The trends in death of primary liver cancer caused by specific etiologies worldwide: results from the Global Burden of Disease Study 2019 and implications for liver cancer management

DOI: https://doi.org/10.21203/rs.3.rs-2200639/v1

Abstract

Background: Over past decades, epidemiological patterns of liver cancer (LC) have changed dramatically. The Global Burden Of Disease (GBD) study provides an opportunity to tracking the progress in cancer control with its annual updated reports at national, regional, global level, which can facilitate the health decision-making and the allocation of health resources. Therefore, we aim to estimate the global, regional and national trends of death caused by liver cancer due to specific etiologies and attributable risks from 1990 to 2019.

Materials and Methods: Data was collected from the GBD study 2019. Estimated annual percentage changes (EAPC) were used to quantify the trends of age-standardized death rate (ASDR). We applied a linear regression for the calculation of estimated annual percentage change in ASDR.

Results: From 1990 to 2019, the ASDR of liver cancer decreased globally (EAPC = −2.23, 95% confidence interval [CI]: −2.61 to −1.84). Meanwhile, declining trends were observed in both sexes, socio-demographic index (SDI) areas, and geographies, particularly East Asia (EAPC =−4.98, 95%CI: −5.73 to −4.22). The ASDR for all four major etiologies decreased globally, particularly LC owing to hepatitis B (EPAC = −3.46, 95% CI: −4.01 to −2.89). At the national level, China has seen dramatic decreases in death rates, particularly in the etiology of hepatitis B (EAPC = −5.17, 95% CI: −5.96 to −4.37). However, mortality from liver cancer increased in certain countries, including Armenia and Uzbekistan. Controlling smoking, alcohol, and drug use contributed to a drop in LC-related mortality in the majority of socio-demographic index areas. However, the excessive BMI was portrayed as the underlying cause for LC fatalities.

Conclusion: From 1990 to 2019, there was a worldwide decrease in deaths caused by liver cancer and its underlying causes. However, rising tendencies have been observed in low-resource regions and countries. The trends in drug use- and high BMI-related death from liver cancer and its underlying etiologies were concerning. The findings indicated that efforts should be increased to prevent liver cancer deaths through improved etiology control and risk management.

Background

Liver cancer was the fourth leading cause of neoplasm death after lung, colorectal, and stomach cancer in 2017 [1]. Liver cancer burden varies obviously by sex and geographic region due to risk actor exposure [2]. Major risk factors include infections (hepatitis B virus [HBV], hepatitis C virus [HCV], liver flukes in endemic areas), behavioral factors (alcohol, tobacco), metabolic factors (excess body fatness), and aflatoxins [3]. Trends of death caused by liver cancer underlying specific etiologies and attributable risks were demonstrated using the latest version of Global Burden of Disease (GBD) study, providing an important data to public health strategies [4].

Over past decades, epidemiological patterns of liver cancer have changed dramatically [5]. The Global Burden of Disease (GBD) study revealed that the age-standardized death rate (ASDR) declined in most socio-demographic index (SDI) areas, but rose in the low SDI areas (3%) from 2006 to 2016 [6]. ASDR considerably decreased in regions with high liver cancer burden such as East Asia and Western sub-Saharan Africa from 1990 to 2015, but increased more than doubled in Philippines, Moldova, and Guatemala [7]. However, survival of liver cancer only increased by 5–10% in most countries during the period 1995–2014, particularly in some developed countries [8]. Changing survival patterns of liver cancer were influenced by many factors, including vaccine coverage, local medical resource, metabolic syndrome, and lifestyles [9–11]. Prevention and treatment of hepatitis B contributed for the majority of decrease in death caused by liver cancer [12]. Furthermore, the detection of liver cancer at an early stage had markedly improved the 5-year survival [13]. Nevertheless, the high prevalence of alcohol use, drug use, and obesity were growing risks in the expansion of liver cancer death in recent years [14–16]. All these risk factors were preventable, and dynamically varied in different countries over time, emphasizing the necessity of tracking the temporal trends of burden caused by liver cancer.

To the best of our knowledge, this study is the first to describe the long-term secular trends in the mortality of etiology-specific liver cancer from GBD 2019 worldwide. The GBD study provides an opportunity to tracking the progress in cancer control with its annual updated reports at national, regional, global level, which can facilitate the health decision-making and the allocation of health resources. Therefore, we aim to estimate the global, regional and national trends of death caused by liver cancer due to specific etiologies and attributable risks from 1990 to 2019.

Methods

Ethics statement

This research was approved by the Ethics Committee of Southern Medical University (Guangzhou, China). The methods were carried out following the Declaration of Helsinki and its later amendments or comparable ethical standards.

Data sources

Annual death cases and age standardized deaths of liver cancer from 1990 to 2019, by sex, age, region, country, etiology (HBV, HCV, alcohol consumption, and non-alcoholic steatohepatitis) and attributable risks (smoking, alcohol use, drug use, high fasting plasma glucose and high body-mass index (BMI)) were obtained using the Global Health Data Exchange (GHDx) query tool (http://ghdx.healthdata.org/gbd-results-tool). Data from a total of 204 countries and territories were available. These countries and territories were then categorized into 5 regions in terms of socio-demographic index (SDI), including low, low-middle, middle, high-middle, and high. Moreover, the world was separated into 21 regions in terms of geography, e.g. East Asia (Table 1). The general methods for the GBD 2019 and the methods for estimations of disease burden in liver cancer have been detailed in previous studies [1, 4]. In brief, all ICD9 and ICD10 codes associated with primary liver cancer (155-155.963 and C22.0-9, respectively) from individual cancer registries or aggregated databases of cancer registries are included in these estimates.

