Global, regional, and national burden of nonalcoholic fatty liver disease (NAFLD) among people aged 15 to 49 years from 1990 to 2021, with projections to 2050: A systematic analysis based on the 2021 global burden of disease study

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a growing global health concern due to its increasing prevalence and potential to cause serious liver complications. NAFLD is rising among people aged 15 to 49 years, a critical age group for workforce and reproduction, yet its burden and trends in this population remain insufficiently studied. This study aimed to evaluate the prevalence, incidence, mortality, and disability-adjusted life years (DALYs) associated with NAFLD in this age group across 204 countries and territories from 1990 to 2021, using data from the global burden of disease (GBD) 2021 database. Trends in disease burden were assessed using average annual percentage change (AAPC), with stratified analyses by sex, age, and socio-demographic index (SDI). Bayesian age-period-cohort (BAPC) models were employed to project future trends and quantify the contributions of major risk factors. By 2021, the global incidence, prevalence, mortality, and DALY rates of NAFLD in people aged 15 to 49 years were 909.48 per 100,000 persons (95% UI: 647.19–1216.77), 16,580.43 per 100,000 persons (95% UI: 12,851.14–20,866.60), 0.45 per 100,000 persons (95% UI: 0.27–0.72), and 22.77 per 100,000 person-years (95% UI: 13.74–35.81), respectively. Between 1990 and 2021, both incidence and prevalence increased, whereas mortality and DALYs remained relatively stable. NAFLD burden declined as SDI increased, peaking at an SDI of approximately 0.6 before gradually decreasing. Males consistently exhibited higher burden than females. The leading contributors to age-standardized mortality were tobacco use and elevated fasting glucose, with the impact of metabolic risk factors rising over time. Burden increased with age, with incidence peaking at age 22.5 and subsequently declining. By 2050, the number of new NAFLD cases among people aged 15 to 49 years is projected to reach 48.29 million globally, with the number of deaths expected to rise to 23,396.5. The substantial increase in NAFLD burden over the past 3 decades highlights the urgent need for early screening and diagnosis. These findings may inform future public health planning aimed at reducing the disease burden among people aged 15 to 49 years.

1. Introduction

Nonalcoholic fatty liver disease (NAFLD) is a persistent hepatic condition intricately associated with metabolic disorders. Due to swift economic advancement and the widespread adoption of unhealthy lifestyles, NAFLD has become a major public health issue,^[1,2] affecting approximately 315 million people globally by 2023.^[3] Progression of NAFLD may result in liver fibrosis, cirrhosis, and potentially hepatocellular carcinoma. Notwithstanding the rising prevalence, effective early diagnostic and therapeutic alternatives for NAFLD are still constrained.^[4] Present treatment approaches primarily emphasize lifestyle alterations and the management of metabolic complications, as no targeted pharmacological therapies are presently accessible. However, adherence to lifestyle modifications – such as sustained dietary changes and regular physical activity – is often suboptimal, which frequently undermines treatment efficacy.^[5]

While NAFLD has traditionally been associated with older adults, recent evidence indicates a rising burden among younger populations, particularly those aged 15 to 49 years.^[4] This demographic represents a critical segment of the labor force and reproductive age group, and early-onset NAFLD may lead to prolonged disease duration, higher lifetime healthcare costs, and premature mortality.^[6] Importantly, modifiable risk factors such as obesity, sedentary behavior, poor dietary patterns, and metabolic syndrome are highly prevalent and increasingly observed in this age group.^[7] These factors are amenable to early intervention, underscoring the need to better understand NAFLD burden and trends in this population to inform age-specific prevention and public health strategies.^[8]

The global burden of disease (GBD) is a systematic framework for evaluating health conditions and risk factors associated with diseases globally across various nations and regions. It measures the comprehensive effect of diverse diseases and injuries on human health by considering environmental, socioeconomic, and behavioral factors, facilitating comparisons of trends over time and across regions. Although prior studies have investigated the global burden of NAFLD attributable to specific metabolic risk factors such as high fasting plasma glucose,^[9] no research has concentrated solely on people aged 15 to 49 years. Given the strong association between NAFLD and socioeconomic status, stratification by the socio-demographic index (SDI) – a composite indicator incorporating income per capita, average years of schooling, and fertility rates – is essential to reveal regional disparities and guide equitable resource allocation.^[10] Additionally, sex-specific differences in NAFLD prevalence, progression, and metabolic profiles have been consistently observed, highlighting the need for sex-stratified analysis to better understand the burden across populations.^[11] This study aimed to assess the prevalence, incidence, mortality, and disability-adjusted life years (DALYs) associated with NAFLD among people aged 15 to 49 years across 204 countries and territories from 1990 to 2021, as well as to examine temporal trends, sex and regional disparities, and to project the future burden and contributions of major risk factors.

2. Material and methods

2.1. Data source

Data were obtained from the GBD 2021 database (https://vizhub.healthdata.org/gbd-results/), which provides comprehensive information on 371 diseases and injuries, as well as 88 risk factors, across 204 countries and regions worldwide, utilizing standardized assessment criteria and data collection methods. The core focus of this study is to analyze the epidemiological characteristics and health burden of diseases among people aged 15 to 49 years from 1990 to 2021.^[12] Data extraction was conducted across multiple dimensions: demographic characteristics (including age group and gender), temporal range (1990–2021), and geographical distribution (204 countries and regions, including World Health Organization member states, 5 SDI regions, and 21 GBD regions).The SDI, a composite measure reflecting socioeconomic development, combines the total fertility rate among individuals under 25 years old, average years of education among those aged 15 and above, and per capita income.^[13] Based on SDI values, the 204 countries and regions were classified into 5 development categories: low, lower-middle, middle, upper-middle, and high SDI. Furthermore, the 21 GBD regions were grouped according to geographic proximity and epidemiological similarities, allowing for more targeted regional analyses.^[14]

2.2. Analysis indicators

The disease burden of NAFLD in people aged 15 to 49 years was evaluated using 4 key indicators: prevalence, incidence, mortality, and DALYs, along with their 95% uncertainty intervals (UI). Additionally, age-standardized prevalence rate (ASPR), age-standardized incidence rate (ASIR), age-standardized mortality rate (ASMR), and age-standardized DALYs rate (ASDR) were calculated based on the age structure of the GBD world standard population to more accurately reflect the disease burden in this age group.

