Introduction: The etiology of liver diseases has changed significantly, but its impact on the comparative burden of cirrhosis between males and females is unclear. We estimated sex differences in the burden of cirrhosis across 204 countries and territories from 2010 to 2019. Methods: We analyzed temporal trends in the burden of cirrhosis using the methodology framework of the 2019 Global Burden of Disease study. We estimated annual frequencies and age-standardized rates (ASRs) of cirrhosis incidence, death, and disability-adjusted life-years (DALYs) by sex, region, country, and etiology. Results: In 2019, the frequency of incident cases, deaths, and DALYs due to cirrhosis was 1,206,125, 969,068, and 31,781,079 in males versus 845,429, 502,944, and 14,408,336 in females, respectively. From 2010 to 2019, the frequency of cirrhosis deaths increased by 9% in males and 12% in females. Incidence ASRs remained stable in males but increased in females, while death ASRs declined in both. Death ASRs for both sexes declined in all regions, except in the Americas where they remained stable. In 2019, alcohol was the leading cause of cirrhosis deaths in males, and hepatitis C in females. Death ASRs declined for all etiologies in both sexes, except in nonalcoholic steatohepatitis (NASH). The ratio of female-to-male incidence ASRs in 2019 was lowest in alcohol(0.5), and highest in NASH(1.3), while the ratio of female-to-male death ASRs was lowest in alcohol(0.3) and highest in NASH(0.8). Conclusion: The global burden of cirrhosis is higher in males. However, incidence and death ASRs from NASH cirrhosis in females are comparable to that of males.

Cirrhosis is a major cause of mortality in patients suffering from chronic liver disease [1]. Complications associated with cirrhosis include ascites, hepatic encephalopathy, hepatorenal syndrome, and hepatocellular carcinoma [2‒5]. The major etiologies for cirrhosis include hepatitis B virus (HBV), hepatitis C virus (HCV), alcohol, and nonalcoholic steatohepatitis (NASH) [6‒8]. However, the global epidemiology of cirrhosis has changed in the last decade [7]. Increasing uptake of vaccination for HBV and availability of direct-acting antivirals (DAAs) have led to a decline in the disease burden contributed by HBV- and HCV-associated cirrhosis, respectively [9‒12]. By contrast, the burden of NASH- and alcohol-associated cirrhosis may have increased, in parallel with the global obesity epidemic and the rising prevalence of metabolic syndrome [6, 13‒15]. However, the impact of these changes in the etiology of liver diseases on the comparative burden of cirrhosis between males and females is unclear.

Prior studies indicate that males have a higher disease burden from HBV-, HCV-, and alcohol-associated cirrhosis, compared to females [16‒18]. However, emerging data suggest that the differences in the burden of cirrhosis may be less pronounced in NASH, with several country-specific studies even reporting a higher risk of progression to advanced fibrosis in females [19]. However, a comprehensive, updated global overview of the comparative burden of cirrhosis between males and females has not been reported. Herein, we report sex differences in the temporal trends of cirrhosis (and other chronic liver diseases) incidence, mortality, and disability-adjusted life-years (DALYs), and the contributions of various liver disease etiologies across 204 countries and territories from 2010 to 2019.

Data Source

This study used data from the Global Burden of Disease Study 2019 (GBD 2019), an international collaborative effort to estimate the burden caused by 369 diseases and 87 risk factors in 204 countries/territories [20]. Data were extracted using the Global Health Data Exchange (GHDx) online query tool (http://ghdx.healthdata.org/gbd-results-tool), a data catalog designed and maintained by the Institute for Health Metrics and Evaluation (IHME). The age-standardized rates (ASRs) of incidence, deaths, and DALYs attributed to cirrhosis and other chronic liver diseases (hereafter collectively referred to as cirrhosis as previously described [7]), stratified by sex, World Health Organization (WHO) region, sociodemographic index (SDI), and country/territory from 2010 to 2019 were also extracted for analysis.

Estimation Methods in the GBD 2019 Study

The methodology used to estimate the disease burden of cirrhosis in the GBD 2019 study has been previously described [6, 20]. Briefly, the International Classification of Diseases Ninth Revision (ICD-9) and ICD Tenth Revision (ICD-10) codes were used to identify cirrhosis [21]. Data for cirrhosis-related mortality were estimated primarily from vital registration systems or verbal autopsy studies from each country/territory [20]. Quality assessment for the data from each county/territory was rated on a scale ranging from 0 (lowest quality) to 5 (highest quality) and is presented in Supplementary material 1 (for all online suppl. material, see https://doi.org/10.1159/000533946).

Multiple statistical methods including misclassification correction, garbage code redistribution, and noise reduction algorithms were utilized to minimize heterogeneity. Cirrhosis-associated mortality by age, sex, country/territory, and year was derived via a Cause of Death Ensemble model, a form of Bayesian geospatial regression analysis. The incidence of cirrhosis for each subgroup was calculated by dividing mortality estimates by the corresponding mortality-to-incidence ratios. DALYs were quantified as the sum of years of life lost and years lived with disability [20]. Mortality estimates for the various etiologies of cirrhosis were derived from a systematic literature search performed by GBD and included population-based studies by the GBD collaborators for five etiologies of cirrhosis: HBV, HCV, alcohol, NASH, and other causes of liver disease. The proportion of cirrhosis due to the five defined etiologies was determined by using aggregated population data from existing literature in five separate DisMod-MR 2.1 models (a Bayesian meta-regression-type model), with further stratified analysis by age, sex, location, and year. As the estimates for disease burden of cirrhosis by age, sex, location, and year were run independently for each etiology, the estimates for each etiology were scaled to sum to 100% by dividing each proportion by the sum of the five proportion estimates for all etiologies of cirrhosis. SDI was used to categorize countries/territories by development status, an indicator examining total fertility rate, average educational attainment in the population over age 15, and measures of income per capita (online suppl. material 2).

Data and Statistical Analysis

ASRs were derived using the direct method to the GBD 2019 population estimate with 5-year age groups [20]. All epidemiological measures were reported with 95% uncertainty intervals (UIs), which were defined as the 2.5th and 97.5th ranked values across a total of 1,000 draws from a posterior distribution. The percentage change in any category from 2010 to 2019 was calculated by dividing the difference in values between 2010 and 2019 by the original value in 2010. The temporal change in ASRs from 2010 to 2019 was estimated by calculating the annual percentage change (APC) and corresponding 95% CIs using the Joinpoint Regression Program, version 4.6.0.0 (Statistical Research and Applications Branch, National Cancer Institute). When the APC and the lower boundary of the 95% CI were both positive, this was considered an increasing trend. When the APC and the upper boundary of the 95% CI were both negative, this was considered a decreasing trend. A neutral trend was considered when the 95% CI crossed zero. The ratio of female-to-male ASRs for cirrhosis-related incidence and deaths was analyzed by country/territory, WHO region, and etiology of liver disease. Statistical analyses were conducted using Rstudio (Version 4.1.1).

