Changing landscape of alcohol‐associated liver disease in younger individuals, women, and ethnic minorities

Alcohol use is the most important determinant of the development of alcohol‐associated liver disease (ALD) and of predicting long‐term outcomes in those with established liver disease. Worldwide, the amount, type, and pattern of use of alcohol vary. Alcohol use and consequent liver disease have been increasing in certain ethnic groups especially Hispanics and Native Americans, likely due to variations in genetics, cultural background, socio‐economic status, and access to health care. Furthermore, the magnitude and burden of ALD have been increasing especially in the last few years among females and young adults who are at the prime of their productivity. It is critical to recognize the problem and care for these patients integrating cultural aspects in liver clinics. At the federal level, a societal approach is needed with the implementation of public health policies aiming to reduce alcohol consumption in the community. By addressing these challenges and promoting awareness, we can strive to reduce the burden of ALD, especially in high‐risk demographic groups to improve their long‐term health outcomes. Finally, we need studies and quality research examining these changing landscapes of demographics in ALD as a basis for developing therapeutic targets and interventions to reduce harmful drinking behaviours in these high‐risk demographic groups.


| INTRODUC TI ON
Globally, alcohol consumption is frequent (43% of the population currently drinks alcohol) and differs among regions (e.g.60% in the European Region vs 2.9% in the Eastern Mediterranean Region). 1 Furthermore, the amount and type of alcohol consumed vary worldwide, with an average of 6.4 litres of pure alcohol per capita per year according to data from 2018. 2 The most commonly consumed beverage types are spirits (44.8%), followed by beer (34.3%) and wine (11.7%). 1 These differences in geographical distribution of patterns of alcohol consumption reflect the sociocultural differences between regions.However, early exposure to alcohol consumption at young age and environmental factors may lead to alcohol misuse.Indeed, the prevalence of heavy episodic drinking among current drinkers can be as high as 60% in some regions. 1 Misuse of alcohol can lead to the development of alcohol use disorder (AUD), a chronic disease characterized by neurobiological features including positive reinforcement and compulsive search for alcohol, and negative emotional state when alcohol is not used. 3The prevalence of AUD globally is 5.1%, but it can be as high as 8.8% in the European Region. 1 Alcohol misuse also leads to several adverse medical implications that practically affect every organ system.Alcohol is the fifth major cause of deaths in men and women and causes up to 139 million disability-adjusted life years.
Alcohol-associated liver disease (ALD) represents one of the most common consequences of alcohol misuse.Although it is correlated to the length of time and amount of alcohol consumption, it embodies a wide spectrum of progressive disease stages that are responsible for almost half of the liver-related mortality worldwide. 4Indeed, alcohol represents more than 50% of the attributable fraction of cirrhosis in the region of the Americas and Europe. 5Furthermore, mortality rates due to ALD have been increasing over the past years. 6This review highlights the changing landscape of ALD and strategies to improve the care of patients with ALD.

| ALD IN YOUNG ER IND IVIDUAL S
Although several disease modifiers predispose an individual to the risk and severity of ALD, younger age has not been reported as such. 8Epidemiological studies have shown a higher risk and prevalence of ALD in young individuals (Table 1), including alcohol-associated fatty liver, 9 alcohol-associated cirrhosis, 10 and alcohol-associated hepatitis (AH). 11In another study using the same database (2006-2014), the most severe forms of AH with acute-on-chronic liver failure (ACLF) were in patients aged <35 yrs.compared to older individuals. 12Not only has the prevalence been increasing in younger individuals, but the outcomes are also worse.For example, in a study using the death certificate database (1999-2016) in the United States, mortality due to cirrhosis increased by 3.4% between 1999 and 2016 with the maximum increase among individuals aged 25-34 years, which was entirely driven by ALD as the liver disease aetiology. 13In another study analysing the NIS database, ALD hospitalizations increased by 200% between 2002 and 2016 in patients aged <35 years, with the highest increase among those with AH in this age group. 14though ALD has evolved as the leading indication for LT surpassing hepatitis C and metabolic dysfunction-associated steatohepatitis (MASH), [15][16][17] transplant activity has been increasing the most in AH, 14 with an over 200% annual increase between 2015 and 2019. 18The increased transplant activity among young AH patients other than more severe disease may also be due to their better medical eligibility for transplantation given younger age and fewer comorbidities.However, this certainly raises ethical challenges and issues in utility and optimal use of donor pool. 19

| Mechanisms of increasing prevalence of ALD in younger individuals
Increased prevalence of ALD and AH among young individuals is likely due to increased amounts and harmful pattern of alcohol use.For example, in an analysis of the National Health and Nutrition Examination Survey (NHANES) database (2006-2016)   of 15 981 individuals, prevalence of harmful alcohol use was 30%, 17%, and 5% in ≤35, 36-64, and ≥65 yrs.age groups, respectively, with about 11-fold increased alcohol use among ≤35 vs. ≥65 yrs. 14ung individuals also report higher frequency of binge pattern (>5 drinks in males or >4 in females in a single drinking episode).
In the recent report by the WHO, 20