2.3. Statistical methods

Global disease burden data for NAFLD among individuals aged 15 to 49 years from 1990 to 2021 were analyzed using Excel 2021 and R version 4.3.3. After data cleaning and organization, statistical analyses and visualizations were performed in R using the dplyr, officer, and ggplot2 packages. A 2-sided P < .05 was considered statistically significant.

2.4. Age group analysis

In accordance with the age grouping standards of GBD 2021, this study divided the subjects into 7 age groups: 15 to 19, 20 to 24, 25 to 29, 30 to 34, 35 to 39, 40 to 44, and 45 to 49 years. This classification enables a detailed analysis of the changing trends in the burden of NAFLD across different age groups and between genders.

2.5. Trend analysis and correlation analysis

This study calculated and visualized the percentage changes in the NAFLD burden across various age groups, genders, regions, and countries from 1990 to 2021. The estimated annual percentage change (EAPC) was used to quantify trends in age-standardized rates. An EAPC with a 95% confidence interval (CI) lower limit >0 indicates an upward trend; conversely, a lower limit <0 indicates a downward trend.^[15] To analyze temporal trends from 1990 to 2021, joinpoint regression models were applied, yielding the average annual percentage change (AAPC) and annual percentage change (APC) for each time segment. If the 95% confidence interval includes 0, the trend is considered stable; a significantly positive AAPC or APC indicates an upward trend, while a significantly negative value indicates a downward trend.^[16] Model fitting and AAPC/APC calculations were performed using Joinpoint software (version 4.9.0.0), and the results were visualized using R. Additionally, Pearson correlation analysis was conducted to assess the relationship between the SDI and the age-standardized NAFLD rate.

2.6. Disaggregation and forecasting

A decomposition analysis was performed to evaluate the independent effects of population growth, aging, and epidemiological changes on the burden of NAFLD, while controlling for other influencing factors.^[17] Furthermore, an age-period-cohort (APC) model was utilized to examine the dynamic impacts of age, time period, and birth cohort on disease outcomes. Based on the Poisson distribution, the APC model decomposes these variables into 3 dimensions to assess their respective contributions to the risk of NAFLD incidence or mortality.^[18] To overcome the challenges of parameter estimation due to collinearity among the 3 factors, the study further implemented a Bayesian age-period-cohort (BAPC) model by integrating Bayesian Markov chain Monte Carlo algorithms. This advanced model was used to project the disease burden of NAFLD from 2022 to 2050.^[19]

The data used in this study were obtained from publicly accessible GBD databases and consisted entirely of de-identified secondary data. No direct human or animal experiments were involved; therefore, ethical approval was not required.

3. Results

3.1. The global burden of NAFLD among people aged 15 to 49 years

In 2021, the ASIR of NAFLD among young and middle-aged adults was 909.48 per 100,000 (95% UI: 647.19–1216.77), the ASPR was 16,580.43 per 100,000 (95% UI: 12,851.14–20,866.60), the ASMR was 0.45 per 100,000 (95% UI: 0.27–0.72), and the ASDR was 22.77 per 100,000 person-years (95% UI: 13.74–35.81). In 2021, there were approximately 35,604,870 new cases of NAFLD (95% UI: 25,275,992–47,726,492), comprising 19,507,816 males (95% UI: 13,899,203–26,101,624) and 16,097,054 females (95% UI: 11,355,345–21,598,640). There were 665,775,582 prevalent cases (95% UI: 516,184,353–837,723,525), comprising 358,660,567 males (95% UI: 278,210,923–450,924,147) and 307,115,015 females (95% UI: 237,731,023–388,120,392). In 2021, NAFLD resulted in 18,653 fatalities (95% UI: 11,261–29,374), comprising 10,771 males (95% UI: 6326–17,230) and 7882 females (95% UI: 4787–12,122). The DALYs associated with NAFLD were 22.77 per 100,000 person-years (95% UI: 13.74–35.81), with 25.81 DALYs per 100,000 person-years for males (95% UI: 15.13–41.28) and 19.69 for females (95% UI: 11.97–30.26). Between 1990 and 2021, all disease burden indicators for NAFLD in people aged 15 to 49 years exhibited positive estimated annual percentage changes (EAPCs), signifying a worldwide escalation in the disease burden among this demographic.

3.2. Regional burden of NAFLD among people aged 15 to 49 years

In 2021, the Middle SDI region exhibited the highest burden of NAFLD among the 5 SDI regions, with an ASIR of 933.79 per 100,000 (95% UI: 663.50–1428.09), an ASPR of 13,292.60 per 100,000 (95% UI: 10,307.31–16,733.27), an age-standardized mortality rate (ASMR) of 0.49 per 100,000 (95% UI: 0.30–0.76), and an ASDR of 24.33 per 100,000 person-years (95% UI: 14.75–37.80). Conversely, the High SDI region exhibited the lowest rates, with an ASIR of 694.05 per 100,000 (95% UI: 497.17–929.18), ASPR of 13,292.60 per 100,000 (95% UI: 10,307.31–16,733.27), ASMR of 0.37 per 100,000 (95% UI: 0.22–0.57), and ASDR of 18.10 per 100,000 person-years (95% UI: 10.76–28.14). The prevalence of NAFLD has escalated across all SDI regions over time. The high-middle SDI region exhibited the most significant increases in ASMR (EAPC = 0.86, 95% CI: 0.46–1.26) and ASDR (EAPC = 0.92, 95% CI: 0.51–1.32), whereas the high SDI region experienced the largest increases in ASIR (EAPC = 1.58, 95% CI: 0.64–2.52) and ASPR (EAPC = 1.58, 95% CI: 0.64–2.52) (table). In 2021, among the 21 GBD regions, Eastern Europe exhibited the highest ASMR at 9.24 (95% UI: 6.39–13.25) and ASDR at 87.41 (95% UI: 45.37–146.98), whereas North Africa and the Middle East recorded the highest ASIR at 1681.18 (95% UI: 1199.89–2257.41) and ASPR at 31,390.08 (95% UI: 24,516.64–38,915.29). In contrast, the high-income Asia Pacific region exhibited the lowest rates for ASMR (0.11, 95% UI: 0.07–0.17), ASPR (9846.02, 95% UI: 7580.80–12,542.39), ASIR (518.14, 95% UI: 370.28–689.09), and ASDR (5.39, 95% UI: 3.32–8.24). Concerning temporal trends, the disease burden escalated to differing extents across GBD regions, with Eastern Europe demonstrating the most significant rises in ASMR (EAPC = 5.65, 95% CI: 4.46–6.86) and ASDR (EAPC = 5.68, 95% CI: 4.46–6.92). The most significant rises in ASIR were observed in East Asia (EAPC = 0.88, 95% CI: 0.66–1.10) and Western Europe (EAPC = 0.98, 95% CI: 0.93–1.02) (Table 1).