Sex Differences in the Global Burden of Cirrhosis in 2019

Globally in 2019, the overall burden of cirrhosis was higher in males compared to females. There were 1,206,125 incident cases, 969,068 deaths, and 31,781,079 DALYs due to cirrhosis in males, and 845,429 incident cases, 502,944 deaths, and 14,408,336 DALYs due to cirrhosis in females, respectively. In 2019, the estimated age-standardized incident rates (ASIRs), age-standardized death rates (ASDRs), and age-standardized DALYs (ASDALYs) of cirrhosis in 2019 were 29.67 per 100,000 (95% UI: 23.86–35.98), 24.81 per 100,000 (95% UI: 23.07–26.75), and 783.31 per 100,000 (95% UI: 723.85–849.07) in males, and 20.91 per 100,000 (95% UI: 17.22–25.15), 11.70 per 100,000 (95% UI: 10.68–12.81), and 343.96 per 100,000 (95% UI: 313.74–376.74) in females, respectively (Tables 1-3).

Table 1.

Age-standardized incidence rates of cirrhosis in 2010 and 2019, and the temporal trend of age-standardized incident rates from 2010 to 2019; stratified by sex

MaleFemale
2010 ASIR, per 100,000 (95% UI)2019 ASIR, per 100,000 (95% UI)annual percentage change in ASIR (95% CI)2010 ASIR, per 100,000 (95% UI)2019 ASIR, per 100,000 (95% UI)annual percentage change in ASIR (95% CI)
Global 29.81 (24.77–35.32) 29.67 (23.86–35.98) −0.04 (−0.19 to 0.11) 20.49 (17.34–23.93) 20.91 (17.22–25.15) 0.26 (0.18–0.34) 
Sociodemographic index 
 High SDI 28.89 (25.93–31.9) 26.44 (22.84–30.14) −0.97 (−1.01 to −0.93) 21.80 (19.85–23.85) 21.26 (18.65–24.01) −0.26 (−0.36 to −0.16) 
 High-middle SDI 32.02 (26.94–37.63) 30.85 (25.14–37.08) −0.44 (−0.53 to −0.36) 18.98 (16.26–22.04) 18.63 (15.47–22.17) −0.17 (−0.41 to 0.07) 
 Middle SDI 29.93 (24.07–36.23) 30.22 (23.63–37.15) 0.15 (−0.09–0.39) 20.82 (17.16–24.91) 21.22 (17.05–25.71) 0.20 (0.08–0.32) 
 Low-middle SDI 28.35 (22.18–35.17) 29.50 (22.55–37.09) 0.48 (0.32–0.64) 19.62 (15.57–24.19) 21.07 (16.32–26.48) 0.81 (0.73–0.89) 
 Low SDI 23.35 (18.11–28.85) 25.47 (19.39–31.86) 1.06 (0.87–1.25) 21.80 (16.96–27.68) 22.77 (17.20–29.47) 0.49 (0.45–0.52) 
Region 
 Africa 25.27 (19.76–31.29) 28.18 (21.42–35.34) 1.28 (1.04–1.51) 21.28 (16.72–26.81) 22.48 (17.06–28.9) 0.64 (0.58–0.66) 
 Eastern Mediterranean 25.19 (20.79–30.25) 27.09 (21.99–33.42) 0.78 (0.71–0.85) 32.91 (26.21–40.94) 34.45 (26.92–43.79) 0.45 (0.32–0.59) 
 Europe 37.64 (33.67–42.12) 35.59 (31.09–40.7) −0.73 (−0.87 to −0.59) 23.34 (21.02–25.81) 22.45 (19.6–25.29) −0.44 (−0.52 to −0.36) 
 Americas 33.10 (28.11–38.35) 32.76 (26.40–39.66) 0.04 (−0.17–0.25) 22.35 (19.65–25.09) 23.43 (19.95–27.1) 0.62 (0.34–0.90) 
 South-East Asia 27.77 (20.73–35.56) 28.58 (20.68–37.29) 0.35 (0.17–0.54) 16.74 (12.69–21.25) 17.91 (13.21–23.18) 0.81 (0.67–0.95) 
 Western Pacific 28.24 (22.53–34.28) 28.06 (22.04–34.19) −0.02 (−0.30 to 0.26) 18.11 (14.84–21.61) 17.80 (14.37–21.68) −0.18 (−0.44 to 0.08) 
Etiology 
 Alcohol 6.93 (5.2–8.84) 7.10 (5.11–9.39) 0.55 (0.12–0.99) 3.22 (2.41–4.18) 3.35 (2.38–4.51) 0.67 (0.34–1.01) 
