disease (NAFLD) and the incidence of NAFLD-associated cirrhosis and other chronic liver diseases increased from 2010 to 2016, which was primarily observed in the 25–49-year age group, indicating that the incidence of liver cancer due to NASH is projected to increase in the next decade in China [35]. Therefore, increasing awareness and urgent actions are required to control metabolic risk factors and prevent the rising burden of NASH-related liver cancer in China [6, 34, 36]. Behavioral modifications and changes in diet and exercise habits should be reiterated. Although the ASIR of alcohol-induced liver cancer did not show a significant difference from 2010 to 2016 in China, we observed that the incidence of alcohol-induced liver cancer increased in several age groups, especially in the 35–45 age group. Moreover, alcohol per capita consumption increased from 2010 to 2016 in people aged > 25 years and is projected to increase [37, 38]. The incidence of cirrhosis and other chronic diseases due to alcohol use has consistently increased in the past decade, primarily in individuals aged between 25 and 49 years. Implementing policies such as increasing prices or taxation for alcohol and adding cancer warnings to alcohol labels may be considered at the national level to postpone the rising burden of alcohol-related liver cancer in China [37].

Our study provides an in-depth analysis of the temporal trends in liver cancer and the contributions of various causes using data from the GBD 2016 and the NCCR of China. Our findings validate several previous studies [6, 16, 34, 39] that reported the increasing impact of NASH and alcohol on the liver cancer burden and provide important information for care providers and policymakers. The current study provides a national overview of the temporal trends in the liver cancer burden and the contributions of various liver cancer etiologic factors in China from 2010 to 2016, unlike most other studies that have focused on a specific region/province or etiology of liver cancer. These data provide a comprehensive impression of the liver cancer burden in China and may help promote future endeavors in liver cancer diagnosis, management, and research. However, it remains critical to keep track of the epidemiology of liver cancer in China over time, particularly given the early signs of potential trends in several regions.

Our study had several limitations. First, the data for this study were derived from the GBD 2016, and the general limitations described by the GBD apply to our study. Second, multifactorial liver cancer was not considered in our study because of the scarcity of data in the GBD dataset. Several risk factors play a role in some liver cancer cases. For example, studies have demonstrated that alcohol consumption increases the risk of liver cancer in patients with HBV- and HCV-related cirrhosis [40, 41]. Therefore, the temporal trends of multiple etiological factors in liver cancer development should be investigated in future studies. Third, the increasing trend in the liver cancer burden was associated with an increase in the number of cancer registry sites. Underreporting and misdiagnosis are inevitable during registration. Finally, the latest data on different administrative regions in China were obtained in 2016 and were recently published in 2022. For consistency, we used the GBD 2016 data instead of the GBD 2019 data. Therefore, continuing to track the epidemiology of liver cancer over time remains critical.

The frequency of new cases, deaths, and DALYs due to liver cancer in China increased substantially from 2010 to 2016, although age-standardized incidence and death rates have remained stable at the national level. South China has the highest liver cancer incidence and death rates in the country, and rural areas usually have higher incidence and death rates than urban areas. NASH and alcohol consumption are the two fastest growing etiological factors of age-standardized liver cancer incidence, highlighting the urgent need to implement measures to overcome these growing issues.

Declaration of Interest

statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

APC

annual percentage change

ASDALYs

age-standardized DALYs

ASDR

age-standardized death rate

ASIR

age-standardized incident rate

ASRs

age-standardized rates

confidence interval

CODEm

Cause of Death Ensemble Model

DALYs

Disability-adjusted life-years

GBD

Global Burden of Disease

GHDx

GlobalHealth Data Exchange

HBV

Hepatitis B virus

HCV

Hepatitis C virus

NAFLD

Non-alcoholic fatty liver disease

NASH

non-alcoholic steatohepatitis

NCCR

National Central Cancer Registry

SEER

Surveillance, Epidemiology, and End Results

uncertainty interval

Declaration of Interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Fundings

This study was funded by the National Natural Science Foundation of China (grant no. NSFC 82100201, 2024C03169, 2017KY393, 2018KY428).

Data Availability

All data generated or analyzed during this study are included in this published paper.

Acknowledgements

We would like to thank the GBD Study 2016 and the National Cancer Center of China for providing the original data for this study.

Author Contributions

Tian Tian: Writing-original draft, writing-review & editing, formal analysis, data curation, resources, conceptualization.

Yangyuna Yang: Writing-review & editing, formal analysis, data curation, resources.

Jie Wu: Supervision, methodology, writing-review & editing, term, conceptualization, project administration.

Jianzhen Shan: Supervision, writing-review & editing, funding acquisition, project administration.

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No competing interests reported.

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Epidemic characteristics, spatiotemporal pattern, and etiologic factors of liver cancer burden in China from 2010 to 2016: A retrospective analysis

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Version 1

Abstract

Background

Methods

Results

Conclusions

Figures

1. Introduction

2. Materials and methods

2.1. Data sources

2.2. Estimates of disease burden

2.3. Statistical analysis

3. Results

3.1. Liver cancer burden in China, 2016

3.2. Burden of liver cancer in seven administrative regions of China in 2016

3.3. Burden of liver cancer classified by area (urban and rural) in China, 2016

3.4. Trends in etiology of liver cancer

3.5. Trends in the etiology of liver cancer stratified by age

4. Discussion

5. Limitations of study

6. Conclusions

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1