Global burden of nonalcoholic fatty liver disease from 1990 to 2046: A global population-based observational trend analysis using GBD 2021 data

Abstract

Nonalcoholic fatty liver disease (NAFLD; now often termed metabolic dysfunction-associated steatotic liver disease), driven by obesity and lifestyle changes, affects approximately 25% of the world’s population and imposes growing public-health, economic, and healthcare burdens with widening disparities. We analyzed incidence, prevalence, mortality, and disability-adjusted life years (DALYs) for NAFLD using data from the Global Burden of Disease 2021 study across 5 socio-demographic index (SDI) quintiles, 21 Global Burden of Disease regions, and 204 countries and territories. We quantified temporal trends (1990–2021), geographic patterns, and SDI correlations; performed age–period–cohort modeling, decomposition and health-inequality analyses; and generated projections to 2046, including frontier analyses. From 1990 to 2021, the global NAFLD burden increased substantially. Incidence increased 1.95-fold over this period, corresponding to an absolute rise of ~23.5 million cases (≈23,497,114), driven chiefly by population growth (~74%) and epidemiologic change (~34%), with additional contributions from population aging. Prevalence, mortality, and DALYs also rose worldwide, with the heaviest burdens observed in intermediate-SDI countries and high-burden regions in North Africa, the Middle East, and Latin America. Inequality analyses indicated widening disparities for prevalence, mortality, and DALYs. Projections suggest continued growth through 2046, with persistent sex differences in prevalence. NAFLD remains a pervasive global health challenge marked by pronounced geographic and sociodemographic disparities. Targeted prevention and intervention strategies are needed, particularly for intermediate-SDI settings and identified high-burden regions.

1. Introduction

Nonalcoholic fatty liver disease (NAFLD) has emerged as a significant global health concern in recent decades, driven by the rising prevalence of obesity, type 2 diabetes, and metabolic syndrome. It is characterized by excessive fat accumulation in the liver unrelated to alcohol consumption. NAFLD encompasses a spectrum of conditions ranging from simple steatosis to nonalcoholic steatohepatitis, which may progress to cirrhosis, hepatocellular carcinoma, and liver failure.^[1,2] The asymptomatic progression of NAFLD in its early stages poses significant challenges for timely diagnosis and intervention, thereby rendering it a critical public health concern. In 2024, international societies updated the nomenclature from NAFLD to metabolic dysfunction-associated steatotic liver disease (MASLD); in this study we retain “NAFLD” for consistency with Global Burden of Disease (GBD) 2021 definitions and address implications of this terminology change in Section 4.

Globally, the prevalence of NAFLD has been observed to rise in tandem with changes in lifestyle, urbanization, and dietary shifts,^[3–5] affecting individuals of all ages and regions. Current estimates indicate that NAFLD affects approximately 25% of the world’s population,^[6] with substantial regional disparities influenced by socioeconomic, genetic, and environmental factors.^[7] High-income countries frequently report elevated prevalence rates due to sedentary lifestyles and dietary patterns rich in fats and sugars, while the burden is rapidly rising in low- and middle-income countries undergoing epidemiological and nutritional transitions.^[8,9]

The epidemiology of NAFLD is further complicated by notable variations across demographic groups, including disparities by sex and age.^[1] Men generally exhibit higher prevalence rates, although postmenopausal women face an increased risk, potentially due to hormonal changes.^[10] The intricate interplay of these factors underscores the necessity of comprehensive studies to elucidate the drivers of these disparities and inform targeted prevention strategies.

Despite the mounting evidence of its public health implications, global attention to NAFLD remains inadequate. In contrast to other chronic liver diseases, NAFLD lacks dedicated policies, funding, and standardized clinical guidelines across many regions. The Institute for Health Metrics and Evaluation is responsible for the annual updates to the GBD studies. These updates incorporate new datasets that become available, improve methodological performance, and adopt changes in the scientific understanding of diseases. Accordingly, the GBD estimates become more complete and accurate over time; GBD 2021 (released in 2024) represents the most recent iteration and supersedes prior versions (GBD 1990, 2010, 2013, 2015, 2016, 2017, 2019, and 2020).^[11]

The primary objective of this study is to present a comprehensive and multifaceted analysis of the global, regional, and national burden of NAFLD from 1990 to 2046. Leveraging advanced statistical methodologies, including age–period–cohort analysis, decomposition techniques, and health inequality assessments, this study examines trends in prevalence, mortality, and disability-adjusted life years (DALYs) while investigating disparities across regions, sexes, and income levels. To enhance clarity and reproducibility, we prespecify study objectives and align terminology with GBD 2021 case definitions. By illuminating the evolving landscape of NAFLD, this analysis provides critical insights into the disease’s potential trajectory and highlights the urgent need for evidence-based interventions and policy development. In the context of the ongoing transition to the endemic phase of the COVID-19 pandemic, this study aims to support the formulation of novel strategies for the public health management of NAFLD, offering guidance for the emerging post-pandemic public health framework.

2. Materials and methods

2.1. Study design and objectives

This was a global, population-based observational trend analysis using secondary data from GBD 2021.

Primary objectives were to quantify levels and trends (1990–2021) in incidence, prevalence, deaths, and DALYs for NAFLD across 5 socio-demographic index (SDI) quintiles, 21 regions, and 204 countries/territories, and to project burden through 2046. Secondary objectives were to: decompose changes by population growth, population aging, and epidemiologic change; assess inequalities by SDI using absolute and relative metrics; and benchmark performance using frontier analysis. A schematic workflow of data sources and analytic steps is provided in Figure S1, Supplemental Digital Content, https://links.lww.com/MD/R350.

2.2. Ethics statement

This study used publicly available, de-identified data from the GBD 2021 study. Therefore, institutional review board approval and informed consent were not required.

2.3. Data source

This study utilized data from the GBD 2021 database (https://ghdx.healthdata.org/gbd-2021), which provides comprehensive estimates for 204 countries and territories, 371 diseases and injuries, and 88 risk factors. We extracted data on incidence, prevalence, DALYs, and deaths for NAFLD including cirrhosis from 1990 to 2021 for all age groups. GBD 2021 employs a Bayesian meta-regression tool, DisMod-MR 2.1, to generate estimates of disease burden. This tool integrates multiple data sources and adjusts for variations in study methods and case definitions. Age-standardized rates were calculated using the GBD world population age standard.^[12–15] All estimates are reported with 95% uncertainty intervals (UIs) derived from 1000 draw-level simulations per GBD methodology.

2.4. Disease definition

NAFLD is classified under the International Classification of Diseases, 11th Revision code DB92, categorized as a level 4 disease under liver cirrhosis, which falls under the broader categories of digestive system diseases and noncommunicable diseases.^[14,15] Terminology note: in line with current nomenclature, NAFLD is often termed MASLD; we retained “NAFLD” to match GBD 2021 case definitions and address implications in Section 4.

2.5. Statistical analysis

2.5.1. Trend analysis (estimated annual percentage change [EAPC])

We employed a comprehensive suite of statistical methods to analyze the NAFLD burden.

EAPC: To quantify long-term trends in age-standardized rates (ASR), we fit a linear regression to the natural logarithm of ASR against calendar year: ln(ASR) = α + β × year + ε. EAPC was summarized as EAPC = 100 × (exp(β) − 1), with 95% confidence intervals (95% CIs) from the model. Intuition: β captures the average proportional yearly change in ASR; a positive EAPC indicates increasing rates over time.