 Hepatitis B 7.41 (5.48–9.53) 6.25 (4.34–8.34) −1.95 (−2.30 to −1.61) 4.11 (3.07–5.3) 3.54 (2.46–4.75) −1.73 (−2.10 to −1.36) 
 Hepatitis C 7.81 (5.98–9.87) 8.20 (6.12–10.64) 0.57 (0.53–0.60) 4.79 (3.69–5.97) 5.10 (3.79–6.58) 0.69 (0.64–0.73) 
 NASH 1.32 (0.84–2.03) 1.43 (0.90–2.23) 1.05 (0.93–1.17) 1.65 (1.09–2.4) 1.82 (1.17–2.71) 1.26 (1.14–1.39) 
 Other causes 6.34 (4.99–7.92) 6.69 (5.18–8.49) 0.57 (0.55–0.59) 6.71 (5.43–8.13) 7.10 (5.64–8.74) 0.63 (0.59–0.68) 
MaleFemale
2010 ASIR, per 100,000 (95% UI)2019 ASIR, per 100,000 (95% UI)annual percentage change in ASIR (95% CI)2010 ASIR, per 100,000 (95% UI)2019 ASIR, per 100,000 (95% UI)annual percentage change in ASIR (95% CI)
Global 29.81 (24.77–35.32) 29.67 (23.86–35.98) −0.04 (−0.19 to 0.11) 20.49 (17.34–23.93) 20.91 (17.22–25.15) 0.26 (0.18–0.34) 
Sociodemographic index 
 High SDI 28.89 (25.93–31.9) 26.44 (22.84–30.14) −0.97 (−1.01 to −0.93) 21.80 (19.85–23.85) 21.26 (18.65–24.01) −0.26 (−0.36 to −0.16) 
 High-middle SDI 32.02 (26.94–37.63) 30.85 (25.14–37.08) −0.44 (−0.53 to −0.36) 18.98 (16.26–22.04) 18.63 (15.47–22.17) −0.17 (−0.41 to 0.07) 
 Middle SDI 29.93 (24.07–36.23) 30.22 (23.63–37.15) 0.15 (−0.09–0.39) 20.82 (17.16–24.91) 21.22 (17.05–25.71) 0.20 (0.08–0.32) 
 Low-middle SDI 28.35 (22.18–35.17) 29.50 (22.55–37.09) 0.48 (0.32–0.64) 19.62 (15.57–24.19) 21.07 (16.32–26.48) 0.81 (0.73–0.89) 
 Low SDI 23.35 (18.11–28.85) 25.47 (19.39–31.86) 1.06 (0.87–1.25) 21.80 (16.96–27.68) 22.77 (17.20–29.47) 0.49 (0.45–0.52) 
Region 
 Africa 25.27 (19.76–31.29) 28.18 (21.42–35.34) 1.28 (1.04–1.51) 21.28 (16.72–26.81) 22.48 (17.06–28.9) 0.64 (0.58–0.66) 
 Eastern Mediterranean 25.19 (20.79–30.25) 27.09 (21.99–33.42) 0.78 (0.71–0.85) 32.91 (26.21–40.94) 34.45 (26.92–43.79) 0.45 (0.32–0.59) 
 Europe 37.64 (33.67–42.12) 35.59 (31.09–40.7) −0.73 (−0.87 to −0.59) 23.34 (21.02–25.81) 22.45 (19.6–25.29) −0.44 (−0.52 to −0.36) 
 Americas 33.10 (28.11–38.35) 32.76 (26.40–39.66) 0.04 (−0.17–0.25) 22.35 (19.65–25.09) 23.43 (19.95–27.1) 0.62 (0.34–0.90) 
 South-East Asia 27.77 (20.73–35.56) 28.58 (20.68–37.29) 0.35 (0.17–0.54) 16.74 (12.69–21.25) 17.91 (13.21–23.18) 0.81 (0.67–0.95) 
 Western Pacific 28.24 (22.53–34.28) 28.06 (22.04–34.19) −0.02 (−0.30 to 0.26) 18.11 (14.84–21.61) 17.80 (14.37–21.68) −0.18 (−0.44 to 0.08) 
Etiology 
 Alcohol 6.93 (5.2–8.84) 7.10 (5.11–9.39) 0.55 (0.12–0.99) 3.22 (2.41–4.18) 3.35 (2.38–4.51) 0.67 (0.34–1.01) 
 Hepatitis B 7.41 (5.48–9.53) 6.25 (4.34–8.34) −1.95 (−2.30 to −1.61) 4.11 (3.07–5.3) 3.54 (2.46–4.75) −1.73 (−2.10 to −1.36) 
 Hepatitis C 7.81 (5.98–9.87) 8.20 (6.12–10.64) 0.57 (0.53–0.60) 4.79 (3.69–5.97) 5.10 (3.79–6.58) 0.69 (0.64–0.73) 
 NASH 1.32 (0.84–2.03) 1.43 (0.90–2.23) 1.05 (0.93–1.17) 1.65 (1.09–2.4) 1.82 (1.17–2.71) 1.26 (1.14–1.39) 
 Other causes 6.34 (4.99–7.92) 6.69 (5.18–8.49) 0.57 (0.55–0.59) 6.71 (5.43–8.13) 7.10 (5.64–8.74) 0.63 (0.59–0.68) 