Table 1

The number and age-standardized rate of death due to liver cancer in global, sexes, SDI areas and geographic regions in 1990 and 2019, and the percentage change in number and EAPCs from 1990 to 2019
 

1990

2019

1990–2019

Characteristics

Number

No.×103 (95% UI)

ASR (/100,000)

No. (95% UI)

Number

No.×103 (95% UI)

ASR (/100,000)

No. (95% UI)

Change in number (%)

EAPC

No.(95%CI)

Overall

365.22

(329.97-405.77)

8.93

(8.09–9.90)

484.58

(444.09–525.80)

5.95

(5.44–6.44)

32.68

−2.23

(− 2.61-−1.84)

Sex

            

Male

251.00

(218.33-287.14)

12.90

(11.3-14.67)

333.67

(299.58-368.33)

8.73

(7.88–9.60)

32.94

−2.26

(− 2.68-−1.84)

Female

114.22

(100.16-130.72)

5.33

(4.67–6.09)

150.90

(134.12-167.01)

3.46

(3.08–3.83)

32.12

−2.10

(− 2.39-−1.80)

SDI

            

Low

10.56

(9.24–11.90)

4.37

(3.80–4.97)

20.76

(18.22–23.33)

3.93

(3.49–4.38)

96.50

−0.47

(− 0.53-−0.40)

Low-middle

34.78

(31.45–38.18)

5.57

(5.05–6.13)

57.24

(52.13–63.45)

4.23

(3.86–4.68)

64.58

−1.55

(− 1.84-−1.25)

Middle

163.81

(142.72-189.46)

15.00

(13.15–17.26)

196.96

(172.83-223.21)

7.92(6.97–8.93)

20.24

−3.16

(− 3.71-−2.61)

High-middle

107.83

(94.48-122.72)

9.96

(8.75–11.27)

97.19

(87.23-108.11)

4.83(4.34–5.38)

−9.87

−3.69

(− 4.23-−3.15)

High

48.13

(46.47–49.3)

4.69

(4.54–4.81)

112.24

(102.49-118.74)

5.89(5.44–6.21)

133.2

0.42

(0.01–0.83)

Regions

            

East Asia

237.01

(202.34-279.89)

25.52(21.98–29.94)

193.86(163.85-228.76)

9.39(7.98–11.03)

−18.20

−4.98

(− 5.73-−4.22)

South Asia

15.85

(13.38–18.09)

2.82

(2.33–3.27)

38.65

(33.52–44.56)

2.81

(2.43–3.24)

143.79

−0.06

(− 0.16 − 0.04)

Southeast Asia

17.57

(15.68–19.28)

6.76

(6.03–7.45)

42.86

(35.33–51.52)

7.33

(6.08–8.79)

143.90

0.28

(0.20–0.36)

Central Asia

1.51

(1.35–1.66)

3.24

(2.89–3.58)

6.19

(5.39–7.08)

8.72

(7.63–9.88)

310.70

2.93

(2.42–3.45)

High-income Asia Pacific

23.59

(22.76–24.37)

11.62

(11.18-12)

49.68

(43.78–53.5)

10.78

(9.77–11.53)

110.62

−0.86

(− 1.46-−0.25)

Oceania

0.11

(0.09–0.13)

3.85

(3.25–4.47)

0.23

(0.19–0.28)

3.46

(2.93–4.09)

106.99

−0.22

(− 0.29-−0.16)

Australasia

0.46

(0.44–0.48)

1.98

(1.90–2.06)

2.01

(1.83–2.17)

4.12

(3.80–4.46)

332.62

2.88

(2.67–3.09)

Eastern Europe

4.22

(4.06–4.41)

1.55

(1.49–1.62)

9.68

(8.51–11.12)

2.87

(2.51–3.29)

129.05

2.52

(2.27–2.77)

Western Europe

19.88

(19.16–20.42)

3.43

(3.31–3.52)

40.30

(37.22–42.88)

4.41

(4.10–4.68)

102.67

0.80

(0.66–0.94)

Central Europe

8.11

(7.83–8.32)

5.60

(5.38–5.75)

7.20

(6.22–8.33)

3.36

(2.90–3.90)

−11.24

−1.49

(− 1.87-−1.11)

High-income North America

7.07

(6.78–7.25)

2.03

(1.95–2.07)

26.48

(23.64–28.91)

4.29

(3.83–4.68)

274.32

2.66

(2.52–2.80)

Andean Latin America

1.07

(0.95–1.21)

5.23

(4.60–5.87)

1.84

(1.51–2.23)

3.34

(2.73–4.03)

71.18

−1.94

(− 2.37-−1.51)

Central Latin America

3.07

(2.86–3.23)

3.74

(3.46–3.94)

8.42

(7.36–9.75)

3.65

(3.18–4.22)

173.76

0.04

(− 0.28–0.35)

Caribbean

1.64

(1.52–1.74)

6.29

(5.85–6.68)

1.69

(1.42–2.01)

3.29

(2.76–3.89)

3.58

−2.16

(− 2.97-−1.35)

Tropical Latin America

1.88

(1.80–1.95)

2.09

(1.99–2.17)

5.94

(5.54–6.24)

2.50

(2.32–2.62)

215.17

1.06

(0.91–1.21)

Southern Latin America

0.76

(0.68–0.83)

1.65

(1.49–1.81)

2.03

(1.90–2.15)

2.41

(2.26–2.56)

168.33

2.00

(1.78–2.23)

Eastern Sub-Saharan Africa

2.54

(2.08–3.15)

3.15

(2.63–3.99)

5.68

(4.68–6.92)

3.41

(2.85–4.15)

123.76

0.08

(− 0.04–0.21)

Southern Sub-Saharan Africa

1.91

(1.35–3.14)

6.74

(4.71–11.07)

4.04

(3.62–4.54)

7.05

(6.31–7.91)

111.14

−0.43

(− 1.01–0.16)

Western Sub-Saharan Africa

5.31

(4.55–6.17)

5.81

(4.99–6.76)

9.97

(8.36–11.56)

5.29

(4.48–6.04)

87.85

−0.44

(− 0.51-−0.36)

North Africa and Middle East

10.91

(9.58–12.23)

6.39

(5.55–7.19)

26.43

(21.21–32.61)

6.20

(5.06–7.62)

142.20

0.25

(0.10–0.39)

Central Sub-Saharan Africa

0.72

(0.60–0.85)

2.85

(2.43–3.29)

1.39

(1.11–1.75)

2.47

(1.99–3.07)

94.59

−0.64

(− 0.71-−0.57)
EAPC: estimated annual percentage change; ASR, age-standardized rate; CI, confidence interval; UI: uncertainty interval; SDI: socio-demographic index.

For each study the proportions of liver cancer due to the four specific risk factors were calculated. Remaining risk factors related to underlying etiologies were included under a combined “attributable risks” group. Health risks and exposures were summarized in three categories (behavioral, environmental/occupational, and metabolic) with the data of 46,000 empirical data points on the basis of cohort studies and randomized controlled trials. Data on the Human Development Index (HDI) was also acquired from the United Nations Development Program (http://hdr.undp.org/en/data) in our study [17].

Statistical analysis

We used the age-standardized death rate (ASDR) and estimated annual percentage change (EAPC) to quantify the liver cancer death trends [18]. Age-standardization is necessary and representative when comparing in several populations with different age structures or for the same population over time.