Table 1.

ASR and EAPC for Global, 5 SDI Regions, and 21 GBD Regions in 1990 and 2021.

	ASIR			ASPR			ASMR			ASDR
	1990 (per 100,000 population, 95% UI)	2021 (per 100,000 population, 95% UI)	EAPCs (95% CI)	1990 (per 100,000 population, 95% UI)	2021 (per 100,000 population, 95% UI)	EAPCs (95% CI)	1990 (per 100,000 population, 95% UI)	2021 (per 100,000 population, 95% UI)	EAPCs (95% CI)	1990 (per 100,000 population, 95% UI)	2021 (per 100,000 population, 95% UI)	EAPCs (95% CI)
Global	712.16 (504.71, 952.47)	909.48 (647.19, 1216.77)	0.82 (0.77, 0.87)	13,312.03 (10,290.67, 16,872.38)	16,580.43 (12,851.14, 20,866.60)	0.75 (0.69, 0.82)	0.42 (0.25, 0.67)	0.45 (0.27, 0.72)	0.15 (0.03, 0.27)	21.00 (12.58, 33.32)	22.77 (13.74, 35.81)	0.18 (0.06, 0.30)
Sex
Male	770.48 (548.18, 1031.49)	984.86 (703.14, 1315.56)	0.872 (0.803, 0.940)	14,318.42 (11,096.80, 18,142.50)	17,688.75 (13,716.59, 22,243.51)	0.789 (0.713, 0.865)	0.46 (0.27, 0.74)	0.52 (0.31, 0.83)	0.276 (0.124, 0.427)	22.79 (13.49, 36.32)	25.81 (15.13, 41.28)	0.301 (0.151, 0.451)
Female	652.42 (461.27, 873.28)	831.11 (587.89, 1112.81)	0.755 (0.720, 0.791)	12,275.87 (9456.44, 15,562.09)	15,446.30 (11,953.06, 19,522.19)	0.713 (0.655, 0.771)	0.38 (0.23, 0.60)	0.39 (0.24, 0.60)	−0.002 (−0.097, 0.093)	19.14 (11.62, 30.05)	19.69 (11.97, 30.26)	0.038 (−0.051, 0.127)
SDI level
High SDI	512.76 (367.11, 680.58)	694.05 (497.17, 929.18)	1.13 (1.07, 1.19)	9427.48 (7245.84, 12,013.71)	13,292.60 (10,307.31, 16,733.27)	1.25 (1.20, 1.30)	0.41 (0.23, 0.66)	0.37 (0.22, 0.57)	−0.48 (−0.66, −0.30)	19.89 (11.35, 32.26)	18.10 (10.76, 28.14)	−0.47 (−0.63, −0.31)
High-middle SDI	724.18 (516.08, 969.59)	951.37 (679.39, 1269.31)	0.91 (0.79, 1.03)	13,284.13 (10,244.14, 16,867.11)	16,882.35 (13,030.18, 21,271.52)	0.82 (0.69, 0.94)	0.41 (0.23, 0.68)	0.45 (0.26, 0.72)	0.86 (0.46, 1.26)	18.11 (11.15, 28.02)	24.22 (13.96, 38.38)	0.92 (0.51, 1.32)
Middle SDI	791.27 (560.04, 1059.40)	1007.93 (717.80, 1346.75)	0.81 (0.76, 0.86)	14,789.12 (11,441.60, 18,753.65)	17,912.76 (13,854.17, 22,525.86)	0.66 (0.59, 0.74)	0.47 (0.29, 0.73)	0.49 (0.30, 0.76)	−0.00 (−0.10, 0.10)	23.46 (14.22, 36.42)	24.33 (14.75, 37.80)	0.01 (−0.09, 0.10)
Low-middle SDI	756.31 (535.63, 1013.76)	933.79 (663.50, 1248.09)	0.68 (0.64, 0.72)	14,712.74 (11,356.57, 18,652.19)	17,149.95 (13,270.88, 21,638.79)	0.50 (0.45, 0.55)	0.41 (0.23, 0.68)	0.45 (0.26, 0.72)	0.34 (0.25, 0.43)	20.58(11.76, 34.19)	22.63 (13.31, 36.52)	0.35 (0.26, 0.44)
Low SDI	699.81 (493.57, 938.60)	820.35 (582.33, 1096.53)	0.52 (0.48, 0.56)	13,521.01 (10,426.35, 17,178.92)	15,252.53 (11,765.36, 19,386.79)	0.39 (0.35, 0.43)	0.43 (0.26, 0.68)	0.39 (0.24, 0.62)	−0.41 (−0.48, −0.34)	21.44 (12.94, 34.18)	19.90 (11.95, 31.46)	−0.37 (−0.44, −0.30)
21 regions
Andean Latin America	740.60 (522.34, 996.35)	903.77 (641.06, 1205.51)	0.67 (0.66, 0.68)	13,417.37 (10,266.74, 17,188.22)	15,558.93 (11,943.78, 19,615.73)	0.54 (0.52, 0.56)	1.29 (0.65, 2.18)	1.07 (0.56, 1.82)	−0.87 (−1.05, −0.69)	64.23 (32.52, 108.17)	53.11 (27.55, 90.05)	−0.87 (−1.05, −0.69)
Australasia	430.80 (305.56, 577.12)	550.52 (391.71, 736.26)	0.81 (0.77, 0.86)	8148.55 (6207.98, 10,506.28)	10,382.01 (7933.30, 13,182.20)	0.81 (0.78, 0.84)	0.24 (0.14, 0.39)	0.32 (0.21, 0.47)	1.26 (1.08, 1.45)	11.83 (6.68, 18.92)	15.68 (10.03, 22.89)	1.22 (1.05, 1.39)
Caribbean	758.15 (536.17, 1016.24)	872.14 (622.77, 1157.82)	0.52 (0.50, 0.54)	14,487.15 (11,152.81, 18,415.83)	15,979.12 (12,388.48, 20,199.86)	0.36 (0.34, 0.38)	0.80 (0.41, 1.40)	0.85 (0.43, 1.51)	0.20 (−0.15, 0.54)	39.89 (20.15, 69.56)	42.23 (21.15, 74.63)	0.20 (−0.15, 0.55)
Central Asia	800.11 (570.56, 1066.89)	951.83 (682.27, 1265.85)	0.62 (0.57, 0.68)	15,070.62 (11,667.75, 19,133.22)	17,408.66 (13,411.33, 22,035.34)	0.48 (0.44, 0.52)	0.59 (0.33, 0.98)	1.13 (0.59, 1.93)	2.03 (1.64, 2.43)	29.65 (16.58, 49.47)	57.21 (30.01, 97.88)	2.01 (1.61, 2.41)
Central Europe	640.49 (459.50, 852.71)	740.07 (531.28, 983.95)	0.50 (0.47, 0.53)	12,114.70 (9306.16, 15,316.77)	13,670.41 (10,558.55, 17,215.39)	0.42 (0.40, 0.44)	0.43 (0.23, 0.74)	0.51 (0.27, 0.86)	−0.25 (−0.56, 0.07)	21.39 (11.37, 36.41)	24.77 (13.31, 42.05)	−0.26 (−0.56, 0.05)
Central Latin America	881.09 (627.06, 1172.46)	1045.74 (748.02, 1391.21)	0.58 (0.57, 0.59)	15,647.88 (12,049.96, 19,802.02)	18,037.51 (13,899.19, 22,803.50)	0.49 (0.47, 0.50)	1.37 (0.72, 2.31)	1.60 (0.88, 2.56)	0.42 (0.20, 0.63)	67.07 (34.91, 112.16)	78.28 (42.85, 125.02)	0.42 (0.20, 0.64)