ASIR, age-standardized incidence rate; SDI, sociodemographic index; NASH, nonalcoholic steatohepatitis.

Table 2.

Age-standardized death rates of cirrhosis in 2010 and 2019, and the temporal trend of age-standardized incident rates from 2010 to 2019; stratified by sex

MaleFemale
2010 ASDR, per 100,000 (95% UI)2019 ASDR, per 100,000 (95% UI)annual percentage change in ASDR (95% CI)2010 ASDR, per 100,000 (95% UI)2019 ASDR, per 100,000 (95% UI)annual percentage change in ASDR (95% CI)
Global 28.20 (26.90–29.50) 24.81 (23.07–26.75) −1.45 (−1.51 to −1.40) 13.13 (12.33–13.99) 11.70 (10.68–12.81) −1.28 (−1.34 to −1.22) 
Sociodemographic index 
 High SDI 16.09 (15.53–16.77) 14.66 (14.01–15.37) −1.05 (−1.14 to −0.95) 2.46 (2.04–2.95) 2.24 (1.82–2.73) −0.96 (−1.27 to −0.65) 
 High-middle SDI 22.95 (22.11–23.87) 18.42 (17.06–19.84) −2.38 (−2.80 to −1.97) 2.80 (2.38–3.25) 2.19 (1.81–2.62) −2.77 (−3.10 to −2.44) 
 Middle SDI 30.12 (28.36–31.84) 26.53 (24.01–29.39) −1.43 (−1.57 to −1.29) 3.19 (2.72–3.67) 2.93 (2.43–3.45) −0.98 (−1.11 to −0.85) 
 Low-middle SDI 39.93 (36.65–43.09) 35.76 (31.93–40.11) −1.22 (−1.49 to −0.95) 1.46 (1.06–1.90) 1.42 (1.03–1.86) −0.18 (−0.44 to 0.09) 
 Low SDI 48.83 (43.83–54.61) 41.29 (35.06–48.06) −1.84 (−2.06 to −1.62) 3.22 (2.54–3.98) 2.92 (2.26–3.64) −1.06 (−1.13 to −0.99) 
Region 
 Africa 56.66 (49.49–64.49) 48.12 (39.98–57.32) −1.79 (−1.96 to −1.62) 26.81 (23.32–31.06) 23.65 (19.41–27.9) −1.36 (−1.53 to −1.18) 
 Eastern Mediterranean 41.04 (35.07–47.51) 38.01 (28.77–47.79) −0.89 (−1.01 to −0.77) 39.28 (34.56–45.01) 34.25 (28.67–41.5) −1.43 (−1.58 to −1.27) 
 Europe 25.58 (25.02–26.27) 22.05 (20.42–23.67) −1.47 (−1.93 to −1.01) 12.31 (11.90–12.68) 10.61 (9.82–11.49) −1.57 (−1.92 to −1.23) 
 Americas 25.33 (24.41–26.19) 25.2 (23.47–27.15) −0.05 (−0.18 to 0.08) 10.49 (9.90–11.11) 10.41 (9.61–11.27) −0.13 (−0.29 to 0.02) 
 South-East Asia 39.76 (36.87–43.29) 34.02 (29.66–39.14) −1.76 (−2.14 to −1.37) 18.51 (16.41–21.08) 16.22 (13.59–19.72) −1.43 (−1.66 to −1.2) 
 Western Pacific 17.24 (15.93–18.77) 14.14 (12.24–16.17) −2.18 (−2.32 to −2.05) 6.91 (6.24–7.58) 5.38 (4.58–6.21) −2.77 (−2.96 to −2.58) 
Etiology 
 Alcohol 7.60 (6.57–8.72) 6.93 (5.91–8.09) −0.84 (−1.30 to −0.38) 2.46 (2.04–2.95) 2.24 (1.82–2.73) −0.96 (−1.27 to −0.65) 
 Hepatitis B 7.88 (6.90–8.98) 6.01 (5.02–7.08) −3.10 (−3.63 to −2.56) 2.80 (2.38–3.25) 2.19 (1.81–2.62) −2.77 (−3.10 to −2.44) 
 Hepatitis C 7.40 (6.46–8.44) 6.87 (5.88–7.93) −0.85 (−0.91 to −0.79) 3.19 (2.72–3.67) 2.93 (2.43–3.45) −0.98 (−1.11 to −0.85) 
 NASH 1.93 (1.39–2.59) 1.91 (1.36–2.54) −0.02 (−0.12 to 0.08) 1.46 (1.06–1.90) 1.42 (1.03–1.86) −0.18 (−0.44 to 0.09) 
 Other causes 3.40 (2.72–4.24) 3.10 (2.45–3.97) −0.99 (−1.13 to −0.85) 3.22 (2.54–3.98) 2.92 (2.26–3.64) −1.06 (−1.13 to −0.99) 
MaleFemale
2010 ASDR, per 100,000 (95% UI)2019 ASDR, per 100,000 (95% UI)annual percentage change in ASDR (95% CI)2010 ASDR, per 100,000 (95% UI)2019 ASDR, per 100,000 (95% UI)annual percentage change in ASDR (95% CI)
Global 28.20 (26.90–29.50) 24.81 (23.07–26.75) −1.45 (−1.51 to −1.40) 13.13 (12.33–13.99) 11.70 (10.68–12.81) −1.28 (−1.34 to −1.22) 
Sociodemographic index 
 High SDI 16.09 (15.53–16.77) 14.66 (14.01–15.37) −1.05 (−1.14 to −0.95) 2.46 (2.04–2.95) 2.24 (1.82–2.73) −0.96 (−1.27 to −0.65) 
 High-middle SDI 22.95 (22.11–23.87) 18.42 (17.06–19.84) −2.38 (−2.80 to −1.97) 2.80 (2.38–3.25) 2.19 (1.81–2.62) −2.77 (−3.10 to −2.44) 
 Middle SDI 30.12 (28.36–31.84) 26.53 (24.01–29.39) −1.43 (−1.57 to −1.29) 3.19 (2.72–3.67) 2.93 (2.43–3.45) −0.98 (−1.11 to −0.85) 
 Low-middle SDI 39.93 (36.65–43.09) 35.76 (31.93–40.11) −1.22 (−1.49 to −0.95) 1.46 (1.06–1.90) 1.42 (1.03–1.86) −0.18 (−0.44 to 0.09) 
 Low SDI 48.83 (43.83–54.61) 41.29 (35.06–48.06) −1.84 (−2.06 to −1.62) 3.22 (2.54–3.98) 2.92 (2.26–3.64) −1.06 (−1.13 to −0.99) 
Region 
 Africa 56.66 (49.49–64.49) 48.12 (39.98–57.32) −1.79 (−1.96 to −1.62) 26.81 (23.32–31.06) 23.65 (19.41–27.9) −1.36 (−1.53 to −1.18) 
 Eastern Mediterranean 41.04 (35.07–47.51) 38.01 (28.77–47.79) −0.89 (−1.01 to −0.77) 39.28 (34.56–45.01) 34.25 (28.67–41.5) −1.43 (−1.58 to −1.27) 
 Europe 25.58 (25.02–26.27) 22.05 (20.42–23.67) −1.47 (−1.93 to −1.01) 12.31 (11.90–12.68) 10.61 (9.82–11.49) −1.57 (−1.92 to −1.23) 
 Americas 25.33 (24.41–26.19) 25.2 (23.47–27.15) −0.05 (−0.18 to 0.08) 10.49 (9.90–11.11) 10.41 (9.61–11.27) −0.13 (−0.29 to 0.02) 
 South-East Asia 39.76 (36.87–43.29) 34.02 (29.66–39.14) −1.76 (−2.14 to −1.37) 18.51 (16.41–21.08) 16.22 (13.59–19.72) −1.43 (−1.66 to −1.2) 
 Western Pacific 17.24 (15.93–18.77) 14.14 (12.24–16.17) −2.18 (−2.32 to −2.05) 6.91 (6.24–7.58) 5.38 (4.58–6.21) −2.77 (−2.96 to −2.58) 
Etiology 
 Alcohol 7.60 (6.57–8.72) 6.93 (5.91–8.09) −0.84 (−1.30 to −0.38) 2.46 (2.04–2.95) 2.24 (1.82–2.73) −0.96 (−1.27 to −0.65) 
 Hepatitis B 7.88 (6.90–8.98) 6.01 (5.02–7.08) −3.10 (−3.63 to −2.56) 2.80 (2.38–3.25) 2.19 (1.81–2.62) −2.77 (−3.10 to −2.44) 
 Hepatitis C 7.40 (6.46–8.44) 6.87 (5.88–7.93) −0.85 (−0.91 to −0.79) 3.19 (2.72–3.67) 2.93 (2.43–3.45) −0.98 (−1.11 to −0.85) 
 NASH 1.93 (1.39–2.59) 1.91 (1.36–2.54) −0.02 (−0.12 to 0.08) 1.46 (1.06–1.90) 1.42 (1.03–1.86) −0.18 (−0.44 to 0.09) 
 Other causes 3.40 (2.72–4.24) 3.10 (2.45–3.97) −0.99 (−1.13 to −0.85) 3.22 (2.54–3.98) 2.92 (2.26–3.64) −1.06 (−1.13 to −0.99) 

ASDR, age-standardized death rate; SDI, sociodemographic index; NASH, nonalcoholic steatohepatitis.

Table 3.

Age-standardized disability-adjusted life-years (DALYs) rates of cirrhosis in 2010 and 2019, and the temporal trend of age-standardized incident rates from 2010 to 2019; stratified by sex