The ASDR (per 100,000 population) in accordance with the direct method is calculated by summing up the products of the age-specific rates (ai represents the age-specific rate in the ith age group) and the number of persons (or weight) (wi) in the corresponding ith age group from among the selected reference standard population,, then dividing the sum of standard population weights, i.e.,

More importantly, the ASDR trends can serve as a good surrogate for shifting patterns of disease within a population, as well as clues to the changing risk factors. Consequently, we can assess the effectiveness of current prevention strategies and establish more targeted ones, if needed, based on the analyses in the ASDR [19].

Estimated annual percentage change (EAPC) is a reliable method and widely used measure for describing the magnitude of the trends in ASDR [20, 21]. A regression line was fitted to the natural logarithm of the rates. The EAPC and its 95% confidence interval (CI) were calculated using the linear regression model, i.e.,

y = α + βx + ε,

EAPC = 100×(exp(β) − 1)

where y = ln (ASDR) and x = calendar year. An increasing trend was determined if both EAPC and its 95% CI were > 0. Conversely, a decreasing trend was determined if both EAPC and its 95% CI were < 0. Other outcomes were considered to be “stable” over time. Additionally, in order to explore the impact factors of EAPC, the associations between EAPC and ASDR in 1990, and between EAPC and HDI in 2019 were explored at the national level, respectively. Data were analyzed using R v3.6.2 (R Institute for Statistical Computing, Vienna, Austria). A P value of less than 0.05 was deemed to be statistically significant.

Results

Trends Of Death Caused By Liver Cancer (Lc)

Globally, the LC caused 484.58×103 (95% uncertainty interval [UI]: 444.09 ×103 to 525.80×103) death worldwide in 2019, with an increase of 32.68% since 1990 (Table 1). The overall age-standardized death rate (ASDR) decreased by an average 2.23% per year from 1990 to 2019 (EAPC = − 2.23, 95% CI: −2.61 to − 1.84) (Table 1, Fig. 1). Increasing changes of death number occurred in those aged over 50 years, particularly in the group of > 80 years (202.62%) (Table 2, Fig. 2A). The decreasing trends of LC were observed in both sexes and most socio-demographic index (SDI) areas, particularly the high-middle SDI area (EAPC = − 3.69, 95% CI: −4.23 to − 3.15) (Table 1, Fig. 2B). In terms of geographic regions, the ASDR of LC showed increasing trends in nine regions, particularly Central Asia (EAPC = 2.93, 95%CI: 2.42 to 3.45) (Table 1). However, decreasing trends were demonstrated in eight regions, particularly East Asia (EAPC = − 4.98, 95%CI: −5.73 to − 4.22) (Fig. 2C).

Table 2

The number of death due to liver cancer caused by specific etiologies in 2019 and the percentage changes in number during 1990–2019 in age groups

Age Groups

LC

LCHB

LCHC

LCAL

LCNA

  

Number

×103(95% UI)

Change in number

(%)

Number

×103(95% UI)

Change in number

(%)

Number

×103(95% UI)

Change in number (%)

Number

×103(95% UI)

Change in number (%)

Number

×103(95% UI)

Change in number (%)

  

5 to 9

0.63

(0.52–0.75)

−15.53

0

0

0

0

0

0

0

0

10 to 14

0.93

(0.78–1.11)

−16.37

0.34

(0.26–0.43)

−37.00

0.01

(0.01–0.02)

−1.61

0

0

0

0

15 to 19

0.70

(0.62–0.79)

−45.64

0.37

(0.30–0.45)

−56.92

0.01

(0.01–0.02)

−19.20

0.01

(0-0.02)

−4.66

0.14

(0.1–0.19)

2.87

20 to 24

1.17

(1.05–1.3)

−46.46

0.75

(0.65–0.87)

−53.59

0.03

(0.02–0.05)

−18.53

0.05

(0.03–0.07)

5.53

0.15

(0.11–0.20)

0.56

25 to 29

2.33

(2.10–2.57)

−32.02

1.7

(1.45–1.96)

−37.00

0.08

(0.05–0.14)

−10.16

0.12

(0.07–0.20)

17.13

0.17

(0.12–0.25)

10.57

30 to 34

5.38

(4.78–6.05)

−21.95

4.10

(3.50–4.76)

−26.08

0.25

(0.17–0.36)

−2.27

0.34

(0.23–0.50)

20.70

0.27

(0.19–0.37)

16.16

35 to 39

8.99

(7.84–10.21)

−42.52

6.57

(5.44–7.77)

−47.01

0.59

(0.38–0.91)

−23.50

0.82

(0.51–1.25)

−2.49

0.40

(0.28–0.56)

−11.01

40 to 44

15.84

(13.81–18.10)

−28.78

11.06

(9.08–13.29)

−34.37

1.40

(0.96–1.92)

−12.30

1.74

(1.13–2.52)

9.07

0.68

(0.48–0.93)

3.10

45 to 49

26.19

(22.58–29.98)

−2.05

16.92

(13.64–20.87)

−10.33

3.15

(2.16–4.37)

12.33

3.45

(2.15–5.01)

39.08

1.20

(0.83–1.73)

35.52

50 to 54

40.26

(35.32–45.36)

8.02

23.07

(18.59–28.25)

−4.34

6.70

(4.86–8.81)

23.15

6.29

(4.09–9.02)

52.13

2.06

(1.44–2.94)

49.80

55 to 59

50.31

(45.15–56.27)

6.37

24.94

(19.96–30.86)

−9.85

10.79

(7.83–14.35)

16.75

9.30

(6.39–12.67)

56.85

2.84

(1.92–4.04)

49.42

60 to 64

59.69

(54.22–65.19)

18.78

25.60

(20.19–31.80)

−0.29

15.06

(11.15–19.69)

23.37

12.59

(8.83–16.83)

65.73

3.76

(2.58–5.41)

64.57

65 to 69

67.13

(61.81–72.56)

38.91

25.17

(19.45–31.42)

17.20

18.81

(14.96–22.83)

40.11

15.64

(11.64–20.56)

81.99

4.62

(3.26–6.56)

83.97

70 to 74

64.25

(59.36–69.4)

60.22

20.23

(14.99–25.75)

29.52

20.94

(16.98–24.99)

61.21

15.29

(11.4-20.14)

115.08

5.09(3.71–6.93)

106.67

75 to 79

55.89

(51.66–59.75)

79.51

14.76

(11.47–18.47)

49.36

21.51

(17.24–25.77)

77.74

11.98

(9.17–14.99)