Central Sub-Saharan Africa	641.10 (452.57, 866.56)	699.67 (493.29, 933.94)	0.25 (0.21, 0.29)	11,999.23 (9173.16, 15,429.29)	13,103.88 (9993.51, 16,840.74)	0.29 (0.26, 0.32)	0.53 (0.28, 0.95)	0.49 (0.24, 0.89)	−0.32 (−0.44, −0.20)	26.29 (13.72, 47.10)	24.25 (11.93, 44.46)	−0.30 (−0.42, −0.18)
East Asia	730.39 (516.01, 983.69)	943.66 (668.50, 1266.08)	0.88 (0.66, 1.10)	13,622.31 (10,450.52, 17,354.51)	16,558.47 (12,685.92, 21,019.55)	0.71 (0.46, 0.95)	0.30 (0.21, 0.43)	0.19 (0.13, 0.27)	−1.06 (−1.09, −1.02)	14.77 (10.11, 21.27)	9.24 (6.39, 13.25)	0.30 (0.21, 0.40)
Eastern Europe	622.56 (441.56, 832.76)	720.91 (513.05, 965.36)	0.50 (0.46, 0.54)	11,325.27 (8654.90, 14,420.30)	12,654.65 (9746.21, 16,004.59)	0.33 (0.31, 0.35)	0.30 (0.16, 0.50)	1.77 (0.92, 2.98)	−1.68 (−1.91, −1.45)	14.72 (8.01, 24.69)	87.41 (45.37, 146.98)	−1.69 (−1.93, −1.46)
Eastern Sub-Saharan Africa	690.65 (486.93, 925.21)	782.29 (553.83, 1050.29)	0.42 (0.39, 0.45)	12,885.99 (9932.53, 16,357.13)	14,466.41 (11,150.56, 18,390.73)	0.35 (0.33, 0.38)	0.47 (0.28, 0.74)	0.48 (0.29, 0.79)	−0.05 (−0.12, 0.02)	23.16 (13.91, 36.65)	24.21 (14.56, 39.26)	−0.02 (−0.09, 0.05)
High-income Asia Pacific	462.24 (330.35, 616.70)	518.14 (370.28, 689.09)	0.57 (0.48, 0.67)	8350.31 (6341.51, 10,744.15)	10,790.60 (8284.09, 13,772.33)	0.58 (0.51, 0.65)	0.25 (0.16, 0.39)	0.11 (0.07, 0.17)	−3.00 (−3.15, −2.86)	12.30 (7.83, 18.97)	5.39 (3.32, 8.24)	−2.97 (−3.11, −2.84)
High-income North America	456.93 (324.87, 608.08)	560.01 (399.76, 747.43)	0.74 (0.70, 0.78)	8556.22 (6549.33, 10,899.37)	9846.02 (7580.80, 12,542.39)	0.94 (0.88, 1.00)	0.36 (0.20, 0.60)	0.42 (0.24, 0.67)	0.50 (0.38, 0.63)	17.81 (9.93, 29.50)	20.43 (11.82, 32.96)	0.49 (0.34, 0.64)
North Africa and Middle East	1340.92 (952.29, 1804.58)	1681.18 (1199.89, 2257.41)	0.79 (0.75, 0.83)	24,720.30 (19,150.77, 31,022.54)	31,390.08 (24,516.64, 38,915.29)	0.83 (0.78, 0.88)	0.29 (0.17, 0.47)	0.31 (0.18, 0.49)	0.17 (0.15, 0.19)	14.51 (8.64, 23.28)	15.39 (9.24, 24.28)	0.21 (0.18, 0.24)
Oceania	811.06 (578.75, 1087.85)	891.77 (636.62, 1189.31)	0.31 (0.26, 0.35)	13,997.95 (10,733.57, 17,860.47)	15,271.00 (11,717.51, 19,454.83)	0.31 (0.28, 0.35)	0.31 (0.16, 0.55)	0.26 (0.14, 0.44)	−0.86 (−1.00, −0.72)	15.67 (7.82, 27.99)	12.95 (6.99, 22.41)	−0.87 (−1.01, −0.73)
South Asia	648.77 (455.13, 873.60)	816.31 (573.92, 1095.25)	0.72 (0.64, 0.80)	13,319.16 (10,251.35, 16,983.74)	15,219.13 (11,692.09, 19,384.99)	0.42 (0.33, 0.51)	0.36 (0.20, 0.62)	0.36 (0.21, 0.60)	0.03 (−0.09, 0.14)	18.23 (10.00, 31.20)	18.50 (10.58, 30.36)	0.04 (−0.08, 0.17)
Southeast Asia	801.81 (567.36, 1077.16)	946.77 (670.85, 1268.04)	0.58 (0.56, 0.60)	14,781.81 (11,399.30, 18,811.49)	16,574.86 (12,816.77, 20,938.33)	0.40 (0.38, 0.41)	0.42 (0.25, 0.67)	0.43 (0.25, 0.70)	0.15(0.08, 0.21)	20.90 (12.63, 33.88)	21.73 (12.67, 34.94)	0.13 (0.06, 0.20)
Southern Latin America	451.68 (318.75, 606.58)	570.57 (403.63, 766.32)	0.77 (0.73, 0.81)	8658.17 (6652.52, 11,125.26)	11,067.07 (8474.44, 14,175.48)	0.81 (0.77, 0.86)	0.58 (0.29, 1.03)	0.36 (0.19, 0.63)	−0.74 (−0.95, −0.53)	27.86 (13.97, 49.55)	17.71 (9.27, 30.49)	−0.74 (−0.95, −0.53)
Southern Sub-Saharan Africa	866.02 (611.06, 1167.03)	1020.29 (722.53, 1368.63)	0.58 (0.56, 0.59)	15,135.11 (11,643.96, 19,272.33)	17,432.27 (13,471.06, 21,964.83)	0.47 (0.45, 0.49)	0.67 (0.41, 1.05)	0.81 (0.51, 1.26)	0.49 (−0.15, 1.13)	34.34 (21.10, 53.11)	40.75 (25.53, 63.18)	0.43 (−0.25, 1.12)
Tropical Latin America	823.96 (583.14, 1104.43)	990.91 (703.55, 1325.44)	0.67 (0.64, 0.70)	15,740.74 (12,079.32, 20,112.55)	17,517.16 (13,539.07, 22,181.17)	0.39 (0.38, 0.41)	0.51 (0.27, 0.85)	0.43 (0.24, 0.70)	−0.57 (−0.78, −0.37)	25.64 (13.81, 42.59)	21.30 (11.91, 34.39)	−0.64 (−0.84, −0.45)
Western Europe	486.02 (348.99, 644.68)	616.89 (444.12, 816.96)	0.83 (0.77, 0.88)	8980.30 (6915.76, 11,456.04)	11,951.84 (9203.25, 15,070.92)	0.98 (0.93, 1.02)	0.63 (0.34, 1.05)	0.42 (0.25, 0.64)	−1.58 (−1.92, −1.24)	30.85 (16.44, 51.00)	20.36 (12.00, 31.19)	−1.59 (−1.90, −1.27)
Western Sub-Saharan Africa	778.45 (547.21, 1046.25)	911.40 (643.60, 1220.49)	0.51 (0.50, 0.52)	14,884.09 (11,476.39, 18,896.06)	16,708.84 (12,880.63, 21,191.35)	0.34 (0.33, 0.36)	0.55 (0.31, 0.90)	0.54 (0.32, 0.87)	−0.05 (−0.10, 0.01)	27.54 (15.77, 45.43)	27.62 (16.22, 44.31)	−0.02 (−0.08, 0.04)