MaleFemale
2010 ASDALYs, per 100,000 (95% UI)2019 ASDALYs, per 100,000 (95% UI)annual percentage change in ASDALYs (95% CI)2010 ASDALYs, per 100,000 (95% UI)2019 ASDALYs, per 100,000 (95% UI)annual percentage change in ASDALYs (95% CI)
Global 895.05 (856.24–940.39) 783.31 (723.85–849.07) −1.53 (−1.61 to −1.45) 391.71 (369.85–415.55) 343.96 (313.74–376.74) −1.42 (−1.50 to −1.35) 
Sociodemographic index 
 High SDI 476.61 (465.76–490.75) 424.89 (409.14–440.88) −1.27 (−1.35 to −1.18) 203.93 (196.12–211.77) 192.85 (183.61–201.13) −0.55 (−0.71 to −0.40) 
 High-middle SDI 732.93 (709.67–761.62) 584.12 (541.72–631.25) −2.45 (−2.97 to −1.92) 292.57 (284.22–301.70) 226.25 (208.03–246.96) −2.82 (−3.41 to −2.22) 
 Middle SDI 870.76 (824.76–923.23) 768.01 (698.94–844.76) −1.40 (−1.54 to −1.27) 378.50 (354.68–403.25) 317.42 (280.6–357.56) −1.97 (−2.01 to −1.93) 
 Low-middle SDI 1,285.60 (1,186.81–1,380.64) 1,135.95 (1,009.61–1,282.46) −1.44 (−1.96 to −0.91) 565.85 (511.10–622.69) 509.13 (443.46–588.64) −1.12 (−1.39 to −0.86) 
 Low SDI 1,464.96 (1,315.69–1,632.57) 1,230.09 (1,035.08–1,440.67) −1.91 (−2.15 to −1.67) 769.63 (673.96–884.52) 672.27 (574.70–776.18) −1.47 (−1.67 to −1.26) 
Region 
 Africa 1,613.78 (1,406.04–1,842.82) 1,374.76 (1,114.38–1,674.41) −1.74 (−1.91 to −1.58) 707.03 (609.09–811.15) 618.42 (507.00–748.72) −1.43 (−1.61 to −1.24) 
 Eastern Mediterranean 1,020.19 (875.30–1,197.36) 924.29 (705.85–1,178.36) −1.09 (−1.21 to −0.97) 913.71 (815.93–1036.07) 808.01 (675.25–973.37) −1.27 (−1.39 to −1.15) 
 Europe 857.24 (844.87–875.74) 733.87 (678.27–791.45) −1.56 (−2.13 to −0.98) 401.15 (393.10–410.34) 339.79 (312.28–371.99) −1.73 (−2.17 to −1.29) 
 Americas 777.14 (756.97–800.13) 767.11 (712.84–830.73) −0.08 (−0.32 to 0.16) 290.02 (278.30–305.03) 283.15 (263.53–306.62) −0.26 (−0.48 to −0.03) 
 South-East Asia 1,292.74 (1201.69–1,416.85) 1,088.73 (941.30–1,257.78) −2.01 (−2.69 to −1.32) 545.16 (487.88–613.08) 463.99 (388.95–556.44) −1.77 (−2.07 to −1.47) 
 Western Pacific 504.62 (465.38–552.27) 415.83 (359.49–476.32) −2.17 (−2.26 to −2.09) 168.94 (155.14–183.66) 129.73 (112.5–148.8) −2.88 (−3.07 to −2.69) 
Etiology 
 Alcohol 228.69 (196.76–263.78) 208.08 (177.47–242.09) −0.82 (−1.44 to −0.21) 68.33 (56.82–80.83) 61.37 (50.44–73.95) −1.02 (−1.48 to −0.56) 
 Hepatitis B 257.03 (224.88–291.42) 196.73 (162.99–232.19) −3.10 (−3.73 to −2.48) 82.39 (70.46–94.93) 64.64 (53.53–77.99) −2.72 (−3.04 to −2.39) 
 Hepatitis C 229.50 (200.03–264.22) 211.84 (179.41–246.86) −0.95 (−1.03 to −0.86) 91.13 (78.88–104.58) 82.78 (69.29–98.02) −1.13 (−1.30 to −0.96) 
 NASH 52.62 (37.20–70.86) 52.39 (37.17–71.63) 0.02 (−0.26–0.31) 36.13 (26.34–47.42) 35.16 (25.35–46.24) −0.20 (−0.61 to 0.21) 
 Other causes 127.21 (105.30–152.45) 114.28 (93.25–139.98) −1.14 (−1.28 to −0.99) 113.73 (95.54–134.37) 100.02 (81.79–119.88) −1.41 (−1.53 to −1.29) 
MaleFemale
2010 ASDALYs, per 100,000 (95% UI)2019 ASDALYs, per 100,000 (95% UI)annual percentage change in ASDALYs (95% CI)2010 ASDALYs, per 100,000 (95% UI)2019 ASDALYs, per 100,000 (95% UI)annual percentage change in ASDALYs (95% CI)
Global 895.05 (856.24–940.39) 783.31 (723.85–849.07) −1.53 (−1.61 to −1.45) 391.71 (369.85–415.55) 343.96 (313.74–376.74) −1.42 (−1.50 to −1.35) 
Sociodemographic index 
 High SDI 476.61 (465.76–490.75) 424.89 (409.14–440.88) −1.27 (−1.35 to −1.18) 203.93 (196.12–211.77) 192.85 (183.61–201.13) −0.55 (−0.71 to −0.40) 
 High-middle SDI 732.93 (709.67–761.62) 584.12 (541.72–631.25) −2.45 (−2.97 to −1.92) 292.57 (284.22–301.70) 226.25 (208.03–246.96) −2.82 (−3.41 to −2.22) 
 Middle SDI 870.76 (824.76–923.23) 768.01 (698.94–844.76) −1.40 (−1.54 to −1.27) 378.50 (354.68–403.25) 317.42 (280.6–357.56) −1.97 (−2.01 to −1.93) 
 Low-middle SDI 1,285.60 (1,186.81–1,380.64) 1,135.95 (1,009.61–1,282.46) −1.44 (−1.96 to −0.91) 565.85 (511.10–622.69) 509.13 (443.46–588.64) −1.12 (−1.39 to −0.86) 
 Low SDI 1,464.96 (1,315.69–1,632.57) 1,230.09 (1,035.08–1,440.67) −1.91 (−2.15 to −1.67) 769.63 (673.96–884.52) 672.27 (574.70–776.18) −1.47 (−1.67 to −1.26) 
Region 
 Africa 1,613.78 (1,406.04–1,842.82) 1,374.76 (1,114.38–1,674.41) −1.74 (−1.91 to −1.58) 707.03 (609.09–811.15) 618.42 (507.00–748.72) −1.43 (−1.61 to −1.24) 
 Eastern Mediterranean 1,020.19 (875.30–1,197.36) 924.29 (705.85–1,178.36) −1.09 (−1.21 to −0.97) 913.71 (815.93–1036.07) 808.01 (675.25–973.37) −1.27 (−1.39 to −1.15) 
 Europe 857.24 (844.87–875.74) 733.87 (678.27–791.45) −1.56 (−2.13 to −0.98) 401.15 (393.10–410.34) 339.79 (312.28–371.99) −1.73 (−2.17 to −1.29) 
 Americas 777.14 (756.97–800.13) 767.11 (712.84–830.73) −0.08 (−0.32 to 0.16) 290.02 (278.30–305.03) 283.15 (263.53–306.62) −0.26 (−0.48 to −0.03) 
 South-East Asia 1,292.74 (1201.69–1,416.85) 1,088.73 (941.30–1,257.78) −2.01 (−2.69 to −1.32) 545.16 (487.88–613.08) 463.99 (388.95–556.44) −1.77 (−2.07 to −1.47) 
 Western Pacific 504.62 (465.38–552.27) 415.83 (359.49–476.32) −2.17 (−2.26 to −2.09) 168.94 (155.14–183.66) 129.73 (112.5–148.8) −2.88 (−3.07 to −2.69) 
Etiology 
 Alcohol 228.69 (196.76–263.78) 208.08 (177.47–242.09) −0.82 (−1.44 to −0.21) 68.33 (56.82–80.83) 61.37 (50.44–73.95) −1.02 (−1.48 to −0.56) 
 Hepatitis B 257.03 (224.88–291.42) 196.73 (162.99–232.19) −3.10 (−3.73 to −2.48) 82.39 (70.46–94.93) 64.64 (53.53–77.99) −2.72 (−3.04 to −2.39) 
 Hepatitis C 229.50 (200.03–264.22) 211.84 (179.41–246.86) −0.95 (−1.03 to −0.86) 91.13 (78.88–104.58) 82.78 (69.29–98.02) −1.13 (−1.30 to −0.96) 
 NASH 52.62 (37.20–70.86) 52.39 (37.17–71.63) 0.02 (−0.26–0.31) 36.13 (26.34–47.42) 35.16 (25.35–46.24) −0.20 (−0.61 to 0.21) 
 Other causes 127.21 (105.30–152.45) 114.28 (93.25–139.98) −1.14 (−1.28 to −0.99) 113.73 (95.54–134.37) 100.02 (81.79–119.88) −1.41 (−1.53 to −1.29) 

ASDALYs, age-standardized disability-adjusted life-years rate; SDI, sociodemographic index; NASH, nonalcoholic steatohepatitis.