2.5.2. Age–period–cohort (APC) models

APC analysis: we constructed APC models using generalized linear models to disentangle the effects of age, period, and birth cohort on NAFLD burden. The model was specified as log(E[rᵢⱼ]) = μ + αᵢ + βⱼ + γ^k, where rᵢⱼ is the rate for age group i in time period j, αᵢ is the age effect, βⱼ the period effect, and γ^k the cohort effect. Intuition: age effects reflect biological/clinical risk across life course; period effects reflect time-varying exposures, diagnostics, or coding; cohort effects reflect generation-specific exposures.

2.5.3. Frontier analysis (data envelopment analysis [DEA])

Frontier analysis: DEA was used to construct an efficiency frontier, allowing us to assess the relative performance of countries in health improvement. We employed an output-oriented DEA model with variable returns to scale, treating favorable NAFLD outcomes (e.g., lower ASR at given SDI) as outputs to identify best-performing peers. Intuition: countries on the frontier represent attainable performance benchmarks for peers with similar inputs.

2.5.4. Health inequality analysis

Health inequality analysis: we used the slope index of inequality (SII) to measure absolute inequality and the concentration index (CI) to measure relative inequality across SDI-ranked groups. SII was estimated via weighted least squares regressing outcomes on mid-ranked relative SDI; CI was computed via the covariance method between outcomes and the fractional SDI rank. Intuition: SII quantifies the outcome difference between the extremes of the SDI spectrum; CI summarizes whether burden is concentrated among lower- or higher-SDI groups.

2.5.5. Decomposition analysis

Decomposition analysis: we attributed changes in counts (incidence, prevalence, deaths, and DALYs) to population growth, population aging, and epidemiologic change using Das Gupta’s demographic decomposition framework. Intuition: this separates demographic structure effects from changes in age-specific rates, clarifying what drives growth in burden.

2.6. SDI relationship

SDI analysis: we explored the relationship between NAFLD burden and SDI (a composite of income per capita, educational attainment, and total fertility rate) using locally estimated scatterplot smoothing smoothing and Spearman rank correlation.

2.7. Projections to 2046

Nordic cancer prediction model (adapted for APC projections) APC prediction: we projected NAFLD burden from 2022 to 2046 using the Nordic cancer prediction model (adapted for APC projections) age–period–cohort framework implemented within the Integrated Nested Laplace Approximation environment. This approach models recent trends while penalizing implausible extrapolations and propagating uncertainty.

2.8. Software and reproducibility

All statistical analyses were performed using R version 4.4.1. We used the GBD 2021 methodology for age standardization and uncertainty analysis, employing 1000 draw-level estimates to calculate 95% UIs for all metrics. The mgcv package was used for generalized additive models, benchmarking for DEA, Integrated Nested Laplace Approximation for Bayesian modeling, and ggplot2 for data visualization. All code will be made available upon reasonable request to enhance reproducibility.

3. Results

3.1. Global burden of NAFLD from 1990 to 2021: incidence, prevalence, mortality, and DALYs

Between 1990 and 2021, the global disease burden of NAFLD displayed a marked upward trajectory (Fig. 1 and Fig. S2, Supplemental Digital Content, https://links.lww.com/MD/R350). According to data from the Global Burden of Disease study, the incidence of NAFLD increased from 24,856,158.66 cases (95% UI: 22,579,697.49–27,333,109.87) in 1990 to 48,353,272.35 cases (95% UI: 44,229,138.51–52,358,017.44) in 2021, with the age-standardized incidence rate (ASIR) rising from 475.543 to 593.277 per 100,000 population. The EAPC was 0.733% (95% CI: 0.694–0.773) (Table 1). Similarly, NAFLD prevalence exhibited a parallel trend, increasing from 564,432,127.8 cases in 1990 to 1267,867,997 cases in 2021, and the ASR rose from 12,085.091 to 15,018.065 per 100,000 population (Table S1, Supplemental Digital Content, https://links.lww.com/MD/R350). Despite the pronounced escalation in incidence and prevalence, NAFLD-related mortality exhibited a relatively modest rise, with its ASR incrementally increasing from 1.534 to 1.618 per 100,000 population during the same period (Table S2, Supplemental Digital Content, https://links.lww.com/MD/R350). Meanwhile, the DALYs attributable to NAFLD also grew, with the ASR increasing from 40.2 to 42.403 per 100,000 population between 1990 and 2021 (Table S3, Supplemental Digital Content, https://links.lww.com/MD/R350). Collectively, these findings indicate that NAFLD has emerged as an increasingly critical global public health challenge, necessitating heightened attention and efficacious preventive strategies.

Figure 1.

Global and SDI regional trends in age-standardized NAFLD burden, 1990 to 2021. Lines show ASRs for incidence, prevalence, deaths, and DALYs for females and males globally and across five SDI quintiles (GBD 2021). Key message: NAFLD burden rose worldwide with persistent sex differences and highest levels in intermediate-SDI settings. ASR = age-standardized rate, DALY/DALYs = disability-adjusted life year(s), GBD = Global Burden of Disease, SDI = socio-demographic index.

Table 1.

Global, SDI, and regional NAFLD incidence in 1990 and 2021.