| ALD IN WOMEN
While historically considered a predominantly male disorder due to higher rates of alcohol consumption, the incidence of alcoholrelated liver injury in women has been steadily increasing. 14,21This shift is closely linked to the rising number of women engaging in regular alcohol consumption.Gender-based disparities in women are also seen for higher mortality from end-stage liver disease, morbidity with more severe disease of ACLF and multi-organ failure and delisting for being too sick for LT, and worse post-LT patient survival due to alcohol relapse and recurrent ALD 22 (Table 2).Clearly, sickness in LT candidates should be evaluated without a gender bias.

| Mechanisms of increasing prevalence of ALD in women
Increasing harmful alcohol use mainly accounts for worsening trends in advanced liver disease in women.Alcohol use has traditionally been 3 times more common in men vs. women especially in people born in or around 1900, but recently this gender gap in alcohol use has been narrowing.Gender gaps in alcohol consumption and harmful drinking patterns vary worldwide, with the ratio of men-towomen drinking ranging from 1:1 in countries such as New Zealand and 12:1 in India.In a 2016 survey of the US population, 59.1% of men and 51% of women reported consuming alcohol within the last month.In another 2019 US study, women in their teens and early 20s reported getting drunk at higher rates vs. male peers (https:// www.niaaa.nih.gov/ publi catio ns/ broch ures-and-fact-sheets/ under age-drinking).In another analysis of six surveys in the United States (2000-2016), alcohol use in adult women increased by 6% per year, while it decreased by .2% in adult men.Similar figures for binge drinking were 14 and .5%,respectively. 24This narrowing of the gender gap with increasing alcohol use is also observed in older women.
For example, repeated Norwegian cross-sectional surveys between 1994 and 2016 of 20 939 adults aged 60-99 years showed increasing alcohol use, with 8-and 5.9-fold use among women aged 60-69 and 70+ years, respectively.Similar figures were 4.1-and 3.1-fold for men aged 60-69 and 70+ years, respectively. 25men also exhibit increased vulnerability to its detrimental effects on the liver health compared to men, 26 with a faster progression to cirrhosis over a shorter time period. 27Physiological differences, including lower body water content and impaired first-pass metabolism, result in higher blood alcohol levels for women compared to men. 4 Mechanistic studies have shed light on the complex interplay between alcohol consumption and liver injury in women.For example, hormonal factors, such as oestrogen, impact the Kupffer cells and liver enzymes, further exacerbating the gender disparity in ALD susceptibility. 28Oestrogen increases the Kupffer cell sensitization to endotoxins, leading to enhanced hepatic inflammation and injury. 29rthermore, differences in hepatic enzyme activity (such as cytochrome P450 2E1) and alcohol metabolism contribute to the gender disparity observed in ALD susceptibility.In another study, women receiving liver transplant were more likely to relapse to harmful TA B L E 1 Studies observing increasing burden of alcohol-associated liver disease (ALD) in younger individuals.drinking, resulting in an increased risk of recurrent ALD. 30 As genetic polymorphisms of PNPLA3, TM6SF2, and MBOAT7 genes are known to predispose to ALD and genetic polymorphisms of HSD17B13 are known to protect against ALD, it is possible that these sex-based differential effects of these genetic polymorphisms may explain higher vulnerability to ALD in women.In a recent study on 6171 participants (2684 patients with ALD cirrhosis, 1031 with hepatocellular carcinoma; 2588 heavy alcohol users without liver disease; and 899 healthy controls), PNPLA3 polymorphisms were predisposed to cirrhosis and HCC, and HSD17B13 was protective.Interestingly, HSD17B13 polymorphisms nullified the effect of PNPLA3 polymorphisms on the risk of cirrhosis in both men and women but only in men for hepatocellular carcinoma. 31rthermore, gender disparities persist in access to treatment, including LT for AH, 18 and women are less likely to undergo LT for AH and are underrepresented in LT recipients overall. 32As abstinence from alcohol is the cornerstone in improving the long-term outcomes of patients with ALD, disparity in treatment access is a major factor resulting in higher ALD-related mortality and morbidity among women.For example, in an analysis of 66 053 patients with alcoholassociated cirrhosis (32% women) with private insurance, treatment for AUD within 1 year of diagnosis of liver cirrhosis was only provided in 10% (pharmacological treatment in only .8%).Furthermore, women vs men were 16% less likely to receive a face-to-face visit with a mental health specialist and 11% less likely to receive pharmacological treatment for AUD. 33Women often face unique challenges in seeking treatment due to familial responsibilities and perceived stigmatization.Addressing these disparities and providing comprehensive counselling and support services are crucial for improving outcomes in women with ALD.Indeed, women with ALD face additional challenges when it comes to liver transplantation.This highlights the need for improved AUD pharmacological and behavioural treatment, counselling for managing the alcohol use disorder (AUD), and support services to address the unique needs of women with ALD who require liver transplantation. 3,34Few studies have shown that the association between heavy drinking and mental health disorders is stronger in women compared to men.Women are more likely to use alcohol as a means of regulating negative emotions, while men may be driven by positive reinforcement. 35Studies have linked alcohol use disorder in women to post-traumatic stress disorder, anxiety, and depression. 36