126.15

5.25

(3.83–7.13)

125.23

> 80

83.15

(70.45–90.63)

202.62

16.15

(11.97–20.53)

149.70

42.46

(34.28–49.41)

210.77

13.12

(9.74–16.69)

241.84

8.09

(5.76–10.76)

257.80
LC: liver cancer; LCHB, liver cancer due to hepatitis B; LCHC, liver cancer due to hepatitis C; LCAL, liver cancer due to alcohol use; LCNA, liver cancer due to non-alcoholic steatohepatitis

Among the 204 countries/territories, Mongolia and Cameroon had the greatest ASR of death in 1990, while Guinea had the lowest (Fig. 3A, Supplementary table 1). Mongolia continues to have the highest ASR of death in the world in 2019, at 115.23 (91.48-142.48), followed by Gambia; Niger has the lowest ASR of death (Fig. 3B). The most pronounced increasing percentage in number occurred in Cabo Verde (1786.75%), whereas the largest decreasing change was seen in Poland (− 55.12%) (Fig. 3C). Decreasing trends were observed in ninety-one countries/territories of which, particularly in China, with the respective EAPC of − 5.06 (95% CI: −5.84 to − 4.27). On the other hand, increasing trends were seen in eighty-three countries/territories, and the largest ones were Armenia (EAPC = 9.56, 95% CI: 8.02 to 11.12), followed by Uzbekistan (Fig. 4, Supplementary table 1).

The trends of EAPC of death caused by liver cancer had a negatively association with ASDR at a national level in 1990 (ρ = −0.23, P = 0.001, Fig. 5A), but not with the Human Development Index (HDI) in 2019 (ρ = 0.18, P = 0.013, Fig. 5B). Similar correlations were also seen in the four etiologies of liver cancer (Supplementary Fig. 1A-D, Supplementary Fig. 2A-D). Overall, the decreasing trends of death due to liver cancer and its etiologies generally occurred in the countries with high HDI, while increasing trends were more common in countries with low HDI.

Trends of death caused by liver cancer due to hepatitis B (LCHB)

During the period 1990–2019, the death number of LCHB was 191.74×103 (95%UI: 161.86×103 to 223.73×103) worldwide in 2019, with an increase of 0.76% since 1990. The ASDR of LCHB showed a decreasing trend from 1990 to 2019 (EAPC = − 3.46, 95%CI: −4.01 to − 2.89) (Fig. 1, Supplementary table 2). In age groups, the highest death number of LCHB was seen in the group aged 60–64, and the increasing percentage changes occurred in those aged > 65 years (Table 2, Supplementary Fig. 3A). Decreasing trends of LCHB were observed in both sexes, most of SDI areas and geographic regions, particularly the high-middle SDI area and East Asia region, in which the respective EAPC were − 4.85 (95%CI: −5.54 to − 4.15) and − 5.11 (95%CI: −5.88 to − 4.33) (Supplementary Fig. 3B). However, the most pronounced increasing trends were seen in high-income North America and Australasia, with the respective EAPC were 2.34 (95%CI: 2.15 to 2.52) and 2.29 (95%CI: 2.08 to 2.50) (Supplementary Fig. 3C). At the national level, decreasing trends of LCHB were demonstrated in 113 countries/territories, particularly China (EAPC = − 5.17, 95% CI: −5.96 to − 4.37), followed by Saint Kitts and Nevis and Poland. On the contrary, increasing trends were observed in 72 countries/territories, particularly Uzbekistan and Armenia, in which the respective EAPC were 9.53 (95%CI: 8.31 to 10.77) and 9.21 (95%CI: 7.65 to 10.79) (Supplementary table 3, Supplementary Fig. 4A-C).

Trends of death caused by liver cancer due to hepatitis C (LCHC)

LCHC caused 141.81×103 (95%UI: 121.79×103 to 161.83×103) death in 2019, with an increase of 67.50% since 1990. Decreasing trend in ASDR of LCHC was observed worldwide from 1990 to 2019, in which the EAPC was − 1.35 (95%CI: −1.59 to − 1.11) (Fig. 1, Supplementary table 2). During the period 1990–2019, the death number of LCHC declined in the age groups under 65 years, while increased in those aged > 65 years (Table 2, Supplementary Fig. 5A). The trends of LCHC pronouncedly declined in SDI areas, expect the high SDI area (EAPC = 0.10, 95%CI: −0.37 to 0.58) (Supplementary table 2, Supplementary Fig. 5B). Among 21 geographic regions, increasing trends in ASDR were found in eleven regions, particularly Central Asia (EAPC = 3.28, 95%CI: 2.74 to 3.81). Whereas decreasing trends were seen in nine regions, and the most pronounced one was in East Asia (EAPC = − 4.92 (95%CI: −5.59 to − 4.24), Supplementary Fig. 5C). At the national level, decreasing trends of LCHC were seen in 92 countries/territories, particularly China (EAPC = − 5.07, 95%CI: −5.79 to − 4.35), followed by Poland and Bermuda. Whereas increasing trends occurred in 84 countries/territories, and the most pronounced ones were in Armenia and Uzbekistan, in which respective EAPC were 9.54 (95%CI: 7.99 to 11.12) and 9.03 (95%CI: 8.04–10.03) (Supplementary table 3, and Supplementary Fig. 6A-C).

Trends of death caused by liver cancer due to alcohol consumption (LCAL)

Globally, the death number of LCAL increased 89.60% since 1990, and was 90.74×103(73.35×103 to 109.4×103) in 2019. Decreasing trend in ASDR of LCAL was observed worldwide from 1990 to 2019, with the EAPC of − 0.68 (95%CI: −0.87 to − 0.49) (Fig. 1, Supplementary table 4). During the period 1990–2019, percentages in death number of LCAL increased in most age group, particularly the group of > 80 (241.84%) (Table 2, Supplementary Fig. 7A). The ASDR of LCAL showed decreasing trends in both sexes, and most SDI areas, expect the high SDI area (EAPC = 1.03 (95%CI: 0.79 to 1.26) (Supplementary table 4, and Supplementary Fig. 7B). Among 21 geographic regions, decreasing trend was found in six regions, particularly East Asia (EAPC = − 4.40, 95%CI: −5.19 to − 3.60). Whereas increasing trends were seen in thirteen regions, particularly Eastern Europe and Central Asia regions, in which the respective EAPC were 2.97 (95%CI: 2.66 to 3.28) and 2.94 (95%CI: 2.41 to 3.46) (Supplementary Fig. 7C). At the national level, the highest increase in death number of LCAL was observed in Cabo Verde (2060.08%), whereas the largest decreasing one was in Hungary (− 51.16%). Decreasing trends of LCAL were demonstrated in 81 countries/territories, particularly in China and Saint Kitts and Nevis, in which the respective EAPC were − 4.46 (95%CI: −5.28 to − 3.63), and − 4.42 (95%CI: −5.47 to − 3.36). However, increasing trends were seen in 100 countries/territories, and the most pronounced ones were Armenia and Uzbekistan, with the respective EAPC of 10.45 (95%CI: 8.85–12.08) and 10.06 (95%CI: 8.97 to 11.17) (Supplementary table 5, Supplementary Fig. 8A-C).