ASDR = age-standardized DALYs rate, ASIR = age-standardized incidence rate, ASMR = age-standardized mortality rate, CI = confidence interval, DALYs = disability-adjusted life years, EAPCs = estimated annual percentage changes, SDI = socio-demographic index, UI = uncertainty interval.

3.3. National and regional burden of NAFLD in people aged 15 to 49 years

In 2021, Kuwait recorded the highest ASPR of NAFLD among people aged 15 to 49 years at 37,635.21 per 100,000 (95% UI: 29,503.62–46,699.96), while Egypt had the highest ASIR at 2015.91 per 100,000 (95% UI: 1421.94–2744.61). Turkmenistan exhibited the highest ASMR and ASDR among people aged 15 to 49 years, with an ASMR of 2015.91 per 100,000 (95% UI: 1421.94–2744.61) and an ASDR of 166.29 per 100,000 person-years (95% UI: 81.55–304.32). In contrast, Japan had the lowest ASPR at 8816.68 per 100,000 (95% UI: 6766.51–11,218.70), and Canada had the lowest ASIR at 442.03 per 100,000 (95% UI: 312.86–596.18) among people aged 15 to 49 years. Singapore demonstrated the lowest ASMR at 0.04 per 100,000 (95% UI: 0.02–0.06) and the lowest ASDR at 2.03 per 100,000 person-years (95% UI: 1.19–3.25) (Fig. 1A–D). Longitudinal analyses revealed that ASMR and ASDR decreased in approximately half of all countries, with Hungary exhibiting the most pronounced downward trends. In contrast, other components of NAFLD burden among people aged 15 to 49 years increased to varying degrees across different countries and regions (Fig. 2A–D). Notably, the Russian Federation showed the greatest increases in ASMR (EAPC = 6.52, 95% CI: 5.23–7.84) and ASDR (EAPC = 6.54, 95% CI: 5.22–7.88).

Figure 1.