Location	Incidence
	Num_1990 (95% UI)	Num_2021 (95% UI)	ASR_1990 per 100,000 (95% UI)	ASR_2021 per 100,000 (95% UI)	EAPC (95% CI)
Global	24,856,158.66 (22,579,697.49–27,333,109.87)	48,353,272.35 (44,229,138.51–52,358,017.44)	475.543 (432.593–518.194)	593.277 (542.717–643.704)	0.733 (0.694–0.773)
High SDI	3,262,720.597 (2,977,823.551–3,550,597.017)	5,326,140.805 (4,910,092.391–5,729,423.928)	342.717 (312.231–373.46)	450.025 (412.198–488.427)	0.999 (0.951–1.047)
High-middle SDI	5,404,817.625 (4,893,944.225–5,906,253.772)	8,509,328.085 (7,857,781.779–9,203,998.94)	478.36 (435.279–522.096)	611.287 (557.972–665.561)	0.803 (0.711–0.895)
Middle SDI	9,002,611.366 (8,141,914.148–9,945,635.922)	17,017,312.52 (15,552,700.12–18,416,002.69)	533.689 (485.354–580.654)	656.974 (602.082–712.86)	0.683 (0.646–0.721)
Low-middle SDI	5,235,751.858 (4,734,019.629–5,777,133.434)	12,064,461.85 (10,980,813.99–13,233,265.32)	520.735 (474.207–566.643)	623.222 (569.615–676.225)	0.586 (0.552–0.621)
Low SDI	1,925,958.277 (1,735,020.473–2,127,906.338)	5,396,909.323 (4,857,493.864–5,987,672.283)	483.421 (440.216–527.627)	553.739 (503.532–605.081)	0.443 (0.413–0.473)
Andean Latin America	171,832.314 (155,690.714–189,720.273)	399,223.317 (366,915.68–433,221.907)	494.929 (453.456–540.745)	582.608 (536.856–630.666)	0.548 (0.54–0.557)
Australasia	62,855.493 (56,928.693–68,897.795)	117,958.488 (108,097.057–127,026.224)	288.078 (261.954–315.058)	358.845 (328.045–390.768)	0.723 (0.683–0.763)
Caribbean	178,950.117 (162,837.72–196,254.675)	287,884.015 (264,113.467–310,034.301)	513.739 (471.205–559.145)	576.802 (528.704–623.406)	0.423 (0.409–0.437)
Central Asia	347,731.082 (317,651.126–383,978.012)	583,558.982 (530,899.643–636,274.841)	530.144 (485.065–576.45)	612.967 (560.966–665.273)	0.518 (0.473–0.563)
Central Europe	548,337.716 (502,232.085–593,266.006)	569,426.058 (525,602.348–613,240.431)	419.013 (384.119–454.712)	471.534 (433.074–510.899)	0.404 (0.379–0.429)
Central Latin America	881,456.388 (800,893.37–971,674.167)	1,786,199.458 (1,641,450.569–1,939,007.984)	581.198 (531.695–632.776)	669.441 (615.971–726.193)	0.477 (0.466–0.488)
Central Sub-Saharan Africa	193,050.391 (173,259.392–215,527.732)	549,882.738 (493,162.38–610,867.295)	434.612 (395.266–476.05)	469.078 (426.906–513.719)	0.224 (0.189–0.258)
East Asia	6,397,502.754 (5,758,117.661–7,055,942.247)	9,905,422.954 (9,094,622.577–10,735,336.06)	495.869 (449.652–540.965)	620.37 (565.232–675.904)	0.735 (0.574–0.896)
Eastern Europe	1,003,375.738 (918,186.67–1,086,542.813)	1,035,049.768 (952,601.259–1,117,151.812)	418.62 (384.11–454.773)	471.809 (433.228–511.728)	0.407 (0.374–0.439)
Eastern Sub-Saharan Africa	702,062.136 (625,656.652–783,545.725)	1,953,106.134 (1,744,597.892–2,184,436.957)	468.641 (425.873–512.549)	522.514 (475.303–570.838)	0.364 (0.342–0.385)
High-income Asia Pacific	591,333.666 (539,681.509–643,475.197)	728,246.237 (664,400.946–786,976.738)	310.565 (282.75–338.691)	348.79 (319.192–378.614)	0.527 (0.453–0.602)
High-income North America	974,201.216 (886,653.744–1,063,602.529)	1,635,645.929 (1,495,034.227–1,770,494.136)	321.774 (293.448–350.951)	391.24 (357.035–425.569)	0.705 (0.677–0.732)
North Africa and Middle East	2,621,742.995 (2,382,526.779–2,885,697.742)	6,578,945.51 (6,067,957.17–7,080,113.305)	849.022 (777.987–920.823)	1037.642 (963.009–1109.647)	0.705 (0.673–0.737)
Oceania	31,401.523 (28,265.901–34,937.836)	76,653.583 (69,527.755–84,514.604)	542.509 (493.895–593.466)	588.567 (538.685–640.661)	0.268 (0.234–0.301)
South Asia	4,362,687.945 (3,921,919.592–4,818,166.709)	10,765,350.57 (9,758,063.805–11,817,448.59)	464.891 (421.182–507.16)	564.192 (513.265–615.451)	0.609 (0.55–0.669)
Southeast Asia	2,347,042.807 (2,125,152.569–2,601,001.331)	4,606,197.413 (4,201,349.07–5,033,587.853)	541.659 (491.921–590.089)	622.697 (569.31–678.689)	0.484 (0.465–0.504)
Southern Latin America	154,123.806 (140,379.97–168,851.096)	283,022.255 (258,970.006–307,037.96)	313.828 (285.645–343.422)	386.422 (352.6–420.052)	0.682 (0.645–0.718)
Southern Sub-Saharan Africa	273,213.002 (245,837.163–304,043.015)	532,714.012 (484,100.803–584,242.023)	570.398 (520.519–622.357)	651.93 (597.179–709.272)	0.469 (0.459–0.478)
Tropical Latin America	806,667.906 (732,235.238–888,591.41)	1,584,117.687 (1,456,856.301–1,706,172.497)	557.117 (509.054–604.168)	648.829 (596.358–700.521)	0.553 (0.531–0.574)
Western Europe	1,387,072.887 (1,270,984.83–1,508,210.435)	1,871,635.082 (1,719,781.978–2,008,903.796)	324.924 (296.515–354.409)	401.692 (368.546–435.699)	0.731 (0.687–0.776)
Western Sub-Saharan Africa	818,838.769 (737,068.539–907,475.424)	2,501,855.881 (2,243,383.607–2,767,096.315)	521.281 (474.891–569.126)	597.04 (544.272–651.741)	0.439 (0.428–0.451)

Counts and ASRs (per 100,000) with 95% UIs; GBD 2021 definitions.

95% CI = 95% confidence interval, ASR = age-standardized rates, EAPC = estimated annual percentage change, GBD = Global Burden of Disease, NAFLD = nonalcoholic fatty liver disease, SDI = socio-demographic index, UIs = uncertainty intervals.

3.2. Sociodemographic index-based analysis of NAFLD burden from 1990 to 2021

Between 1990 and 2021, the global burden of NAFLD demonstrated notable disparities according to the social development index (Figs. 1, 2, and Fig. S2, Supplemental Digital Content, https://links.lww.com/MD/R350). In high-SDI regions, the ASIR of NAFLD increased from 342.717 per 100,000 population in 1990 to 450.025 in 2021, with an EAPC of 0.999% (95% CI: 0.951–1.047), reflecting the most pronounced rise (Table 1). Regarding prevalence, the ASR in high-SDI regions climbed from 8520.076 to 11,543.685, registering an EAPC of 1.093% (95% CI: 1.047–1.139) and similarly showing the fastest growth (Table S1, Supplemental Digital Content, https://links.lww.com/MD/R350).

Figure 2.

Age-specific patterns of NAFLD burden by sex and region, 2021. Panels depict age-specific rates for incidence, prevalence, deaths, and DALYs for females and males across 5 SDI and 21 GBD regions. Key message: Rates typically increase from early adulthood and peak in middle-to-older ages; males generally show higher rates than females across regions. DALY/DALYs = disability-adjusted life year(s), GBD = Global Burden of Disease, SDI = socio-demographic index.

However, mortality trends varied across SDI levels. In high-SDI and high-middle-SDI regions, mortality showed relatively slow or slightly declining trends, whereas middle-SDI and low-middle-SDI regions exhibited increasing trends (Table S2, Supplemental Digital Content, https://links.lww.com/MD/R350). Concerning DALYs, low-SDI regions experienced a downward trend (EAPC = –0.421, 95% CI: ‐0.464 to ‐0.378), whereas other SDI categories showed varying degrees of increase (Table S3, Supplemental Digital Content, https://links.lww.com/MD/R350).

3.3. Global and regional trends in NAFLD burden: a comprehensive analysis from 1990 to 2021

Between 1990 and 2021, the global burden of NAFLD displayed marked regional disparities and dynamic shifts (Fig. 2, Figs. S3 and S4, Supplemental Digital Content, https://links.lww.com/MD/R350). Regarding incidence, the North Africa and Middle East region consistently reported the highest levels, with the ASIR rising from 849.022 per 100,000 population in 1990 to 1037.642 in 2021, corresponding to an EAPC of 0.705% (95% CI: 0.673–0.737) (Table 1). Prevalence in this region was also the highest, with the ASR increasing from 21,902.488 to 27,686.687 (Table S1, Supplemental Digital Content, https://links.lww.com/MD/R350). Eastern Europe exhibited the most pronounced change in mortality, where the ASR climbed from 0.919 to 2.662, yielding an EAPC of 3.58% (95% CI: 2.945–4.219) (Table S2, Supplemental Digital Content, https://links.lww.com/MD/R350). In terms of DALYs, Eastern Europe again showed the largest uptick, with the ASR advancing from 26.282 to 91.401, corresponding to an EAPC of 4.086% (95% CI: 3.279–4.898) (Table S3, Supplemental Digital Content, https://links.lww.com/MD/R350). By contrast, multiple metrics demonstrated downward trends in the high-income Asia-Pacific region, notably DALYs (EAPC = ‐2.536%, 95% CI: ‐2.684 to ‐2.387). Of note, although the NAFLD burden generally trended upward in most regions, certain areas (including Central Sub-Saharan Africa and Oceania) displayed declining patterns in DALYs. Collectively, these findings underscore the global heterogeneity of the NAFLD burden.

