Dear Editor,
We thank Wang et al. for their letter regarding our recent study on sex-specific trends for alcohol-associated liver disease (ALD) in the United States [
1]. Their analysis of Global Burden of Disease extends our findings by projecting continued disproportionate increases in the burden of ALD among females [
2].
Our initial analysis revealed that between 2000 and 2021, the age-standardized mortality rate from ALD in the U.S. substantially increased among females compared to males. Wang and colleagues’ used Bayesian age–period–cohort (BAPC) models and projected that male incidence will remain relatively stable through 2040, while female incidence will nearly double [
2]. Their estimates further suggest the prevalence of ALD will rise at a faster annual rate in females (6.3%) than in males (3.3%) [
2]. Notably, the alignment of results from an independent analysis underscores the robustness of the observed sex disparity.
A central question in the letter concerns whether the rising ALD burden is primarily driven by demographic shifts (aging and population growth) or by changes in epidemiologic risk (age-specific disease rates) [
3,
4]. Findings from our study suggest that both dynamics contribute. While demographic momentum alone will inevitably increase the absolute burden due to an aging and expanding population, the more concerning factor is the rise in alcohol use and ALD, particularly among females. Our decomposition analysis showed that the sharp increase in female mortality was primarily explained by a positive epidemiologic component, reflecting the rising age-specific incidence of ALD in females. By contrast, male rates remained relatively stable, with demographic changes accounting for most of the modest increases in males. The current analysis likewise demonstrated a substantial epidemiologic contribution to female deaths, incidence, and DALYs, confirming that females’ ALD risk is genuinely intensifying rather than being an artifact of population aging [
1]. This conclusion is also consistent with national mortality data from the CDC WONDER database (1999–2022), which show that while overall U.S. ALD mortality rates nearly doubled, females experienced a disproportionately greater increase [
5]. Females exhibit heightened vulnerability to alcohol’s harmful effects, progressing to fibrosis and cirrhosis after a shorter duration of drinking and facing an elevated risk of hepatocellular carcinoma (HCC) [
6]. Recent cohort analyses indicate that females with ALD also face a higher risk of major adverse liver outcomes, even after matching for demographics, comorbidities, and alcohol use disorder (AUD) treatment [
7]. Collectively, these findings underscore a sex disparity in ALD that is unlikely to resolve without targeted intervention. Although pharmacotherapies for AUD demonstrate no sexspecific differences in efficacy, females remain less likely to access specialist care or receive relapse-prevention medications [
6,
8].
The correspondents underscored the wide uncertainty intervals surrounding forecasts to 2040 and pointed out potential limitations of the GBD modelling framework, such as misclassification of causes of death [
3]. In our analysis, we addressed these issues by applying Bayesian models to generate full posterior predictive distributions and by reporting credible intervals for all estimates. Importantly, across alternative model specifications, the qualitative pattern of steeper increases among females remained consistent. Their own sensitivity analyses with different priors yielded similar sex-specific trends, reinforcing that the observed female predominance is not an artifact of a particular modelling assumption.
We also agree that these findings highlight the urgent need for sex-responsive public health action. Evidence points to a striking and accelerating rise in ALD burden among U.S. females. Without targeted efforts to reduce harmful drinking and improve liver health in this population, the sex gap will continue to widen and preventable alcohol related mortality will grow [
9]. Recent global studies have echoed this trend, noting sharper increases in ALD incidence and mortality among females, particularly during the COVID-19 pandemic, and emphasizing the need for multifaceted interventions [
10]. However, a prior study reported that between 1999 and 2018, alcohol policies in the U.S. remained unchanged [
11]. Effective strategies should combine population-level measures, such as alcohol taxation, availability restrictions, and public education, with targeted approaches like screening and brief interventions in healthcare settings [
12,
13]. Integration with policies addressing other noncommunicable diseases, such as unhealthy diet, physical inactivity, cancer, and tobacco use, may further reduce the prevalence and mortality associated with ALD, HCC, and other liver diseases [
14,
15].
In conclusion, we appreciate this correspondence, which reinforces the central conclusions of our study. Independent analyses using BAPC models and decomposition techniques converge on the same warning: a rapid and disproportionate rise in ALD among U.S. females is imminent. Taken together, the evidence suggests that both demographic changes and escalating epidemiological risks are driving this surge. We echo the call for urgent public health action and emphasize that recognition of sex-specific dynamics in ALD is essential for designing effective interventions and policies.
FOOTNOTES
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Authors’ contribution
Writing, original draft: Pojsakorn Danpanichkul, Luis Antonio Diaz. Writing, review, and editing: Juan Pablo Arab, Ju Dong Yang, Amit G. Singal. All authors have read and approved the final version of the manuscript for submission.
-
Conflicts of Interest
Amit G. Singal has served as a consultant or on advisory boards for Genentech, AstraZeneca, Eisai, Exelixis, Bayer, Elevar Therapeutics, Merck, Boston Scientific, Sirtex, HistoSonics, Fujifilm Medical Sciences, Exact Sciences, Roche Diagnostics, Abbott, and Glycotest Diagnostics. Ju Dong Yang consults for AstraZeneca, Eisai, Exact Sciences, and Fujifilm Medical Sciences. The other authors declare no competing interests.
Abbreviations
alcohol-associated liver disease
Bayesian age–period–cohort
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Citations
Citations to this article as recorded by
, Luis Antonio Diaz2,3,4, Juan Pablo Arab3,4,5, Amit G. Singal6, Ju Dong Yang7