Global prevalence of NAFLD among individuals aged 15–49 yr across both genders in 204 countries and territories. (A) Age-standardized prevalence rate (ASPR) of non-alcoholic fatty liver disease (NAFLD) in 2021; (B) Age-standardized mortality rate (ASMR) of NAFLD in 2021; (C) Age-standardized incidence rate (ASIR) of NAFLD in 2021; (D) Age-standardized disability rate (ASDR) of NAFLD in 2021.

Figure 2.

Global temporal trends of NAFLD prevalence among individuals aged 15–49 yr across both genders in 204 countries and territories from 1990–2021. (A) EPAC of the ASPR in NAFLD; (B) EPAC of the ASIR in NAFLD; (C) EPAC of the ASMR in NAFLD; (D) EPAC of the ASDR in NAFLD.

3.4. Age-sex-time association analysis of NAFLD in people aged 15 to 49 years

Age-sex association analysis in 2021 revealed that the ASPR, ASMR, and ASDR of NAFLD increased with age across different age groups, whereas the ASIR decreased with age (Fig. 3A–D). Global age-time analysis showed that ASIR and ASPR of NAFLD in all age groups gradually increased from 1990 to 2021, while ASMR and ASDR only experienced slight increases during the same period (Fig. S1A–D, Supplemental Digital Content, https://links.lww.com/MD/P972). Sex-time association analysis indicated that, globally, ASIR, ASPR, and ASDR among people aged 15 to 49 years showed a consistent upward trend from 1990 to 2021. However, ASMR and ASDR began to decline in 2009 and stabilized around 2011. Notably, the disease burden among males was approximately twice that of females (Fig. S2A–D, Supplemental Digital Content, https://links.lww.com/MD/P972).

Figure 3.

Age- and sex-specific burden of NAFLD in individuals aged 15–49 yr in 2021. (A) ASPR; (B) ASIR; (C) ASMR; (D) ASDR. Values are presented by age group and sex, with error bars indicating 95% uncertainty intervals (95% UI).

3.5. Trends in the disease burden of NAFLD in people aged 15 to 49 years

Joinpoint regression analysis indicated that, globally, the ASIR and ASPR of NAFLD among people aged 15 to 49 years generally increased from 1990 to 2021. In contrast, the ASMR and ASDR peaked in 2005, then declined, before exhibiting a slow increase again after 2012. Specifically, the AAPC was 6.361 (95% CI: 6.330–6.392) for ASMR, 107.099 (95% CI: 105.767–108.432) for ASPR, 0.001 (95% CI: 0.001–0.001) for ASIR, and 0.049 (95% CI: 0.038–0.061) for ASDR. Notably, years with significant changes across all 4 indicators were concentrated around 2015 (Fig. 4A–D).

Figure 4.

Joinpoint regression analysis of trends in NAFLD prevalence among individuals aged 15–49 yr from 1990 to 2021: (A) Age-standardized prevalence rate (ASPR); (B) Age-standardized incidence rate (ASIR); (C) Age-standardized mortality rate (ASMR); (D) Age-standardized disability rate (ASDR). Vertical dashed lines denote joinpoints at which significant alterations in trend transpired.

3.6. Association between NAFLD disease burden and SDI in people aged 15 to 49 years

Globally and across the 21 GBD regions, there was a nonlinear relationship between the SDI and the ASIR, ASPR, ASMR, and ASDR of NAFLD. Specifically, the NAFLD disease burden tended to decline slowly as SDI increased, reaching its highest levels at an SDI of approximately 0.6, after which it gradually decreased with further increases in SDI. Among the 21 GBD regions, North Africa and the Middle East showed the fastest increases in ASPR and ASIR, while Eastern Europe had the steepest rises in ASMR and ASDR (Fig. 5A–D). Across 204 countries, significant associations were observed between SDI and each NAFLD burden indicator: ASIR (P = 1.478 × 10⁻⁴), ASPR (P = 7.151 × 10⁻⁵), ASMR (P = 4.771 × 10⁻⁴), and ASDR (P = 2.222 × 10⁻⁴). Additionally, EAPCs for ASPR and ASIR increased with rising SDI, suggesting that the burden of NAFLD among people aged 15 to 49 years is becoming more severe in countries with higher SDI (Fig. 6A–D).

Figure 5.

Association between SDI and NAFLD burden among individuals aged 15–49 yr in 2021 by region. (A) ASPR; (B) ASIR; (C) ASMR; (D) ASDR. Each dot represents a region or global value, and shaded areas indicate 95% uncertainty intervals (95% UI).

Figure 6.

Trends in the EAPC of NAFLD burden among individuals aged 15–49 yr in relation to incidence rate and SDI by country in 2021. (A) ASPR; (B) ASIR; (C) ASMR; (D) ASDR. Each dot represents a country, with fitted trend lines and 95% uncertainty intervals (95% UI).

3.7. APC analysis of the burden of disease in people aged 15 to 49 years with NAFLD

Analysis of the age effect indicated that the age-standardized incidence rate peaked at 22.5 years before declining. Period effect analysis demonstrated a gradual increase in age-standardized incidence rates from 1990 to 2021. Cohort effect analysis revealed a greater burden of age-standardized incidence among more recently born cohorts compared to earlier cohorts (Fig. 7A–D). The results of the analysis for other age periods are detailed in the supplementary figure (Figs. S3A–D, S4A–D, and S5A–D, Supplemental Digital Content, https://links.lww.com/MD/P972).

Figure 7.

Age-period-cohort analysis of ASIR among people aged 15–49 yr in 2021. (A) Net drift and local drift by age group, showing annual percent change in incidence rate; (B) Age effects, indicating the incidence rate by age group; (C) Period effects, presenting rate ratios across calendar periods; (D) Cohort effects, presenting rate ratios across birth cohorts. Shaded areas represent 95% confidence interval (95% CI).

3.8. Decomposing the disease burden attributable to NAFLD in people aged 15 to 49 years

Decomposition analysis revealed that the influence of population growth on the global NAFLD disease burden – and across all 5 SDI regions and 21 GBD regions – demonstrated a similar pattern of contribution. Population growth emerged as the primary driver of the increasing NAFLD disease burden. In contrast, the contributions of population aging and epidemiologic changes varied across regions and did not exert a consistent impact on the disease burden of NAFLD (Fig. 8A–D).