From 2010 to 2019, there was an 11% increase in incident cirrhosis cases in males and a 16% increase in females. Over the same period, cirrhosis ASIRs remained stable in males (APC −0.04%; 95% CI: −0.19 to 0.11) but increased in females (APC 0.26%; 95% CI: 0.18–0.34) (Table 1). The frequency of cirrhosis-related deaths increased by 9% in males versus 12% in females from 2010 to 2019, although ASDRs decreased in both males (APC −1.45%, 95% CI: −1.51 to −1.40) and females (APC −1.28%, 95% CI: −1.34 to −1.22) (Table 2). There was a 4% increase in DALYs attributed to cirrhosis in males and a 6% increase in females, although ASDALYs decreased in both males (APC −1.53%, 95% CI: −1.61 to −1.45) and females (APC −1.42%, 95% CI: −1.50 to −1.35) (Table 3).

Sex Differences in the Burden of Cirrhosis, by World Health Organization Region

In 2019, the Western Pacific had the largest number of incident cirrhosis cases in both males (329,064) and females (216,373). However, the largest increase in incident cirrhosis cases from 2010 to 2019 was in Africa in both males (+42%) and females (+36%). From 2010 to 2019, cirrhosis ASIRs in males increased in Africa, the Eastern Mediterranean, and South-East Asia, with the greatest increase in Africa (APC 1.28, 95% CI: 1.04–1.51), and remained stable or decreased in other world regions (Table 1). In females over the same period, cirrhosis ASIRs increased in Africa, the Eastern Mediterranean, the Americas, and South-East Asia, with the largest increase in South-East Asia (APC 0.81, 95% CI: 0.67–0.95), and remained stable or declined in the remaining WHO regions. The ratio of female-to-male ASIRs for cirrhosis in 2019 was 0.7 globally and ranged from 0.6 in South-East Asia to 1.3 in the Eastern Mediterranean.

In 2019, South-East Asia experienced the largest number of cirrhosis-related deaths in both males (300,456) and females (142,284) (Fig. 1d), although the largest percentage increase in cirrhosis-related deaths from 2010 to 2019 was in the Eastern Mediterranean (+23%) and Americas (+23%) in males and the Americas in females (+25%). From 2010 to 2019, in males, cirrhosis ASDRs decreased in all WHO regions with the greatest decline in the Western Pacific (APC -2.18, 95% CI: −2.32 to −2.05), except for the Americas where the cirrhosis ASDR remained stable (APC -0.05, 95% CI: −0.18 to 0.08) (Table 2). In females in the same period, cirrhosis ASDRs also decreased in all WHO regions except for the Americas where it remained stable (APC -0.13, 95% CI: −0.29 to 0.02). The ratio of female-to-male cirrhosis ASDRs in 2019 was 0.5 globally and was lowest in the Western Pacific (0.4) and highest in the Eastern Mediterranean (0.9) (Fig. 2e, f). By country, the ratio of female-to-male cirrhosis ASDRs in 2019 ranged from 0.2 (95% CI: 0.2–0.2) in Papua New Guinea to 1.5 (95% CI: 1.3–1.8) in Pakistan (Fig. 3a). The estimated ASRs for DALYs attributable to cirrhosis stratified by sex and WHO region are presented in Table 3.

Fig. 1.

a Frequency of incident cirrhosis cases in males versus females from 2010 to 2019, by etiology of liver disease. b Frequency of cirrhosis-related deaths in males versus females from 2010 to 2019, by etiology of liver disease. c Frequency of cirrhosis-related deaths in males versus females in 2019, by etiology of liver disease. d Frequency of cirrhosis-related deaths in males versus females in 2019, by World Health Organization region. e Contribution of global cirrhosis-related deaths in male versus females in 2019, by etiology of liver disease.

Fig. 1.

a Frequency of incident cirrhosis cases in males versus females from 2010 to 2019, by etiology of liver disease. b Frequency of cirrhosis-related deaths in males versus females from 2010 to 2019, by etiology of liver disease. c Frequency of cirrhosis-related deaths in males versus females in 2019, by etiology of liver disease. d Frequency of cirrhosis-related deaths in males versus females in 2019, by World Health Organization region. e Contribution of global cirrhosis-related deaths in male versus females in 2019, by etiology of liver disease.

Close modal
Fig. 2.

a Age-standardized incidence rates (ASIRs) of cirrhosis in males versus females from 2010 to 2019 by etiology of liver disease. b Age-standardized death rates (ASDRs) of cirrhosis in males versus females from 2010 to 2019 by etiology of liver disease. c Ratio of female-to-male age-standardized incidence rates (ASIRs) of cirrhosis from 2010 to 2019 by etiology of liver disease. d Ratio of female-to-male age-standardized death rates (ASDRs) of cirrhosis from 2010 to 2019 by etiology of liver disease. e Age-standardized death rates (ASDRs) of cirrhosis in males versus females in 2019 by World Health Organization region. f Ratio of female-to-male age-standardized death rates (ASDRs) of cirrhosis from 2010 to 2019 by World Health Organization region.

Fig. 2.

a Age-standardized incidence rates (ASIRs) of cirrhosis in males versus females from 2010 to 2019 by etiology of liver disease. b Age-standardized death rates (ASDRs) of cirrhosis in males versus females from 2010 to 2019 by etiology of liver disease. c Ratio of female-to-male age-standardized incidence rates (ASIRs) of cirrhosis from 2010 to 2019 by etiology of liver disease. d Ratio of female-to-male age-standardized death rates (ASDRs) of cirrhosis from 2010 to 2019 by etiology of liver disease. e Age-standardized death rates (ASDRs) of cirrhosis in males versus females in 2019 by World Health Organization region. f Ratio of female-to-male age-standardized death rates (ASDRs) of cirrhosis from 2010 to 2019 by World Health Organization region.

Close modal
Fig. 3.

a Ratio of female-to-male age-standardized death rates (ASDRs) of cirrhosis (from all major etiologies) in 2019, by country/territory. b Ratio of female-to-male age-standardized death rates (ASDRs) of NASH cirrhosis in 2019, by country/territory.

Fig. 3.

a Ratio of female-to-male age-standardized death rates (ASDRs) of cirrhosis (from all major etiologies) in 2019, by country/territory. b Ratio of female-to-male age-standardized death rates (ASDRs) of NASH cirrhosis in 2019, by country/territory.

Close modal

Sex Differences in the Burden of Cirrhosis, by Sociodemographic Index

In 2019, the largest frequency of incident cirrhosis cases occurred in middle SDI countries in both males (402,727) and females (285,833). However, in the study period from 2010 to 2019, the largest increase in incident cirrhosis cases was in low SDI countries for both males (+37%) and females (+32%). In males, from 2010 to 2019, cirrhosis ASIRs increased in low and low-middle SDI countries, with the greatest increase in low SDI countries (APC 1.06, 95% CI: 0.87–1.25) (Table 2). In females over the same period, cirrhosis ASIRs increased in low, low-middle, and middle SDI countries, with the greatest increase in low-middle SDI countries (APC 0.81, 95% CI: 0.73–0.89).