3.4. Sex- and age-specific trends in the global burden of NAFLD from 1990 to 2021

Between 1990 and 2021, the global burden of NAFLD exhibited pronounced sex-related differences (Fig. 3 and Fig. S5, Supplemental Digital Content, https://links.lww.com/MD/R350). Overall, the burden in males exceeded that in females, although both showed increasing trends. In terms of incidence, the ASIR in 2021 reached 621.154 per 100,000 for males and 563.174 per 100,000 for females, with the EAPC being slightly higher in males (0.749% vs 0.709%) (Table 2). Regarding prevalence, the 2021 ASR for males was 15,731.398, whereas it was 14,310.638 for females, with a similar pattern of higher EAPC in males (0.744% vs 0.712%) (Table S4, Supplemental Digital Content, https://links.lww.com/MD/R350).

Figure 3.

EAPC in NAFLD burden by age, sex, and region, 1990 to 2021. EAPCs for age-specific rates in incidence, prevalence, deaths, and DALYs for both sexes combined, females, and males across SDI and GBD regions. Key message: Incidence/prevalence trend upward in most regions, while mortality/DALY trends are heterogeneous. DALY/DALYs = disability-adjusted life year(s), EAPC = estimated annual percentage change, GBD = Global Burden of Disease, SDI = socio-demographic index.

Table 2.

Global NAFLD incidence by age and sex, 1990 and 2021.

Factor	Incidence
	Num_1990 (95% UI)	Num_2021 (95% UI)	ASR_1990 per 100,000 (95% UI)	ASR_2021 per 100,000 (95% UI)	EAPC (95% CI)
Sex
Male	13,259,943.89 (12,037,899.65–14,608,809.97)	25,232,811.09 (23,143,239.1–27,352,824.82)	501.176 (456.714–546.994)	621.154 (569.615–675.134)	0.749 (0.694–0.803)
Female	11,596,214.77 (10,496,152.41–12,736,326)	23,120,461.25 (21,081,233.38–25,053,974.38)	448.861 (408.227–490.396)	563.174 (513.265–612.38)	0.709 (0.68–0.739)
Age
<5	/	/	/	/	/
5 to 9	/	/	/	/	/
10 to 14	/	/	/	/	/
15 to 19	4,505,153.761 (3,442,833.385–5,653,029.14)	6,843,922.724 (5,242,960.737–8,636,864.694)	867.337 (662.818–1088.328)	1096.818 (840.245–1384.158)	0.787 (0.759–0.815)
20 to 24	4,577,630.508 (3,502,724.92–5,794,127.873)	7,128,909.209 (5,483,966.409–8,973,147.096)	930.246 (711.809–1177.458)	1193.806 (918.344–1502.642)	0.839 (0.794–0.884)
25 to 29	3,417,801.024 (2,304,555.773–4,635,083.879)	5,866,528.915 (3,981,255.395–7,946,946.082)	772.176 (520.663–1047.193)	997.127 (676.689–1350.733)	0.879 (0.827–0.931)
30 to 34	2,502,452.209 (1,729,478.715–3,449,717.397)	5,079,618.961 (3,513,863.017–6,956,569.094)	649.275 (448.723–895.048)	840.328 (581.303–1150.835)	0.866 (0.797–0.936)
35 to 39	2,049,991.28 (1,369,729.65–2,949,957.53)	4,163,252.557 (2,777,993.582–5,990,622.66)	581.98 (388.858–837.474)	742.29 (495.304–1068.102)	0.806 (0.743–0.869)
40 to 44	1,550,297.028 (1,029,401.47–2,177,919.422)	3,433,799.533 (2,288,531.83–4,853,965.569)	541.151 (359.325–760.23)	686.416 (457.477–970.306)	0.777 (0.731–0.823)
45 to 49	1,214,227.464 (770,598.14–1,700,574.234)	3,088,838.379 (1,987,421.163–4,368,376.588)	522.933 (331.875–732.389)	652.335 (419.726–922.563)	0.74 (0.699–0.781)
50 to 54	1,131,154.98 (715,360.113–1,758,758.225)	2,922,686.007 (1,851,893.186–4,477,932.366)	532.129 (336.527–827.373)	656.897 (416.228–1006.451)	0.676 (0.631–0.721)
55 to 59	1,078,974.659 (712,784.095–1,576,468.784)	2,782,790.825 (1,818,388.573–4,059,629.366)	582.6 (384.873–851.225)	703.208 (459.505–1025.864)	0.586 (0.541–0.63)
60 to 64	1,015,342.012 (661,413.392–1,410,597.771)	2,378,606.704 (1,549,196.502–3,307,751.061)	632.182 (411.815–878.279)	743.203 (484.052–1033.518)	0.496 (0.469–0.524)
65 to 69	797,808.68 (511,127.266–1,115,001.487)	2,034,589.33 (1,306,668.752–2,840,369.037)	645.427 (413.502–902.036)	737.592 (473.702–1029.708)	0.396 (0.383–0.409)
70 to 74	493,472.721 (320,907.153–683,731.062)	1,295,922.583 (823,069.313–1,793,252.74)	582.88 (379.049–807.609)	629.58 (399.86–871.191)	0.267 (0.252–0.282)
75 to 79	295,472.665 (179,603.604–427,291.488)	677,658.744 (413,241.382–986,192.423)	480.01 (291.775–694.156)	513.828 (313.336–747.77)	0.17 (0.152–0.188)
80 to 84	146,266.943 (93,168.263–225,914.559)	377,732.863 (242,464.746–583,625.32)	413.465 (263.366–638.611)	431.285 (276.84–666.368)	0.099 (0.069–0.129)
85 to 89	58,222.76 (38,211.372–86,544.437)	180,817.09 (117,829.116–270,291.389)	385.299 (252.87–572.722)	395.472 (257.709–591.165)	0.06 (0.024–0.095)
90 to 94	17,354.859 (10,885.842–25,067.693)	73,240.473 (45,846.891–106,596.208)	404.996 (254.034–584.985)	409.408 (256.28–595.863)	0.03 (0.006–0.055)
95 plus	4535.111 (2481.956–7167.827)	24,357.448 (13,321.777–38,524.232)	445.454 (243.786–704.049)	446.9 (244.422–706.827)	0.012 (‐0.008–0.032)

Age-grouped counts and ASRs (95% UIs).

95% CI = 95% confidence interval, ASR = age-standardized rates, EAPC = estimated annual percentage change, NAFLD = nonalcoholic fatty liver disease, UIs = uncertainty intervals.

Mortality showed a more substantial rise in males (EAPC = 0.323%), compared to females (EAPC = 0.105%), although the ASR values for the 2 sexes converged by 2021 (1.658 vs 1.570 per 100,000) (Table S5, Supplemental Digital Content, https://links.lww.com/MD/R350). Similarly, the increase in DALY(s) was more pronounced in males (EAPC = 0.284%) than in females (0.057%), leading to higher ASR values in males by 2021 (44.895 vs 39.811) (Table S6, Supplemental Digital Content, https://links.lww.com/MD/R350). These findings underscore a faster-growing NAFLD burden among males, despite the overall rise for both sexes.

Globally, NAFLD also demonstrated clear age-related trends from 1990 to 2021. For incidence, the 20 to 24-year age group showed the highest EAPC at 0.839% (95% CI: 0.794–0.884), whereas the 95+ age group exhibited the lowest rate of increase (EAPC = 0.012%, 95% CI: ‐0.008 to 0.032) (Table 2). In terms of prevalence, individuals aged 40 to 49 had the highest EAPC (approximately 0.794%), whereas those aged 15 to 19 had the lowest (0.595%, 95% CI: 0.583–0.606) (Table S4, Supplemental Digital Content, https://links.lww.com/MD/R350).

