Correspondence to letter to the editor on “Sex disparities in alcohol-associated liver disease and subtype differences in alcohol-attributable cancers in the United States”

Dear Editor,

We are grateful to Liu [1] for thoughtful comments and critical appraisal of our manuscript [2], which aimed to provide a comprehensive assessment of sex-specific trends in alcohol-associated liver disease (ALD) and alcohol-attributable cancers using the most recent Global Burden of Disease (GBD) 2021 framework [3].

We appreciate the suggestion to deepen our policy analysis. While our primary aim was to identify epidemiological trends in ALD and alcohol-attributable cancers, we agree that incorporating policy context enhances translational relevance. As highlighted by Liu, interventions such as alcohol taxation and minimum unit pricing have proven effective. Indeed, recent evidence from Latin America demonstrated that a higher number of alcohol-related public health policies was associated with lower ALD mortality and alcohol use disorder (AUD) prevalence [4]. Likewise, Rehm et al. [5] showed that integrated alcohol policies led to significant reductions in per capita alcohol consumption. While our study did not directly assess the impact of specific policies, we used state-level variation as a proxy to reflect differenc-es in policy implementation and enforcement [6]. The results underscore the need for coordinated national strategies that incorporate evidence-based policy tools, including excise taxes, advertising restrictions, and limitations on alcohol availability, particularly in regions with the highest burden. However, policy-level efforts alone are insufficient. Reducing alcohol-related mortality requires a multi-level approach. At the individual level, patient education can promote awareness and encourage behavior change. Provider-level strategies, such as routine alcohol screening and brief interventions [7], should be more widely adopted. At the neighborhood level, interventions targeting the density of alcohol outlets through zoning regulations can influence consumption patterns [8]. These efforts should be combined with broader policy measures to form a comprehensive public health response.

We concur that ethnic disparities in ALD outcomes are of critical importance. As noted, the GBD framework does not currently disaggregate U.S. data by ethnicity, limiting our ability to examine intra-national disparities [3]. However, recent studies, utilizing the National Health and Nutrition Examination Survey dataset [9,10], fill this gap by demonstrating markedly different ALD trajectories across racial and ethnic groups. Notably, Hispanic individuals had disproportionately high ALD prevalence despite lower overall alcohol consumption, and Asian females had the lowest rates of liver transplantation once waitlisted [9]. These findings highlight the structural and biological contributors to ALD and AUD disparities and reinforce our call for more granular data in future GBD iterations. Policy interventions are also a key to addressing racial and ethnic disparities in alcohol mortality, often driven by unequal healthcare access, neighborhood factors, and exposure to alcohol-related harms [11,12].

We appreciate the attention drawn to the rise in ALD among women. Our study identified steeper increases in ALD-related mortality and cancer burden among women than men, which warrants targeted interventions. The sexbased biological mechanisms underlying greater susceptibility to alcohol-induced liver injury in women include differences in alcohol metabolism, hormonal modulation of inflammation, and altered gut permeability [13]. These mechanisms, combined with sociocultural barriers to AUD treatment and care engagement, contribute to the accelerated disease progression observed in women [14]. We support efforts to develop sex-specific clinical pathways and public health messaging to address these disparities.

We also acknowledge the limitations of CODEm and the potential for cause-of-death misclassification in alcohol-related conditions. The GBD 2021 capstone publication notes this challenge, especially in settings with underdeveloped health reporting systems [3]. However, in high-income countries like the U.S., death certificate coding is generally reliable, and K70 codes have demonstrated reasonable validity. Moreover, our findings align closely with those from national registries and independent analyses, including Zhang et al. [15], which used GBD methodology to describe similar upward trends in ALD incidence. While refinements in cause attribution will always be necessary, the consistency of our findings across multiple sources underscores the robustness of our conclusions.

We thank Liu for their constructive engagement with our work. We believe our study offers timely insight into evolving patterns of ALD and alcohol-attributable cancer burden in the U.S., with important implications for both research and policy. Future investigations should aim to integrate policy effectiveness, ethnicity-specific risk, and sex-based biological mechanisms into a unified framework for reducing the burden of alcohol-related diseases.

Abbreviations

ALD

alcohol-associated liver disease

AUD

alcohol use disorder

GBD

global burden of disease

SLD

steatotic liver disease