Figure 8.

Decomposition analysis of changes in NAFLD burden among people aged 15–49 yr from 1990–2021 by region and SDI level. (A) ASPR; (B) ASIR; (C) ASMR; (D) ASDR. Black dots represent the overall change for each metric.

3.9. Predictive analysis of the disease burden of NAFLD in people aged 15 to 49 years

The global burden of NAFLD among people aged 15 to 49 years is expected to increase from 2022 to 2050, according to projection analysis. The ASIR is expected to reach 1088.79 per 100,000 (95% UI: 794.84–1382.75), the ASPR to 19,136.04 per 100,000 (95% UI: 15,683.05–22,589.03), the ASMR to 0.52 per 100,000 (95% UI: 0.38–0.67), and the ASDR to 19,136.03 per 100,000 person-years (95% UI: 15,683.05–22,589.03) by 2050 (Fig. S6A–D, Supplemental Digital Content, https://links.lww.com/MD/P972). These estimates result in 48,580,588 new cases of NAFLD among people aged 15 to 49 years worldwide by 2050 (95% UI: 35,464,887.93–61,696,288.79), a total prevalence of 853,824,792.58 people aged 15 to 49 years affected (95% UI: 699,756,852.43–1007,892,732.72), 23,396.47 deaths (95% UI: 16,831.78–29,961.16), and 1140,912.39 life-years lost (95% UI: 876,612.82–1405,211.96) due to NAFLD in this population (Fig. S7A–D, Supplemental Digital Content, https://links.lww.com/MD/P972).

3.10. Risk factors for ASMR

Currently, only risk factors contributing to the ASMR in NAFLD have been identified. The 5 reported risk factors are behavioral risks, high fasting plasma glucose, metabolic risks, smoking, and tobacco use. Among them, metabolic risks are the most important risk factors for ASMR (Fig. 9A–D). Over time, the disease burden of NAFLD attributable to different risk factors has shown varied trends; notably, the burden associated with high fasting plasma glucose and metabolic risks has exhibited a consistent upward trajectory year after year (Fig. 10A–D).

Figure 9.

Risk factor attribution for NAFLD in 15–49-yr olds: Global patterns and SDI-regional disparities (2021).

Figure 10.

Comparative analysis of NAFLD risk factor trajectories: Global versus 5 SDI regions, ages 15–49 yr (1990–2021).

4. Discussion

This study’s findings indicate that, from 1990 to 2021, the prevalence of people aged 15 to 49 years with NAFLD rose from 343 million to 666 million cases, alongside an increase in the age-standardized incidence rate (ASIR) from 13,312.03 per 100,000 in 1990 to 16,580.43 per 100,000 in 2021. The EAPC for all disease burden indicators demonstrated positive growth during this period, signifying a consistently increasing burden of NAFLD among people aged 15 to 49 years. These findings align with prior reports regarding trends in global, all-age NAFLD. Data from GBD 2019 indicated that the global prevalence of individuals with NAFLD escalated from 561 million to 1236 million between 1990 and 2019, while the ASPR increased from 10.49% to 15.97%, reflecting an average annual growth rate of 1.47%.^[20] In addition, a meta-analysis by Younossi et al reported a global NAFLD prevalence of 25.2%, with an increasing trend over time, particularly in regions experiencing rapid economic and lifestyle transitions.^[4] Another study based on national survey data from the United States also demonstrated a significant rise in NAFLD prevalence, from 20% in the early 2000s to over 30% by 2018.^[21] These findings independently support the notion that the global burden of NAFLD is on the rise. Notably, while the ASIR among people aged 15 to 49 years declines after age 22.5, the ASPR, ASIR, and ASDR all increase substantially with advancing age. This underscores the importance of early intervention to further reduce NAFLD incidence in younger populations. This study also found that the age-standardized NAFLD burden is higher in regions with a medium SDI compared to other regions, and relatively lower in high SDI regions. These differences may be associated with regional disparities in economic development, dietary patterns, and genetic background.^[22] Additionally, high SDI regions may benefit from greater healthcare coverage and more widespread access to health checkups and medical services,^[23] which can facilitate earlier detection of NAFLD. Studies have confirmed that early screening has a positive effect in reducing both the incidence and mortality of NAFLD.^[24,25] Currently, screening programs are available for certain populations in North America; however, low participation rates have limited the overall effectiveness of these programs.^[26] Countries with moderate SDI exhibit the highest age-standardized burden of NAFLD among the 5 SDI regions. Research has demonstrated that factors such as obesity,^[27] high-fat diets,^[28] and type 2 diabetes^[29] are closely linked to the development of NAFLD. The lifestyle and dietary patterns prevalent in medium SDI countries contribute to a higher prevalence of these risk factors, thereby increasing NAFLD incidence rates. Notably, the most pronounced increase in incidence rates was observed in high SDI regions (EAPC: 1.13), indicating that these regions are experiencing a shift in disease prevalence patterns. This trend underscores the need for targeted preventive strategies and optimization of healthcare resource allocation in order to address the evolving burden of NAFLD. Therefore, public health interventions targeting modifiable risk factors – such as obesity, poor diet, physical inactivity, type 2 diabetes, and metabolic syndrome – are particularly important in medium- and high-SDI countries to reduce the disease burden of NAFLD. Notably, in 2021, both the ASMR and ASDR in Eastern Europe were significantly higher than in other regions. Eastern Europe’s higher latitude, greater annual temperature variation, and pronounced economic disparities compared to Western and Northern Europe suggest that geographic location, lifestyle, and economic development substantially impact the NAFLD disease burden in this region.^[30] Furthermore, the ASIR and ASPR have been increasing most rapidly in North Africa and the Middle East, trends closely associated with rapid urbanization, rising obesity rates, and a high prevalence of diabetes and other metabolic risk factors. This trend is particularly concerning, as many countries in these regions may lack the healthcare infrastructure necessary to address the escalating burden of NAFLD. At the national level, countries such as Kuwait, Egypt, and Turkmenistan exhibit comparatively high levels of NAFLD disease burden, while high-income countries such as Japan, Canada, and Singapore demonstrate significantly lower burden levels. These disparities are likely attributable to differences in dietary habits (such as high-fat, high-sugar diets and elevated calorie intake), prevalence of obesity, genetic backgrounds, and the comprehensiveness of existing public health systems.^[31]