Regarding mortality, the most rapid uptick was observed among the 25 to 29-year age group, with an EAPC of 0.594% (95% CI: 0.362–0.826), while the 50 to 54-year age group experienced the most substantial decrease (EAPC = ‐0.014%, 95% CI: ‐0.168 to 0.141) (Table S5, Supplemental Digital Content, https://links.lww.com/MD/R350). A similar pattern emerged for DALYs, where the 25 to 29-year age group exhibited the highest EAPC at 0.596% (95% CI: 0.367–0.827), and the 50 to 54-year age group showed the lowest (‐0.011%, 95% CI: ‐0.165 to 0.144) (Table S6, Supplemental Digital Content, https://links.lww.com/MD/R350). Notably, although younger and middle-aged populations demonstrated faster-growing NAFLD burdens, older adults (particularly those aged 80 years and above) also experienced a marked surge in both mortality and DALYs. These data collectively indicate that NAFLD poses an increasingly significant burden across all age groups, albeit with distinct patterns according to age.

3.5. Global disparities in NAFLD burden: a comparative analysis of 204 countries from 1990 to 2021

Between 1990 and 2021, the global burden of NAFLD showed pronounced cross-country variations (Fig. 4, Figs. S6–S8, Supplemental Digital Content, https://links.lww.com/MD/R350). Regarding incidence, Equatorial Guinea demonstrated the most notable increase, with an EAPC of 1.187% (95% CI: 1.121–1.252). Its ASIR rose from 405.350 per 100,000 to 553.066, reflecting a 325.2% overall increase. In contrast, the Democratic Republic of the Congo recorded the lowest EAPC (0.161%, 95% CI: 0.123–0.199) (Table S7, Supplemental Digital Content, https://links.lww.com/MD/R350). For prevalence, Italy displayed the highest EAPC of 1.122% (95% CI: 1.009–1.235), whereas Cambodia registered the lowest (0.077%, 95% CI: 0.051–0.102) (Table S8, Supplemental Digital Content, https://links.lww.com/MD/R350).

Figure 4.

Global distribution and change in NAFLD incidence, 1990 to 2021. Maps show incident case counts (1990, 2021), percent change (1990–2021), ASR (1990, 2021), and EAPC (1990–2021). Key message: Substantial geographic heterogeneity, with notable increases in North Africa, the Middle East, and Latin America. ASR = age-standardized rate, EAPC = estimated annual percentage change.

The Russian Federation exhibited the most striking change in mortality, with an EAPC of 4.253% (95% CI: 3.589–4.921), as the ASR climbed from 0.813 to 2.878 per 100,000. By contrast, South Korea’s mortality trend declined, with an EAPC of ‐3.080% (95% CI: ‐3.206 to ‐2.955) (Table S9, Supplemental Digital Content, https://links.lww.com/MD/R350). In terms of DALYs, the Russian Federation again recorded the largest increase (EAPC = 4.818%, 95% CI: 3.955–5.688), whereas South Korea showed the most pronounced reduction (EAPC = ‐3.412%, 95% CI: ‐3.506 to ‐3.317) (Table S10, Supplemental Digital Content, https://links.lww.com/MD/R350). Overall, these findings reveal the global heterogeneity of the NAFLD burden, reflecting disparities in prevention, diagnosis, and treatment efforts. Notably, some countries (e.g., the Russian Federation) exhibited significant upward trends across multiple indicators, suggesting that these regions may face more severe NAFLD-related challenges, necessitating more proactive interventions.

3.6. Comparative age–period–cohort analysis of NAFLD burden: gender-specific trends and risk factors

The age-specific patterns of NAFLD show both similarities and distinctions across sexes (Fig. 5). In the total population (Table S11, Supplemental Digital Content, https://links.lww.com/MD/R350), incidence peaked in the 20 to 24-year age group (relative risk [RR] = 1.484, 95% CI: 1.481–1.487, P < .001), whereas prevalence reached its maximum in the 75 to 79-year age group (RR = 1.415, 95% CI: 1.414–1.415, P < .001). Among males (Table S12, Supplemental Digital Content, https://links.lww.com/MD/R350), the incidence peak at ages 20 to 24 was even more pronounced (RR = 1.614, 95% CI: 1.607–1.621, P < .001), followed by a secondary increase in the 60 to 69-year age range. Females (Table S13, Supplemental Digital Content, https://links.lww.com/MD/R350) displayed a comparable but less extreme pattern, with the highest incidence in the 20 to 24-year age group (RR = 1.347, 95% CI: 1.343–1.350, P < .001), and a notable rise in the 60 to 69-year range. For all groups, mortality and DALYs escalated with advancing age, albeit at different peak ages. In the total population, mortality was highest in the 95 to 99-year age group (RR = 3.722, 95% CI: 3.613–3.835, P < .001). Among males and females, mortality also peaked in the 95 to 99-year group, with RRs of 3.582 and 3.871, respectively.

Figure 5.

APC analysis of global NAFLD burden, 1990 to 2021. APC effects for incidence, prevalence, deaths, and DALYs. Key message: Rising period effects and generation (cohort) patterns suggest shifting exposures/diagnostics over time. APC = age–period–cohort, DALY/DALYs = disability-adjusted life year(s).

Period effects from 1990 to 2021 showed a consistent upward trend in all NAFLD indicators across both sexes. In the total population (Table S11, Supplemental Digital Content, https://links.lww.com/MD/R350), incidence (RR = 1.027), prevalence (RR = 1.162), mortality (RR = 1.345), and DALYs (RR = 1.201) during 2017 to 2021 were significantly higher (all P < .001) than in the baseline period of 1990 to 1991. A similar pattern was observed for males (Table S12, Supplemental Digital Content, https://links.lww.com/MD/R350), with a slightly lower RR for incidence (RR = 1.010) but comparable risks for other indicators. Females (Table S13, Supplemental Digital Content, https://links.lww.com/MD/R350) showed slightly higher RRs for incidence (RR = 1.039) and DALYs (RR = 1.207) in the most recent period. These consistent period effects across sexes suggest that environmental or societal factors contributing to NAFLD risk have escalated similarly for both males and females over time.

Birth cohort effects illuminate generational patterns of NAFLD risk. In the total population (Table S11, Supplemental Digital Content, https://links.lww.com/MD/R350), later birth cohorts exhibited a higher incidence risk, with those born between 1997 and 2001 presenting the highest RR (RR = 1.281, 95% CI: 1.279–1.284, P < .001). However, older birth cohorts displayed higher risks in prevalence, mortality, and DALYs. Among males (Table S12, Supplemental Digital Content, https://links.lww.com/MD/R350), the birth cohort effect for incidence was especially pronounced, with the 1997 to 2001 cohort reaching an RR of 1.373 (95% CI: 1.369–1.378, P < .001). Females (Table S13, Supplemental Digital Content, https://links.lww.com/MD/R350) followed a similar but less marked trajectory, showing an RR of 1.200 (95% CI: 1.198–1.203, P < .001) for the 1997 to 2001 cohort.

Notably, both sexes in earlier birth cohorts (e.g., 1897–1901) faced greater risks for prevalence, mortality, and DALYs. This suggests that although newer generations may encounter elevated NAFLD incidence, older generations shoulder a greater burden of disease progression and outcomes. Specifically, in the total population, those born between 1897 and 1901 showed RRs of 1.209 for prevalence, 2.959 for mortality, and 1.940 for DALYs (all P < .001, Table S11, Supplemental Digital Content, https://links.lww.com/MD/R350). Among males, corresponding RRs were 1.220, 3.003, and 1.976 (all P < .001, Table S12, Supplemental Digital Content, https://links.lww.com/MD/R350). For females, these values were 1.221, 2.957, and 1.931 (all P < .001, Table S13, Supplemental Digital Content, https://links.lww.com/MD/R350).