Trends of death caused by liver cancer due to non-alcoholic steatohepatitis (LCNA)

The death number of LCNA was 34.73×103 (95%UI: 28.39×103 to 43.18×103) globally in 2019, with an increase of 95.10% since 1990. The ASDR of LCNA showed a decreasing trend from 1990 to 2019 (EAPC = − 0.74, 95%CI: −1.02 to − 0.46) (Fig. 1, Supplementary table 4). The death number of LCNA increased in most age groups, particularly in those above 80 years (257.80%) (Table 2, Supplementary Fig. 9A). Decreasing trends of LCNA were observed in both sexes and most SDI areas, but increasing trend was observed in the high SDI area (EAPC = 1.45, 95%CI: 1.09 to 1.81) (Supplementary table 4, Supplementary Fig. 9B). Among 21 geographic regions, increasing trends were seen in fourteen regions, particularly Central Asia (EAPC = 4.14, 95%CI: 3.64 to 4.65). However, decreasing trends were observed in five regions, particularly East Asia (EAPC = − 4.10, 95%CI: −4.86 to − 3.32) (Supplementary Fig. 9C). At the national level, increasing trends were observed in 123 countries/territories, particularly Armenia and Uzbekistan, with the respective EAPC were 10.87 (95%CI: 9.25–12.51) and 10.39 (95%CI: 9.44–11.34). On the other hand, decreasing trends were seen in 56 countries//territories, and the pronounced ones were in Poland and China, with the respective EAPC were − 4.38 (95%CI: −5.73 to − 3.01) and − 4.20 (95%CI: −5.01 to − 3.39) (Supplementary table 5, Supplementary Fig. 10A-C).

Trends in underlying etiologies attributable risks-related death caused by LC

During the period 1990–2019, decreasing trends were observed in smoking-, alcohol use-, and drug use-related death caused by LC worldwide particularly smoking-related (EAPC = − 2.62, 95%CI: −3.06 to − 2.16, Table 3, Fig. 6A). However, increasing trend was seen in the high body-mass index (BMI)-related one (EAPC = 0.31, 95%CI: 0.05 to 0.58)) (Table 3, Fig. 6A). After stratified analysis, we found that the overall rate of death caused by liver cancer by attributable risks in different age groups in 2019 demonstrated an increase in mortality with increasing age groups when compared to the results in 1990 (Fig. 7A). In the over-80s group in particular, there was a clear trend towards an increasing number of deaths due to the four attributable risks, particularly alcohol use and drug use (Fig. 7A). Compared with females, males had more pronounced decreasing trends in risks-related death of LC, particularly smoking-related one (EAPC = − 2.73, 95%CI: −3.19 to − 2.26) (Table 4, Fig. 6B and 6C ). Smoking is the most important contributory risk among male, while drug use is the most significant contributory risk among women (Figs. 7B and 7C).

Table 3

The number and age-standardized rate of death caused by liver cancer and underlying etiologies in risks globally, in both sexes, in 1990 and 2019, and percentage changes in number and the EAPCs from 1990 to 2019
 

1990

2019

1990 − 2019

Characteristics

Number

×103 (95% UI)

ASR per 100k

(95% UI)

Number

×103 (95% UI)

ASR per 100k

(95% UI)

Change in number (%)

EAPC

(95%CI)

LC

            

Smoking

66.46(36.89–95.85)

1.64(0.91–2.36)

85.88(50.01-122.99)

1.04(0.61–1.49)

29.23

−2.62(− 3.06-−2.16)

Alcohol use

54.07(42.16–67.93)

1.34(1.05–1.67)

96.05(77.51-116.17)

1.17(0.94–1.41)

77.66

−0.98(− 1.22-−0.74)

Drug use

38.52(28.99–49.48)

0.96(0.72–1.23)

71.45(57.09–89.24)

0.88(0.71–1.1)

85.48

−1.19(− 1.57-−0.81)

High fasting plasma glucose

1.99(0.45–4.43)

0.05(0.01–0.11)

4.73(1.15–10.41)

0.06(0.01–0.13)

137.15

−0.17(− 0.43 − 0.1)

High body-mass index

23.18(6.96–52.46)

0.57(0.17–1.29)

60.8(24.24-114.62)

0.74(0.29–1.39)

162.34

0.31(0.05–0.58)

LCHB

            

Smoking

36.89(19.39–55.63)

0.89(0.47–1.33)

38.07(20.93–56.37)

0.46(0.25–0.67)

3.20

−3.72(− 4.35-−3.09)

Alcohol use

5.58(0.15–14.60)

0.12(0-0.33)

4.58(0.2-11.74)

0.05(0-0.14)

−17.92

−4.52(− 5.34-−3.69)

Drug use

1.76(1.10–2.68)

0.04(0.03–0.06)

3.12(2.1–4.6)

0.04(0.03–0.06)

77.42

−1.44(− 1.94-−0.95)

High body-mass index

10.8(2.69–26.45)

0.25(0.06–0.62)

24.07(8.74–48.33)

0.29(0.1–0.58)

122.95

−0.57(− 1.04-−0.1)

LCHC

            

Smoking

14.09(7.72–19.94)

0.37(0.2–0.52)

21.95(12.52–31.73)

0.27(0.16–0.39)

55.74

−1.74(− 2.07-−1.41)

Alcohol use

0.63(0.01–2.25)

0.02(0-0.06)

0.73(0.01–2.65)

0.01(0-0.03)

16.52

−3.34(− 3.91-−2.78)

Drug use

36.76(27.51–47.29)

0.91(0.69–1.18)

68.33(54.6–85.4)

0.84(0.67–1.05)

85.87

−1.18(− 1.55-−0.8)

High body-mass index

6.59(2.13–14.13)

0.17(0.06–0.37)

19.07(7.58–35.43)