Middle SDI countries accounted for the most cases of cirrhosis-related deaths in males (313,510; 32% of global cirrhosis-related deaths) and females (156,105; 31%). The largest percentage increase in cirrhosis-related deaths from 2010 to 2019 was in middle-SDI countries in males (+23%) and in low-middle SDI countries in females (+19%). From 2010 to 2019, in males, cirrhosis ASDRs decreased in all SDI quantiles, with the greatest decrease in high-middle SDI countries (APC -2.38, 95% CI: -2.80 to −1.97) (Table 2). In females, cirrhosis ASDRs also decreased in all SDI quantiles except for low-middle SDI countries which remained stable (APC -0.18, 95% CI: −0.44 to 0.09). The estimated ASRs for DALYs attributable to cirrhosis stratified by sex and SDI are presented in Table 3.

Sex Differences in the Burden of Chronic Liver Disease, by Etiology

The estimated ASRs of cirrhosis incidence, deaths, and DALYs stratified by sex and etiology of liver disease are summarized in Tables 1-3. In 2019, the leading cause of incident cirrhosis cases was HCV in both males (338,716) and females (212,972) (Fig. 1a). However, from 2010 to 2019, NASH was the fastest-growing etiology of incident cirrhosis cases in both males (+23%) and females (+30%). From 2010 to 2019 cirrhosis, ASIRs from alcohol, HCV, NASH, and other causes in males increased, with the largest increase in NASH (APC 1.05%, 95% CI: 0.93–1.17), while ASIR of HBV cirrhosis decreased (APC -1.95%, 95% CI: −2.30 to −1.61%) (Table 1; Fig. 2a). In females, cirrhosis ASIRs from alcohol, HCV, NASH, and other causes all increased over the study period, with the largest increase in NASH (APC 1.26, 95% CI: 1.14–1.39), while the ASIR of HBV cirrhosis decreased (APC -1.73%, 95% CI: -2.10 to −1.36). The ratio of female-to-male ASIRs for cirrhosis in 2019 varied substantially by etiology and was lowest in alcohol (0.5) and highest in NASH (1.3) (Fig. 2c).

In 2019, the leading cause of cirrhosis-related deaths in males was alcohol (274,729) and HCV in females (126,846) (Fig. 1b). From 2010 to 2019, the fastest-growing etiology of cirrhosis-related deaths was NASH in both males (+25%) and females (+25%). In males, from 2010 to 2019, cirrhosis ASDRs decreased for all etiologies except for NASH, which remained stable (APC −0.02, 95% CI: −0.12 to 0.08) (Table 1; Fig. 2b). In males, the greatest decrease in cirrhosis ASDRs was in HBV (APC −3.10, 95% CI: −3.63 to −2.56). In females, cirrhosis ASDRs decreased across all etiologies over the study period, except in NASH, where ASDRs were stable (APC −0.18, 95% CI: −0.44 to 0.09), with the largest decrease in HBV cirrhosis (APC −2.77, 95% CI: −3.10 to −2.44). The ratio of female-to-male ASDRs for cirrhosis in 2019 was lowest in alcohol (0.3) and highest in NASH (0.8) (Fig. 2d).

Sex Differences in the Burden of Cirrhosis, by Etiology and Region

The ASIRs, ASDRs, and ASDALYs of cirrhosis from 2010 to 2019 stratified by sex, etiology, and region are summarized in online suppl. material 3–5. From 2010 to 2019, among males, the ASIRs of NASH cirrhosis increased in five of six WHO regions, with the greatest increase in Africa (APC 2.74%; 95% CI: 2.50–2.97), and remained stable only in Europe (APC −0.12%; 95% CI: −0.25 to 0.02). Among females in the same period, ASIRs of NASH cirrhosis increased in all six WHO regions, with the greatest increase in South-East Asia (APC 2.51%; 95% CI: 2.01–3.01).

From 2010 to 2019, in males, the ASDRs of NASH cirrhosis increased only in the Americas (APC 0.78%; 95% CI: 0.40–1.17) and remained stable or decreased in the remaining five WHO regions. Similarly, in females, the ASDRs of NASH cirrhosis increased in the Americas (APC 0.43%; 95% CI: 0.16–0.71) and declined in the remaining five WHO regions. From 2010 to 2019, the greatest increase in ASDALYs due to NASH cirrhosis occurred in the Americas for both males (APC 1.03%; 95% CI: 0.65–1.41) and females (APC 0.48%; 95% CI: 0.16–0.80).

Utilizing data from the GBD 2019 study, we determined that the global burden of cirrhosis was higher in males compared to females, with a greater frequency of incident cases (1,206,125 vs. 845,429), deaths (969,068 vs. 502,944) and DALYs (31,781,079 vs. 14,408,336) in males and females, respectively, in 2019. Between 2010 and 2019, the frequency of incident cases of cirrhosis, deaths, and DALYs for both males and females increased. However, over the study period, ASIRs due to cirrhosis remained stable in males but increased in females, while ASDRs and ASDALYs declined in both males and females. The growth of the global population growth likely contributed to the differing trends in frequencies and ASRs. The greatest frequency of deaths related to cirrhosis in 2019 for both males and females occurred in South-East Asia. ASDRs related to cirrhosis in both males and females declined in all world regions during the study period, except in the Americas, where ASDRs remained stable.

From 2010 to 2019, NASH was the fastest-growing cause of incident cirrhosis cases and deaths in both males and females. The global ratio of female-to-male ASIRs for NASH cirrhosis in 2019 was 1.3, suggesting that the global incidence of NASH cirrhosis in females has exceeded that of males. Individuals with NASH tend to be older compared to those with viral hepatitis, and the loss of estrogen after menopause may accelerate disease progression to cirrhosis among postmenopausal females with NASH [19, 22‒24]. Recent cohort studies have also suggested that prolonged exposure to excess body weight, in terms of duration and severity, is associated with development of NASH cirrhosis [25, 26]. The higher incidence of obesity in females in most countries could have partially contributed to global trends in the incidence of NASH cirrhosis [27]. The global ASDRs for NASH cirrhosis remained stable in both males and females, unlike other etiologies of cirrhosis, where ASDRs declined. However, ASDRs related to NASH cirrhosis in both males and females in the Americas increased during the study period, in contrast to other world regions where ASDRs remained stable or declined. Among the various etiologies of liver disease, the female-to-male ratio of ASDRs was highest in NASH (0.8). Patients with NASH often experience reduced quality of life and a high degree of comorbidity burden, with female sex being associated with greater impairments in quality of life [28]. Taken together, these data highlight the need for increased awareness among care providers and healthcare policymakers that the burden of NASH cirrhosis in females approaches that of males. Public health policies targeted at maintenance of overall metabolic health and with an emphasis on weight reduction to maintain BMI within a normal range are required at global and regional levels to combat the metabolic risk factors for NASH [29, 30]. Greater awareness of the rising burden of NASH is also required in the primary care setting, with the latest American Gastroenterological Association (AGA) guidelines recommending the use of noninvasive testing to identify high-risk patients that require further evaluation by specialist care [31‒33].