Overall, these findings underscore the multifaceted and evolving nature of NAFLD risk, driven by complex interactions among age, period, and cohort factors for both sexes.

3.7. Socio-demographic index and nonalcoholic fatty liver disease burden: a global analysis from 1990 to 2021

Between 1990 and 2021, the relationship between the burden of NAFLD and the SDI underwent notable changes (Fig. 6, Figs. S9–S11, Supplemental Digital Content, https://links.lww.com/MD/R350). In 1990, the ASIR and age-standardized prevalence rate (ASPR) of NAFLD were negatively correlated with the SDI (ASIR: ρ = ‐0.195, P = .005; ASPR: ρ = ‐0.163, P = .020). However, by 2021, this relationship had weakened and was no longer statistically significant (ASIR: ρ = ‐0.124, P = .076; ASPR: ρ = ‐0.060, P = .398) (Fig. 6A–B, E–F). The negative correlations between SDI and both the age-standardized mortality rate (ASMR) and the age-standardized disability-adjusted life years (ASDR) remained relatively stable over the 31-year period (Fig. 6C–D, G–H).

Figure 6.

SDI–NAFLD associations across SDI regions, 1990 vs 2021. Scatter/smoother plots for ASRs of incidence, prevalence, deaths, and DALYs vs SDI in 1990 and 2021. Key message: Nonlinear SDI relationships with intermediate-SDI peaks; patterns shifted upward over time. ASRs = age-standardized rates, DALY/DALYs = disability-adjusted life year(s), SDI = socio-demographic index.

Regional analyses revealed pronounced geographic disparities in NAFLD burden (Fig. S9A–D, Supplemental Digital Content, https://links.lww.com/MD/R350). The incidence and prevalence in North Africa and the Middle East were considerably higher than predicted based on their SDI, whereas Central Sub-Saharan Africa was substantially below expectations. In terms of mortality and ASDR, Andean Latin America and Central America exceeded the anticipated values, whereas East Asia was lower than expected. Across 204 countries, the NAFLD burden initially increased and then declined with rising SDI, with a turning point at an SDI of approximately 0.60 to 0.65 (Figs. S9A–D, S10A–D, Supplemental Digital Content, https://links.lww.com/MD/R350). This pattern may reflect an initial surge in unhealthy lifestyles accompanying early stages of economic development, followed by a reduction in disease burden linked to improved healthcare and heightened health awareness.

3.8. Global, SDI-stratified, and regional decomposition analysis of NAFLD burden changes from 1990 to 2021

From 1990 to 2021, the global burden of NAFLD underwent significant changes. A decomposition analysis provides insights into the driving factors behind these shifts (Fig. 7). Worldwide, the incidence of NAFLD increased by 23,497,113.68 cases (Table S14, Supplemental Digital Content, https://links.lww.com/MD/R350), of which population growth contributed 73.85%, epidemiological changes 34.025%, and population aging offset 7.874% of the increase. Prevalence rose by 703,435,869.7 cases (Table S15, Supplemental Digital Content, https://links.lww.com/MD/R350), primarily driven by population growth (60.302%) and population aging (12.588%). The number of NAFLD-related deaths increased by 78,791.85 (Table S16, Supplemental Digital Content, https://links.lww.com/MD/R350), predominantly attributable to population aging (35.701%) and population growth (57.986%). DALYs grew by 1,978,013.039 years (Table S17, Supplemental Digital Content, https://links.lww.com/MD/R350), mostly due to population growth (63.082%) and population aging (29.925%).

Figure 7.

Decomposition of NAFLD burden changes, 1990 to 2021. Contributions of population growth, population aging, and epidemiologic change to changes in incidence, prevalence, deaths, and DALYs (overall/female/male; SDI and GBD regions). Key message: Growth is primarily driven by population growth and epidemiologic change, with aging contributing variably. DALY/DALYs = disability-adjusted life year(s), GBD = Global Burden of Disease, SDI = socio-demographic index.

Changes in the NAFLD burden differed by SDI levels. In high-SDI regions, the increase in incidence was largely driven by population growth (58.165%) and epidemiological changes (53.532%) (Table S14, Supplemental Digital Content, https://links.lww.com/MD/R350). Middle-SDI regions experienced the largest rise in prevalence (260,793,737.7 cases) mainly prompted by population growth (57.485%) and aging (20.945%) (Table S15, Supplemental Digital Content, https://links.lww.com/MD/R350). In low-SDI regions, the surge in mortality was predominantly propelled by population growth (120.761%), while aging offset part of this increase (‐5.935%) (Table S16, Supplemental Digital Content, https://links.lww.com/MD/R350). Concerning DALYs, the greatest increase occurred in high-middle-SDI regions (327,364.71 years), with population aging (50.972%) and growth (50.134%) each making nearly equivalent contributions (Table S17, Supplemental Digital Content, https://links.lww.com/MD/R350).

Between 1990 and 2021, NAFLD burden changes showed significant variations across 21 global regions. For incidence (Table S14, Supplemental Digital Content, https://links.lww.com/MD/R350), East Asia recorded the largest increase at 3,507,920.2 cases, where population growth accounted for 70.492%, while population aging offset 21.891% of the rise. South Asia followed closely, adding 6,402,662.628 cases, largely driven by population growth (77.874%). Regarding prevalence (Table S15, Supplemental Digital Content, https://links.lww.com/MD/R350), East Asia again ranked first, with an increase of 159,314,121.8 cases, mainly attributable to population growth (40.565%) and aging (32.916%). In terms of mortality (Table S16, Supplemental Digital Content, https://links.lww.com/MD/R350), East Asia saw an increase of 8912.436 deaths, of which aging contributed 93.475%. However, South Asia led in DALYs (Table S17, Supplemental Digital Content, https://links.lww.com/MD/R350), with an increase of 331,136.527 years, predominantly spurred by population growth (73.671%). Notably, certain regions, such as Eastern Europe, showed unique patterns for select indicators; for instance, epidemiological changes contributed 84.882% of the mortality increase in that region. These findings highlight the region-specific nature of NAFLD burden changes, underscoring the importance of tailoring NAFLD management strategies to diverse geographic contexts.

3.9. Health inequality trends in NAFLD from 1990 to 2021

An additional analysis investigated the trends in health inequalities of NAFLD across all age groups between 1990 and 2021 (Fig. 8 and Table S18, Supplemental Digital Content, https://links.lww.com/MD/R350). The findings reveal a decrease in inequality for NAFLD incidence: the slope index declined from 38.906 (95% CI: ‐8.102 to 85.914) in 1990 to ‐8.644 (95% CI: ‐70.896 to 53.609) in 2021. However, the CI showed a subtle shift in the direction of incidence inequality, moving from ‐0.006 (95% CI: ‐0.025 to 0.014) in 1990 to 0.006 (95% CI: ‐0.016 to 0.029) in 2021.

Figure 8.

Health inequality in NAFLD burden across countries, 1990 to 2021. SII (absolute) and CI (relative) for ASRs of incidence, prevalence, deaths, and DALYs among 204 countries/territories. Key message: Inequalities widened for prevalence, mortality, and DALYs; morbidity inequality shows limited improvement. ASRs = age-standardized rates, CI = concentration index, DALY/DALYs = disability-adjusted life year(s), SII = slope index of inequality.