0.24(0.09–0.44)

189.50

0.77(0.6–0.95)

LCAL

            

Smoking

10.22(5.65–15.05)

0.26(0.14–0.38)

17.66(9.74–26.16)

0.21(0.12–0.32)

72.78

−1.12(− 1.33-−0.91)

Alcohol use

47.86(38.59–58.61)

1.2(0.97–1.46)

90.74(73.35–109.4)

1.1(0.89–1.33)

89.60

−0.68(− 0.87-−0.49)

High body-mass index

4.55(1.56–9.70)

0.11(0.04–0.24)

14.64(5.56–28.32)

0.18(0.07–0.34)

221.53

1.37(1.28–1.46)

LCNA

            

Smoking

2.58(1.42–3.87)

0.07(0.04–0.10)

4.96(2.79–7.54)

0.06(0.03–0.09)

92.28

−1.04(− 1.38-−0.71)

High fasting plasma glucose

1.02(0.24–2.29)

0.03(0.01–0.06)

3.04(0.74–6.87)

0.04(0.01–0.09)

196.45

0.69(0.48–0.89)
LCHB, liver cancer due to hepatitis B; LCHC, liver cancer due to hepatitis C; LCAL, liver cancer due to alcohol use; LCNA, liver cancer due to non − alcoholic steatohepatitis; EAPC: estimated annual percentage change; ASR, age-standardized rate; CI, confidence interval.

Table 4

The age-standardized rate of liver cancer death attributed to risks globally in sexes and 2019, and percentage changes in number and the EAPCs from 1990 to 2019
 

Male

Female

Characteristics

ASR per 100k

No. (95% UI)

Change in number (%)

EAPC

No.(95%CI)

ASR per 100k

No. (95% UI)

Change in number (%)

EAPC

No.(95%CI)

LC

            

Smoking

2.02(1.18–2.87)

26.50

−2.73(− 3.19-−2.26)

0.19(0.10–0.30)

60.75

−1.36(− 1.59-−1.13)

Alcohol use

2.01(1.64–2.42)

83.67

−0.88(− 1.13-−0.64)

0.44(0.34–0.55)

57.10

−1.34(− 1.55-−1.13)

Drug use

1.13(0.92–1.38)

83.75

−1.23(− 1.63-−0.82)

0.67(0.50–0.88)

87.99

−1.11(− 1.45-−0.76)

High fasting plasma glucose

0.07(0.01–0.16)

165.46

0.07(− 0.25–0.39)

0.05(0.01–0.12)

112.21

−0.41(− 0.63-−0.19)

High body-mass index

1.19(0.40–2.41)

172.72

0.41(0.12–0.70)

0.33(0.06–0.74)

134.06

0.06(− 0.10–0.23)

LCHB

            

Smoking

0.92(0.52–1.35)

2.52

−3.76(− 4.40-−3.13)

0.03(0.02–0.05)

24.94

−2.41(− 2.74-−2.09)

Alcohol use

0.11(0-0.28)

−18.06

−4.49(− 5.31-−3.66)

0

18.43

−2.23(− 2.77-−1.69)

Drug use

0.07(0.05–0.10)

73.04

−1.59(− 2.13-−1.05)

0.01(0.01–0.02)

110.32

−0.14(− 0.32 − 0.04)

High body-mass index

0.51(0.17–1.06)

129.42

−0.51(− 1.00-−0.01)

0.08(0.01–0.18)

91.44

−0.81(− 1.11-−0.51)

LCHC

            

Smoking

0.49(0.28–0.71)

52.96

−1.87(− 2.21-−1.52)

0.1(0.05–0.15)

68.44

−1.23(− 1.48-−0.99)

Alcohol use

0.02(0-0.06)

6.80

−3.55(− 4.14-−2.95)

0(0-0.01)

99.20

−1.35(− 2.00-−0.71)

Drug use

1.06(0.86–1.30)

84.53

−1.21(− 1.60-−0.81)

0.66(0.49–0.87)

87.69

−1.12(− 1.46-−0.77)

High body-mass index

0.31(0.10–0.62)

213.22

1.02(0.80–1.23)

0.17(0.03–0.37)

159.09

0.45(0.31–0.58)

LCAL

            

Smoking

0.43(0.24–0.63)

73.54

−1.18(− 1.4-−0.97)

0.03(0.01–0.05)

63.43

−1.03(− 1.13-−0.93)

Alcohol use

1.88(1.53–2.27)

100.72

−0.52(− 0.7-−0.34)

0.44(0.33–0.55)

56.95

−1.34(− 1.55-−1.13)

High body-mass index

0.32(0.11–0.63)

239.37

1.49(1.40–1.58)

0.05(0.01–0.12)

151.92

0.54(0.45–0.62)

LCNA

            

Smoking

0.11(0.06–0.16)

89.65

−1.24(− 1.62-−0.87)

0.02(0.01–0.04)

103.35

−0.38(− 0.57-−0.20)

High fasting plasma glucose

0.04(0.01–0.10)

234.67

0.91(0.66–1.17)

0.03(0.01–0.08)

163.91

0.46(0.30–0.62)
LCHB, liver cancer due to hepatitis B; LCHC, liver cancer due to hepatitis C; LCAL, liver cancer due to alcohol use; LCNA, liver cancer due to non-alcoholic steatohepatitis; EAPC: estimated annual percentage change; ASR, age-standardized rate; CI, confidence interval.

In the SDI level, smoking- and alcohol consumption-related death of LC showed decreasing trends in most SDI areas, and the largest one was smoking-related death in high-middle SDI area (EAPC = − 3.91, 95%CI: −4.52 to − 3.29, Table 5). Whereas high fasting plasma glucose- and high BMI-related death presented increasing trends in most of SDI areas, particularly the high fasting plasma glucose-related deaths in high SDI area (EAPC = 2.82, 95%CI: 2.58 to 3.06). During the period 1990–2019, smoking-, alcohol use- and drug use-related death caused by four specific etiologies showed decreasing trends worldwide, and in both sexes, and most SDI areas, particularly the one caused by LCHB in the high-middle SDI area (EAPC = − 5.59, 95%I: −6.48 to − 4.69) (Table 5, Supplementary Fig. 11A, Supplementary Fig. 12). In terms of drug use, the most pronounced decreasing trend was observed in the etiology of LCHC in middle SDI area (EAPC = − 2.85, 95%CI: −3.51 to − 2.18). Whereas the increasing trends mainly occurred in low- and high- SDI areas, particularly in the four specific etiologies of LCHB in high SDI area, with EAPC of 2.17(95%CI: 1.94 to 2.40) (Table 5, Supplementary Fig. 11B, Supplementary Fig. 13). However, high BMI- and high fasting plasma glucose-related death caused by four specific etiologies showed increasing trends worldwide, and in both sexes, and most SDI areas. The most pronounced increasing trends were observed in the high fasting plasma glucose-related death caused by LCNA in high SDI area, with the EAPC of 3.11 (95%CI: 2.84 to 3.38) (Table 5, Supplementary Fig. 11C, Supplementary Fig. 14). In terms of high BMI, the largest decreasing trend was observed in the etiology of LCAL in low-middle SDI area (EAPC = 2.57, 95%CI: 2.41 to 2.73) (Table 5, Supplementary Fig. 11D, Supplementary Fig. 15).