In 2019, alcohol was the first and third leading cause of cirrhosis-related deaths in males (274,729) and females (97,235), respectively. Despite increasing global alcohol-per-capita consumption, global ASDRs for alcohol-associated cirrhosis declined in both males and females, but underreporting and underdiagnosis are a concern [34]. However, ASDRs for alcohol-associated cirrhosis in the Americas increased over the study period in females, in contrast to other regions where ASDRs remained stable or declined. Despite data suggesting that women may be more susceptible to alcohol-induced liver injury, the burden of alcohol-associated cirrhosis is lower in females, compared with males, due to lower levels of alcohol consumption [8, 35]. Differences in genotype between males and females, such as variants in GABRA6 and GABRA2, could partially account for sex-based discrepancies in susceptibility to alcohol-use disorder and subsequently alcohol-associated cirrhosis [36], although further research is required to elucidate the pathophysiology of sex-based differences in the burden of alcohol-associated cirrhosis. Countries with a rising burden of alcohol-associated cirrhosis may also consider adopting policies to reduce alcohol consumption, such as enforcing a minimum price for alcohol and increasing alcohol taxation [37‒40].

HBV was the third and fourth leading cause of cirrhosis-related deaths in males and females, respectively. ASDRs for HBV cirrhosis decreased from 2010 to 2019 for both males (APC −3.10%) and females (APC −2.77%), likely related to increasing HBV vaccination coverage and availability of safe and effective antivirals [41, 42]. Despite the progress made, HBV cirrhosis continues to exert a considerable disease burden globally and accounted for an estimated 236,948 and 94,319 deaths in males and females in 2019. Increased political will and resources are required to achieve HBV elimination [43, 44]. HCV was the second and first leading cause of cirrhosis-related deaths in 2019 among males (268,176) and females [126,846]), respectively. However, despite the large disease burden of HCV cirrhosis, ASDRs from HCV cirrhosis declined over the study period for both males (APC −0.85%) and females (APC −0.98%). This decline may be related to the increasing availability of DAAs for HCV, although the full impact of DAAs on the burden of HCV cirrhosis may require more time to manifest. Overall, the burden of cirrhosis related to viral hepatitis remains higher in males compared to females. In contrast to NASH, individuals with viral hepatitis tend to be younger; hence, premenopausal females may be at lower risk of developing advanced fibrosis and cirrhosis compared to males, possibly related to the inhibitive effect of estrogen on stellate cell activation and fibrosis [24, 45, 46].

In Context with Current Literature

Prior to the current study, data regarding the comparative global burden of cirrhosis in males and females were limited. Our study builds upon previous studies of GBD 2017 [6, 7] by providing an in-depth analysis of sex differences in the temporal trends of cirrhosis burden by region, SDI, and etiology of liver disease. These data validate several country-specific studies that suggested that the burden of advanced fibrosis or cirrhosis between males and females with NASH may be comparable [19, 47]. This also highlights the need for further studies investigating the pathophysiology of sex-based differences in the burden of cirrhosis, including potential variations in genotype and gut microbiome which have been shown to affect disease progression in cirrhosis [36, 48, 49]. Further insight into sex-based differences in the natural history of cirrhosis is also required, with recent evidence based on analysis of transplant registries suggesting that disease regression and recompensation are possible, although data on sex-based differences remain limited [50].

Strengths and Limitations

The current study provides an updated, comprehensive global overview of the sex differences in the burden of cirrhosis, unlike previous studies which focused on a specific country or etiology of liver disease. However, our study shares the same limitations as the GBD 2019 study [21]. The availability of data was dependent on the quality of each country’s registry, and when data were not available, GBD 2019 utilized complex modeling to estimate data from past trends, potentially introducing bias into the estimates. There was likely to be underdiagnosis and underreporting in regions such as Africa, hence the estimates in this study require cautious interpretation. Data from the coronavirus disease 2019 (COVID-19) pandemic period were also lacking, and the effect of disrupted routine health services during the pandemic on the disease burden of cirrhosis should be investigated in future studies [51].

In summary, the global burden of cirrhosis is substantially higher in males compared to females. Age-adjusted mortality declined for all etiologies of liver disease for males and females, except in NASH. The age-adjusted incidence rates of NASH cirrhosis in females exceeded that of males, while age-adjusted mortality rates in females approached that of males. Measures are required to tackle obesity and diabetes to reduce the global burden of NASH cirrhosis in both males and females.

Study approval and consent to participate. Ethical approval and consent were not required as this study was based on publicly available data.

R.L. receives funding support from NIAAA (U01AA029019), NIEHS (5P42ES010337), NCATS (5UL1TR001442), NIDDK (U01DK130190, U01DK061734, R01DK106419, P30DK120515, R01DK121378, R01DK124318), NHLBI (P01HL147835), and DOD PRCRP (W81XWH-18-2–0026). R.L. serves as a consultant to Aardvark Therapeutics, Altimmune, Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bristol-Myer Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse bio, Hightide, Inipharma, Intercept, Inventiva, Ionis, Janssen Inc., Madrigal, Metacrine, Inc., NGM Biopharmaceuticals, Novartis, Novo Nordisk, Merck, Pfizer, Sagimet, Theratechnologies, 89 bio, Terns Pharmaceuticals and Viking Therapeutics. In addition, his institutions received research grants from Arrowhead Pharmaceuticals, Astrazeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Galectin Therapeutics, Galmed Pharmaceuticals, Gilead, Intercept, Hanmi, Intercept, Inventiva, Ionis, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, Novo Nordisk, Merck, Pfizer, Sonic Incytes and Terns Pharmaceuticals. Co-founder of LipoNexus Inc.

S.G.L. has received educational or research funding from Abbott, Merck Sharpe and Dohme, Gilead Sciences. S.G.L. has served as an advisory board member for Gilead Sciences, Merck Sharpe and Dohme, Abbvie, and Abbott, and has served as a speaker for Gilead Sciences, Abbott, Merck Sharpe and Dohme, Roche. D.H. has served as an advisory board member for Eisai and receives funding support from Singapore Ministry of Health’s National Medical Research Council under its NMRC Research Training Fellowship (MOH-000595-01).

No external funding received.

All authors approve the final version of the manuscript, including the authorship list and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All authors have read and approved the final version of the manuscript for submission.

Conceptualization: D.Q.H. and R.L.; data curation: D.T., K.E.C., and Z.Y.W.; formal analysis: D.T.; supervision: D.Q.H.; validation: K.E.C., Z.Y.W., C.H.N., J.X., and W.H.L.; writing, original draft: D.T., K.E.C., Z.Y.W., C.H.N., and D.Q.H.; and writing, review, and editing: D.T., K.E.C., Z.Y.W., C.H.N., J.X., W.H.L., P.T., A.T., C.E.F., M.M., B.N., E.X.T., M.P.T., M.S.S., Y.Y.D., S.G.L., R.L., and D.Q.H.

Additional Information

Darren Tan, Kai En Chan, and Zhen Yu Wong contributed equally to this work and shared first authorship.

Data from the Global Burden of Disease (GBD) study in 2019 can be accessed using the Global Health Data Exchange (GHDx) query tool (http://ghdx.healthdata.org/gbd-results-tool) which is maintained by the Institute for Health Metrics and Evaluation. Further inquiries can be directed to the corresponding author.

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