In contrast, NAFLD prevalence exhibited a marked increase in inequality. The slope index more than doubled, rising from 3826.31 (95% CI: 2855.908 to 4796.711) in 1990 to 8063.503 (95% CI: 6334.898 to 9792.109) in 2021. The CI similarly increased from 0.032 (95% CI: 0.017 to 0.048) to 0.088 (95% CI: 0.066 to 0.11). Mortality inequalities also intensified, with the slope index growing from 0.709 (95% CI: 0.409 to 1.009) in 1990 to 1.939 (95% CI: 1.477 to 2.402) in 2021. However, the CI for mortality declined slightly, from 0.214 (95% CI: 0.159 to 0.269) in 1990 to 0.205 (95% CI: 0.154 to 0.257) in 2021.

A similar pattern emerged for DALYs, where the slope index increased substantially from 16.663 (95% CI: 8.118 to 25.208) in 1990 to 39.6 (95% CI: 26.868 to 52.333) in 2021. Yet, the DALYs CI decreased modestly, from 0.179 (95% CI: 0.13 to 0.228) in 1990 to 0.166 (95% CI: 0.11 to 0.222) in 2021. Taken together, these findings suggest that although NAFLD incidence inequality has improved, inequalities in prevalence, mortality, and DALYs persist and, in many respects, are intensifying.

3.10. Frontier analysis of NAFLD burden across countries

NAFLD exhibits substantial geographic variations and sociodevelopmental inequalities worldwide. Employing a frontier analytical approach, we evaluated the burdens of NAFLD incidence, prevalence, mortality, and DALYs across 204 countries (Fig. 9; Tables S19–S22, Supplemental Digital Content, https://links.lww.com/MD/R350). The findings reveal that Middle Eastern countries (including Kuwait, Qatar, and Saudi Arabia) ranked poorest in incidence and prevalence, occupying the top 3 positions in terms of effective shortfall (Tables S19 and S20, Supplemental Digital Content, https://links.lww.com/MD/R350). In Kuwait, the ASIR reached 1174.175 (95% UI: 1092.513–1257.532) per 100,000 population, far exceeding the frontier value of 253.649. By contrast, Northern European nations such as Norway, Denmark, and Finland performed relatively well on these indicators.

Figure 9.

Frontier (DEA) analysis of NAFLD burden and SDI, 1990 to 2021 and 2021. DEA-based frontiers relating SDI to ASRs for incidence, prevalence, mortality, and DALYs over time and in 2021. Key message: Persistent efficiency gaps (some countries achieve lower ASRs at similar SDI, indicating attainable performance benchmarks). ASRs = age-standardized rates, DALY/DALYs = disability-adjusted life year(s), DEA = data envelopment analysis, SDI = socio-demographic index.

Regarding mortality, Egypt (9.442, 95% UI: 6.469–13.188 per 100,000) and Mongolia (8.641, 95% UI: 6.215–12.11 per 100,000) stood out with the highest rates, whereas developed countries such as Switzerland (0.939, 95% UI: 0.7–1.207 per 100,000) and Norway (0.768, 95% UI: 0.611–0.935 per 100,000) demonstrated comparatively lower rates (Table S21, Supplemental Digital Content, https://links.lww.com/MD/R350). In terms of DALYs, Mexico (201.863, 95% UI: 149.298–265.643 per 100,000) and Egypt (196.554, 95% UI: 137.899–273.456 per 100,000) showed the highest burden, whereas Singapore (10.636, 95% UI: 8.015–14.319 per 100,000) and Papua New Guinea (12.276, 95% UI: 7.31–21.782 per 100,000) fared significantly better (Table S22, Supplemental Digital Content, https://links.lww.com/MD/R350). These results underscore the global inequities of NAFLD burden, highlighting the urgency of developing targeted intervention strategies for high-risk countries.

3.11. Projected global burden of NAFLD from 2022 to 2046

The global burden of NAFLD is expected to rise considerably over the coming decades. According to analyses based on the Norpred disease-burden prediction model, between 2022 and 2046, NAFLD incidence, prevalence, mortality, and DALYs will change to varying degrees (Fig. 10; Tables S23–S25, Supplemental Digital Content, https://links.lww.com/MD/R350). Overall, the ASIR is projected to increase from 841.237 per 100,000 population in 2022 to 930.637 per 100,000 in 2046, representing an approximately 10.6% rise (Table S23, Supplemental Digital Content, https://links.lww.com/MD/R350). Prevalence is also anticipated to climb substantially, increasing from 21,328.922 to 23,056.426 per 100,000. Notably, although the absolute number of deaths is predicted to grow, the ASMR is projected to decrease slightly, from 2.283 to 2.155 per 100,000.

Figure 10.

Projected global NAFLD burden, 2022 to 2046. Projected counts and ASRs for incidence, prevalence, deaths, and DALYs for overall, females, and males using Nordpred-INLA (95% UIs). Key message: Burden is projected to rise through 2046 with persistent sex disparities; projections incorporate uncertainty and attenuation of recent trends. ASRs = age-standardized rates, DALY/DALYs = disability-adjusted life year(s), INLA = Integrated Nested Laplace Approximation, Nordpred = Nordic cancer prediction model (adapted for APC projections), UIs = uncertainty intervals.

An analysis by sex indicates that the NAFLD burden among males is expected to remain consistently higher than among females (Tables S24 and S25, Supplemental Digital Content, https://links.lww.com/MD/R350). By 2046, the ASIR for males is projected to reach 1000.771 per 100,000, compared with 855.218 per 100,000 for females. Similarly, the ASPR among males (24,454.456 per 100,000) will substantially exceed that among females (21,667.888 per 100,000). However, the gap in mortality between the sexes is expected to narrow. In 2046, the ASMRs for males and females are estimated to be 2.227 and 2.076 per 100,000, respectively.

4. Discussion

This study provides several critical and novel findings regarding the global burden of NAFLD: the incidence and prevalence of NAFLD have shown a significant upward trajectory globally from 1990 to 2021, with the most rapid increases observed in high-SDI regions; regional disparities were pronounced, with North Africa and the Middle East displaying the highest incidence and prevalence, while Eastern Europe exhibited the steepest rises in mortality and DALYs; males consistently exhibited higher NAFLD burdens across all metrics compared to females, with faster growth rates in incidence, prevalence, mortality, and DALYs; age-specific trends revealed that younger and middle-aged populations experienced the most significant increases in NAFLD burden, although older adults also demonstrated notable surges in mortality and DALYs; decomposition analysis identified population growth as the primary driver of NAFLD burden increases, with population aging and epidemiological changes contributing variably across SDI levels; and despite a predicted decline in ASMRs, the absolute burden of NAFLD is projected to rise substantially by 2046, underscoring the urgency of targeted interventions, especially in high-risk regions and demographics.

The study revealed notable regional disparities in the prevalence of NAFLD. North Africa and the Middle East consistently exhibited the highest ASIR and prevalence, with ASIR increasing from 849.022 cases per 100,000 people in 1990 to 1037.642 cases per 100,000 people in 2021. A study examined the dietary patterns in the MENA region, revealing low consumption of whole grains, nuts, and seafood, while saturated fats and unhealthy dietary patterns were prevalent. These dietary patterns were associated with a high prevalence of metabolic syndrome and other related health problems.^[7] Consequently, the ASMR and DALY were found to be considerably elevated in Eastern Europe, with mortality rates increasing 3-fold over the study period. These findings are consistent with those of previous studies in Eastern Europe,^[16] suggesting that the lack of comprehensive policies and clinical guidelines for NAFLD and limited healthcare resources in managing advanced NAFLD and its associated cirrhosis are challenging in parts of the region.