Table 5

The EAPCs of death due to liver cancers underlying etiologies in attributable risks in SDI quintiles from 1990 to 2019
 

Low SDI

Low-middle SDI

Middle SDI

High-middle SDI

High SDI

Characteristics

EAPC (95%CI)

EAPC (95%CI)

EAPC (95%CI)

EAPC (95%CI)

EAPC (95%CI)

LC

          

Smoking

−0.65(− 0.76-−0.55)

−2.21(− 2.61-−1.81)

−3.35(− 3.94-−2.75)

−3.91(− 4.52-−3.29)

−0.45(− 0.89-−0.01)

Alcohol use

−0.17(− 0.23-−0.11)

−0.48(− 0.67-−0.28)

−1.76(− 2.21-−1.31)

−2.26(− 2.61-−1.92)

0.90(0.65–1.15)

Drug use

1.21(1.09–1.33)

−0.33(− 0.59-−0.08)

−2.82(− 3.48-−2.15)

−2.54(− 3.03-−2.05)

1.78(1.41–2.15)

High fasting plasma glucose

1.11(1.01–1.20)

0.34(0.10–0.58)

−1.30(− 1.75-−0.84)

−1.91(− 2.26-−1.56)

2.82(2.58–3.06)

High body-mass index

1.62(1.57–1.67)

1.31(1.07–1.56)

0.05(− 0.37–0.47)

−1.02(− 1.38-−0.66)

1.70(1.35–2.04)

LCHB

          

Smoking

−0.88(− 1.02-−0.74)

−3.11(− 3.67-−2.56)

−4.09(− 4.78-−3.41)

−5.05(− 5.82-−4.27)

−0.47(− 1.08–0.13)

Alcohol use

−0.73(− 0.94-−0.52)

−4.31(− 5.23-−3.38)

−4.48(− 5.39-−3.56)

−5.59(− 6.48-−4.69)

−1.68(− 2.33-−1.04)

Drug use

1.03(0.91–1.14)

−1.61(− 2.16-−1.05)

−2.11(− 2.73-−1.49)

−2.66(− 3.33-−1.98)

2.17(1.94–2.40)

High body-mass index

1.37(1.33–1.42)

0.47(0.08–0.86)

−0.75(− 1.34-−0.16)

−1.89(− 2.47-−1.31)

1.42(0.96–1.89)

LCHC

          

Smoking

−0.66(− 0.75-−0.58)

−1.25(− 1.44-−1.07)

−2.37(− 2.79-−1.94)

−2.74(− 3.18-−2.31)

−1.04(− 1.55-−0.54)

Alcohol use

−0.87(− 0.96-−0.78)

−3.46(− 4.35-−2.56)

−4.48(− 5.54-−3.41)

−5.26(− 6.12-−4.39)

−2.71(− 3.40-−2.01)

Drug use

1.22(1.10–1.34)

−0.26(− 0.50-−0.03)

−2.85(− 3.51-−2.18)

−2.53(− 3.01-−2.05)

1.77(1.39–2.14)

High body-mass index

1.56(1.49–1.63)

1.82(1.69–1.95)

0.82(0.62–1.01)

−0.43(− 0.63-−0.22)

1.31(0.91–1.71)

LCAL

          

Smoking

−0.49(− 0.58-−0.4)

−1.02(− 1.24-−0.79)

−1.72(− 2.10-−1.34)

−2.07(− 2.37-−1.78)

0.28(0.02–0.54)

Alcohol use

−0.17(− 0.23-−0.1)

−0.33(− 0.49-−0.16)

−1.41(− 1.80-−1.03)

−1.90(− 2.18-−1.62)

1.03(0.79–1.26)

High body-mass index

2.13(2.09–2.17)

2.57(2.41–2.73)

1.68(1.43–1.92)

0.06(− 0.07–0.19)

2.36(2.15–2.57)

LCNA

          

Smoking

−0.12(− 0.21-−0.03)

−1.04(− 1.3-−0.77)

−1.7(− 2.18-−1.21)

−2.41(− 2.93-−1.88)

0.74(0.39–1.09)

High fasting plasma glucose

1.21(1.11–1.31)

0.98(0.8–1.16)

−0.28(− 0.67 − 0.11)

−0.96(− 1.24-−0.68)

3.11(2.84–3.38)
LCHB, liver cancer due to hepatitis B; LCHC, liver cancer due to hepatitis C; LCAL, liver cancer due to alcohol use; LCNA, liver cancer due to non-alcoholic steatohepatitis; EAPC: estimated annual percentage change; ASR, age-standardized rate; CI, confidence interval.

Discussion

The GBD study from 1990 to 2017 by Lin L et al. [22] showed that the global liver cancer incidence and mortality had been increasing. Similarly, the ASIR (age standardized incidence rate) of liver cancer due to hepatitis B, hepatitis C, and other causes increased between 1990 and 2016 with EAPC in 0.22 (95%CI 0.08 − 0.36), 0.57 (95%CI 0.48 − 0.66), and 0.51 (95%CI 0.41 − 0.62), respectively by Liu Z et al. [20]. However, our study revealed that total liver cancer and etiology-specific liver cancer cases all showed a decreasing trend in mortality from 1990 to 2019 globally. This decrease might be driven by reductions in aflatoxin exposure, increasing hepatitis B vaccination rates and the cumulative effect of hepatitis B viral suppression from new-generation anti-viral agents, such as entecavir and tenofovir [23]. Additionally, our study did not include estimates of the subnational (provincial or regional) or other potential factors (economic status, non-alcoholic fatty liver disease, obesity and smoking).