This study found that the disease burden of NAFLD is significantly associated with both age and gender. By 2021, both the ASIR and ASPR were higher in men than in women, and in over 65% of regions, men had higher DALY and mortality rates compared to women. The data suggest that, relative to women, men tend to have greater amounts of visceral fat and generally engage in less physical activity. Increased visceral fat is closely linked to elevated risk for metabolic diseases,^[32] which is consistent with the risk factor analysis findings in this study. Additionally, estrogen is known to exert a protective effect on the liver in women, reducing hepatic fat accumulation.^[33] Women with higher estrogen levels have a lower risk of developing NAFLD, while androgens may contribute to increased hepatic fat accumulation. Men typically have higher levels of androgens, which contributes to an increased risk of developing NAFLD, consistent with the findings of this study.^[34] Moving forward, it is important to strengthen screening and health education in regions where the ASIR among men is rising. In regions with a high disease burden among women, efforts should focus on expanding access to healthcare services, promoting health education, and implementing targeted lifestyle intervention programs to help reduce global gender disparities in NAFLD burden. From an age perspective, the ASPR, ASMR, and ASDR all peak in the 45 to 49 age group. Notably, the ASIR is highest among those aged 15 to 19, a pattern that reflects the natural history of disease progression. These findings further underscore the necessity of prioritizing public health interventions and investments targeting people aged 15 to 49 years to effectively curb the incidence of NAFLD. Joinpoint regression analysis revealed that although NAFLD mortality rates experienced a brief decline after 2005, the overall disease burden has continued to increase. This trend may be largely attributable to the rapidly growing global prevalence of obesity and metabolic syndrome.^[35,36] Projections from this study indicate that by 2050, the worldwide number of people with NAFLD, as well as NAFLD-related deaths and DALYs, will increase substantially. These findings suggest that NAFLD will remain a major public health challenge for healthcare systems globally in the coming decades.

Using data from the GBD database, this study identified tobacco (smoking) and metabolic risk – particularly high fasting blood glucose – as the 2 most significant factors influencing NAFLD mortality. Smoking appears to directly impact insulin resistance by lowering adiponectin levels, which are linked to lipid metabolism and visceral fat accumulation, thereby increasing central obesity. Notably, smoking in combination with type 2 diabetes elevates specific inflammatory cytokines (IL-1, IL-6, IL-8), which promote oxidative stress in the liver and exacerbate NAFLD progression.^[37] Additionally, smoking leads to increased nicotine levels in the gut, and the accumulation of nicotine activates the intestinal AMPKα pathway, triggering ceramide production and further advancing NAFLD.^[38] Metabolic risk factors, especially high fasting blood glucose, have shown a consistently increasing influence on NAFLD patients across all SDI regions, consistent with previous findings.^[39] Hyperglycemia-induced insulin resistance disrupts hepatic lipid metabolism, promoting fat accumulation in liver cells. According to recent research from 2023,^[40] individuals with type 2 diabetes have a 2.28-fold higher risk of developing liver fibrosis compared to controls, making type 2 diabetes a major driver of the NAFLD burden – particularly in low-SDI countries. The evolving trends in attributable risk factors are closely related to economic constraints, limited healthcare access, inadequate health education, and nutritional imbalances. These findings underscore the importance of developing personalized intervention strategies to effectively reduce NAFLD mortality risk in the future.

This study offers a comprehensive and systematic examination of the NAFLD burden; however, numerous challenges persist. A primary concern is the heterogeneity and imbalance of data sources; outcomes obtained from the GBD database are significantly influenced by the scope and quality of data collection across various regions. The absence of comprehensive data from low-income countries may lead to a systematic underappraisal of the actual disease burden. Methodological constraints are also evident. Although advanced statistical modeling techniques are utilized, these models may inadequately represent the intricacies of clinical realities, especially in data-deficient environments. Population-level data may neglect individual-level variations, including genetic predisposition, lifestyle influences, and environmental exposures. This study did not comprehensively integrate multidimensional social factors that could affect disease distribution. Factors such as socioeconomic status, healthcare accessibility, and cultural practices can profoundly influence the prevalence and progression of NAFLD; however, existing analytical frameworks may not sufficiently incorporate these moderating variables. Furthermore, despite the study covering an extensive duration, it may be difficult to comprehensively represent the swiftly evolving dynamics of health ecosystems. Emerging risk factors, including metabolic disorders and changes in gut microbiota, may exert considerable yet underappreciated effects on disease onset. To augment the scientific merit of forthcoming research, endeavors should concentrate on amalgamating high-quality data from varied sources, executing more profound individual-level analyses, and perpetually observing the evolving impact of emerging risk factors. These measures will facilitate the creation of more precise and comprehensive disease burden assessment models.

5. Conclusion

Overall, the global disease burden of NAFLD among people aged 15 to 49 years continues to rise, closely associated with age, gender, regional economic levels, and metabolic risk factors. To address this growing challenge, global public health systems must adopt proactive measures to strengthen disease management and prevention strategies, particularly in high-risk regions, in order to mitigate the public health crisis posed by NAFLD.

Acknowledgments

We acknowledge the Global Burden of Disease Study 2021 for making their database openly available.

Author contributions

Conceptualization: Mengqin Wang, Nengwei Zhang.

Data curation: Mengqin Wang.

Formal analysis: Qiqige Wuyun.

Funding acquisition: Nengwei Zhang.

Investigation: Qiqige Wuyun, Dongbo Lian.

Methodology: Dongbo Lian.

Project administration: Guangzhong Xu.

Resources: Guangzhong Xu.

Validation: Guangyi Zhu.

Visualization: Guangyi Zhu.