Conversely, the decline in DALYs in high-income Asia-Pacific countries, with an EAPC of ‐2.536%, was closely associated with the success of early detection and management programs implemented in the region.^[11,17] However, the rapid rise in the incidence and prevalence of NAFLD in low- and middle-income countries, particularly in South Asia and sub-Saharan Africa, is closely related to the rising incidence of metabolism-related diseases, including diabetes, and the impact of limited healthcare resources^[18] in these regions.

A health inequality analysis underscores the intricate relationship between socioeconomic development and the burden of NAFLD. High-SDI countries, such as Kuwait and Saudi Arabia, demonstrate disproportionately high ASIR and prevalence rates, exhibiting significant positive deviations from SDI expectations. These trends are indicative of the impact of urbanization, lifestyle changes, and a lack of liver health awareness in these countries. For instance, Saudi Arabia has experienced a rapid increase in NAFLD and nonalcoholic steatohepatitis cases due to the high prevalence of obesity and diabetes,^[19] while Kuwait has an extremely high rate of obesity, leading to an increased risk of metabolic disorders and related diseases.^[20] This demonstrates that there are some NAFLD health management gaps with other high SDI countries. Concurrently, the rise in ASIR and prevalence in low SDI countries, such as the Democratic Republic of the Congo, has been negligible due to the underdevelopment of pertinent public health sectors in these nations. This phenomenon can be partially ascribed to underreporting and diagnostic challenges^[21,22] rather than a genuine absence of disease. The morbidity inequality index (SII) exhibited a substantial increase from 3826.31 in 1990 to 8063.503 in 2021, indicating a pronounced disparity between high- and low-SDI countries. Concurrently, the morbidity concentration index has exhibited a corresponding increase, signifying that the burden of NAFLD is becoming increasingly concentrated in affluent regions. This phenomenon may be attributed to the prevalence of NAFLD in wealthier regions, which is associated with urbanization, sedentary lifestyles, and high-calorie diets.^[23] Studies have identified obesity and metabolic syndrome as the primary drivers of the concentration of NAFLD in wealthier regions.^[3,24] Conversely, mortality exhibited a contrasting trend, demonstrating a decline in high SDI countries and a substantial increase in medium SDI regions, such as Eastern Europe and Central Asia. This variation can be attributed to the differential effectiveness of healthcare systems across different regions.

Age-period-cohort analyses have revealed significant disparities in the prevalence of NAFLD across various age groups and birth cohorts. Younger cohorts, specifically those born between 1997 and 2001, exhibited a higher RR of NAFLD incidence compared to earlier cohorts, attributable to rising obesity rates, unhealthy diets, and low physical activity in these generations.^[25] Older age groups, particularly those aged 80 years and over, exhibited the highest mortality and DALYs, underscoring the cumulative effect of comorbidity and disease progression.^[26] The period effect indicates a sustained rise in all indicators, reflecting the global increase in metabolic risk factors and broader societal changes. Of particular note is the disproportionately high RR of mortality and DALYs observed in low- and middle-income countries in recent times, suggesting the exacerbation of global health disparities.

Decomposition analyses attribute the increased burden of NAFLD to population growth (60.302% of the increase in prevalence), population aging (12.588%), and epidemiologic changes (34.025%). These factors manifested differently across regions, with aging exerting a more pronounced effect in high SDI regions, while population growth dominated in low SDI regions. Projections indicate that the global burden of NAFLD will rise by approximately 10.6% and 8% in ASIRs and DALYs, respectively, by the year 2046. While there is potential for stabilization of mortality rates through improvements in medical care, disparities in burden are projected to persist.

Integrated metabolic care (embed NAFLD within comprehensive pathways for obesity, type 2 diabetes, and dyslipidemia, prioritizing high-risk groups (men, individuals with metabolic abnormalities, mid-life adults); evidence-based lifestyle interventions) scale weight management, diet quality improvement, and physical activity programs, complemented by structural policies (food/environmental and urban design levers) to amplify population-level impact.^[27,28] early detection and tiered follow-up (implement noninvasive risk stratification and streamlined referral pathways to improve early identification and reduce late-stage complications; resource allocation) prioritize intermediate-SDI and identified hot-spot regions (e.g., parts of North Africa/Middle East and Latin America) for prevention and secondary care, and strengthen diagnosis-treatment-follow-up capacity in low- and middle-SDI settings; integration into noncommunicable disease (NCD) strategies (incorporate NAFLD within broader NCD frameworks to share registries, information systems, and performance indicators, improving cost-effectiveness).

In 2024, international consensus replaced NAFLD with MASLD. To maintain alignment with GBD 2021 case definitions and modeling, we retain “NAFLD” in the main analyses and discuss implications of the terminology change here. While the rename does not alter our time-series estimates, future surveillance and cross-study comparisons should explicitly map NAFLD to MASLD definitions to avoid misinterpretation during the transition.

5. Limitation

Notwithstanding its numerous merits, the study is not without limitations. A primary challenge in GBD analyses is the inconsistency in the availability of primary epidemiological data, which contributes to instability in the estimates. When data are inadequate to produce burden estimates for all 204 countries and territories (disaggregated by year, sex, and age), the results depend on the predictive validity of modeling processes. While acknowledging the limitations of this approach, which cannot fully replace high-quality primary data, it ensures that regions or diseases with limited or no data are still included in critical analyses. For available primary data, GBD processing methods endeavor to account for known sources of variation. However, due to measurement errors and reporting inaccuracies, fully isolating these variations is not always possible. Challenges such as flawed methodologies and potential underreporting of diseases persist. Furthermore, the estimation of 95% UIs necessitates refinement. GBD analyses seek to encapsulate uncertainty from diverse processes, including stochastic variation in input data, age-sex splitting, bias corrections, and other statistical adjustments. Nevertheless, comprehensively addressing all sources of uncertainty across the burden estimation pipeline remains a substantial challenge.

6. Conclusions

Using GBD 2021, this study provides a comprehensive assessment of NAFLD burden from 1990 to 2021 with projections to 2046. NAFLD has increased across incidence, prevalence, deaths, and DALYs and is expected to continue rising, with burdens unevenly distributed (highest in intermediate-SDI settings and hot-spot regions in North Africa, the Middle East, and parts of Latin America) and consistently higher in males; later-born cohorts also show elevated risk. Inequality metrics indicate widening disparities for prevalence, mortality, and DALYs, underscoring a growing equity gap. These findings support targeted, policy-relevant action: integrate NAFLD into metabolic care pathways, scale evidence-based lifestyle interventions and early detection, and prioritize resources for intermediate-SDI and other high-burden regions within broader NCD strategies to curb future growth and narrow disparities.

Acknowledgments

We gratefully acknowledge the Global Burden of Disease Study 2021 (GBD 2021) for providing the comprehensive dataset that formed the foundation of this research. The GBD’s rigorous methodology and extensive global coverage have been instrumental in enabling our in-depth analysis of NonAlcoholic Fatty Liver Disease burden across diverse populations and time periods.

Author contributions

Conceptualization: Guiming Chen, Yao Li.

Data curation: Guiming Chen.

Formal analysis: Guiming Chen.

Project administration: Guiming Chen.

Resources: Ying Xiao, Yao Li.

Software: Yao Li.

Supervision: Guiming Chen, Peng Bai.

Validation: Guiming Chen, Ying Xiao, Yao Li.

Visualization: Guiming Chen, Ying Xiao, Yao Li.

Writing – original draft: Guiming Chen, Yanming Sha.

Writing – review & editing: Guiming Chen, Yanming Sha.

Supplementary Material

medi-105-e47604-s001.pdf ^{(2.4MB, pdf)}