For etiology-specific liver cancer cases, the magnitude and rate of decline were more pronounced for liver cancer attributable to HBV and HCV than for liver cancer attributable to other etiologies. Obviously, the most rapid decline in LC, LCHB and LCHC cases occurred between 2000 and 2005. There were recent upward trends in liver cancer due to underlying etiologies attributable to high body-mass index (BMI), especially in LCHB cases. Metabolic risk factors for liver cancer will continue to increase in prevalence and may become the dominant risk factor in the next 5 years in western populations.

Chronic HBV infection has been widely acknowledged as the leading cause of liver cancer worldwide [24]. Considerable progress had achieved in the etiology prevention and therapeutic measures of LC over the past decades. Under the recommendation of World Health Organization, Hepatitis B vaccine for infants were available in 186 countries by 2016, and coverage with the full recommended dose was estimated more than 80% worldwide [25]. Effective prevention of HBV has dramatically declined the incidence of LC in high-risk countries/territories [26]. Meanwhile, liver ultrasonography was the most common LC surveillance test, which was widely available to the high-risk population in many countries [27]. Among the HBsAg carriers, semiannual alpha-fetoprotein (AFP) was sensitive in LC detection, and significantly prolonged survival rates [28]. Chronic HCV infects over 170 million people worldwide. Chronic infection occurs in 50–80% of cases and eventually leads to cirrhosis and hepatocellular carcinoma [29]. Although preventive vaccine of HCV was unavailable recently, advance in HCV treatment reduced the incidence and mortality of LC [8, 30, 31]. These also could explain the decreasing trends of death caused by LCHB and LCHC. However, the overall trends of death caused by LC and its underlying etiologies declined slowly, probably due to population growth and aging [4, 32], and the alarming prevalence of unhealthy lifestyle, and metabolic disorders [33, 34].

Increasing trends of death caused by LCNA were seen in most geographic regions, particularly in Australasia and Central Asia region. Studies reported that nonalcoholic fatty liver disease promoted the rapidly increase in the LC death [35, 36], and unsatisfied survival for LC patients [8, 37]. High fasting plasma glucose-related caused by LCNA had increasing trends in high SDI and low SDI area, which probably were explained by the high prevalence of obesity, and metabolic syndromes in these areas [38]. Injecting drug use were likely drivers for the spread of the HCV epidemics in North America and Australia [39, 40]. In addition, the injecting drug use-related HCV burden was highest in these high-income countries [41], which explained why the pronounced increasing trends of drug use-related death caused by LCHC occurred in high SDI area. In conclusion, the low HDI countries generally had a higher burden and worse outcomes than the high HDI countries, which also explained why EAPC had a negative relationship with HDI.

At the national level, the most pronounced decreasing trends of death caused by LC were observed in China, which was mainly due to the effective medical-care system [42], particularly the universal coverage of HBV vaccination over the past decades [43, 44]. Meanwhile, a web-based surveillance system well protected children and adolescents from HBV infection across 31 provinces in China over 11 years [45]. In Poland, the HBV and HCV infections were well managed using Epidemiological Interview Registration System (SRWE) from 1997 to 2018 [46, 47]. The newborns covered by obligatory hepatitis B vaccinations after 1994, and the third HBV vaccine dose covered 91% of children aged two years [47]. Meanwhile, primary prevention activities emphasized the safer medical procedures and reduction for people who inject drugs [48].

However, the ASDR of LC and underlying etiologies showed the largest increasing trends in Armenia and Uzbekistan. Two retrospective cohort studies found that high mortality due to liver cancer was associated with the chloroprene exposure in Armenia in 1990s. Meanwhile, high prevalence of inject drugs and HCV and HIV in the youths, which were daunting challenges [49, 50]. Furthermore, a cross-sectional study reported that alcohol use was frequent in Armenia [51]. In Uzbekistan, the seroprevalence of HBV and HCV infections was high, and the transmission of HCV was common in medical treatment and drug abusers [52]. The disease burden study of hepatitis B in Uzbekistan brought a huge health problem, especially in young adults [53]. Therefore, the highest increasing trend in ASDR of LCHB demands a long-term vision and cost-effective intervention in the high-risk countries. Additionally, strategies to address the other well-established risk factors such as promoting widespread public education, interrupting mother-to-infant transmission, monitoring of blood donors and blood products, improving the proportions of the age structure and implementing annual surveillance should be prioritised.

There were still several limitations in this study. First, the GBD death estimates depend upon the quality and quantity of data, and potential bias due to misclassification and miscoding, which probably affected the accuracy and reliability of the findings. Second, the diagnostic standards of LC and underlying etiologies had refined over time, which complicated the trends estimation of LC. Last but not least, in terms of death caused by LC and four etiologies, only five attributable risks were available in the GBD estimates, but there certainly existed other potential risk factors, so risk-related trends cannot be fully assessed. Analysis on birth-cohort effects and others were not involved. Better primary data from a national wide-coverage observational study or cancer registry on liver cancer burden are needed in the future.

Conclusions

The decreasing trends in death caused by liver cancer and underlying etiologies were observed worldwide from 1990 to 2019. However, increasing trends occurred in low-resource regions and countries. The trends of drug use- and high BMI-related death caused by liver cancer and underlying etiologies were alarming. The findings highlighted that actions should be intensified to reduce the liver cancer death by effective control of etiologies and risk management.

Abbreviations

LC: liver cancer; LCHB, liver cancer due to hepatitis B; LCHC, liver cancer due to hepatitis C; LCAL, liver cancer due to alcohol consumption; LCNA, liver cancer due to non-alcoholic steatohepatitis; GBD: Global Burden of Disease; DALYs: Disability-adjusted life years; ASDR: Age-standardized death rate; UI: Uncertainty interval; CI: Confidence interval; EAPC: Estimated annual percentage change; GHDx: Global Health Data Exchange; SDI: Socio-demographic index.

Declarations

Ethics approval and consent to participate

The study was approved by the ethics committee of Southern Medical University. As data are available in a public, open access repository, consent to participate are not applicable.

Consent for publication 

Not applicable.

Availability of data and materials

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

Competing interests

The authors declared that they have no competing interests.

Funding

Not applicable.

Authors' contributions

Yongzhi Li, Zejin Ou: Project administration and drafting. Danfeng Yu, Huan He: Data analysis and validation. Liting Zheng, Jiaqi Chen: Data analysis and visualization. Caiyun Chen, Hushen Xiong: Data collection and collation. Qing Chen: supervision and drafting and editing.

Acknowledgements

The authors thanks to the Institute for Health Metrics and Evaluation (IHME), Washington University, and the Global Burden of Disease study collaborations.

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