| ALD IN E THNIC MINORITIE S
Apart from variations in drinking patterns and genetics, ethnic differences in drinking alcohol and susceptibility to ALD may explain geographical differences in the burden of AUD and ALD (Table 3).For example, advanced ALD spectrum of alcohol-associated cirrhosis and AH has been increasing in Hispanics and Native Americans. 14,37,38In independently associated with alcohol use and severe phenotype of ALD with ACLF. 14In another study, AH-related inpatient mortality and healthcare burden were lower in African Americans compared to whites. 39In a recent study using the NIS database on cirrhosisrelated hospitalizations in the United States, ALD including AH was the most common aetiology in Native American individuals. 40nsistently, other studies have shown increasing ALD burden and mortality in the United States in Native Americans. 13,41,42

| Mechanisms of increasing prevalence of ALD in ethnic minorities
East Asians have less enzymatic activity to metabolize alcohol, which may explain more alcohol-induced injury in this population.
Furthermore, up to 80% of South Americans with Native American ancestry carry the PNPLA3 G/G polymorphism, a known risk factor for the development of advanced ALD. 43,44 Several social determinants of health including socio-economic and cultural factors, living conditions, and access to care contribute to outcomes in ALD patients. 45Cultural differences in alcohol consumption may also explain ethnic variations in ALD disparities.For example, miners in Bolivia bring offerings to the "devil who rules the underworld" of Bolivia's mines, called "The Uncle."It is believed that these offerings, a 96% pure cane alcohol, are consumed alone to be "protected" during the mining labour.Differences in socio-economic status may also explain the susceptibility.Although low-income population drinks less amount of alcohol compared to higher socio-economic strata, 14,46-48 a higher prevalence of advanced ALD in minorities and low-income groups has been described as the "alcohol-harm paradox."One potential explanation for this phenomenon and observation is a limited access to health care or perception of racial discrimination in minorities. 49,50In one TA B L E 3 Studies observing increasing burden of alcohol-associated liver disease (ALD) in racial/ethnic minorities.study on candidates needing LT (25% for ALD), compared with non-Hispanic whites, a lower likelihood of receiving LT was observed in blacks (HR = .94,95% CI: .91-.98, p < .001),Hispanics (HR = .70,95% CI: .68-.73, p < .001),and Asians (HR = .74,95% CI: .69-.80, p < .001).
Also, compared with non-Hispanic whites, blacks had a significantly higher risk of 5-year post-LT death (HR = 1.31, 95% CI: 1.23-1.39,p < .001). 51In another study cohort of 2271 candidates undergoing LT evaluation, there were no ethnic differences in listing candidates for medical reasons, but blacks and Hispanics were less likely to be listed for psychosocial reasons compared to whites with OR (95% CI) of 1.65 (1.07-2.56)and 2.10 (1.16-3.78),respectively.These findings were unchanged after adjusting the analyses for confounders and other variables, 1.95 (1.12-3.38)and 2.29 (1.08-4.86),respectively. 52In another study on 143 blacks recruited for addiction treatment, 79% reported prior experience of racial discrimination during health care, associated with greater mistrust in the healthcare system leading to delay in seeking addiction treatment. 53As alcohol use on follow-up among patients surviving an index hospitalization is associated with long-term outcomes, 54 disparities in access to AUD treatment also potentially result in ethnic variations in ALD-related healthcare burden.In a retrospective cohort of 297 506 veterans with a diagnosis of AUD, blacks vs.
whites were 32% (29%-35%) less likely to receive pharmacotherapy for AUD, after adjusting for other confounders. 55Ethnic disparities in the prevalence of obesity may also explain ethnicity-based variations in the prevalence and burden of ALD.The age-adjusted prevalence of obesity in one study was 49.6% in blacks followed by 44.8% in Hispanics, 42.2% in whites, and 17.4% in Asians. 56

| ALD IN IND IVIDUAL S WHO ARE OB E S E OR HAVE ME TABOLI C RIS K FAC TO R S
The AASLD guideline 57 requires the exclusion of recent alcohol consumption of >30 g on average per day in men and >20 g on average per day in women when evaluating patients with suspected metabolic dysfunction-associated steatotic liver disease (MASLD).A new diagnostic entity of MetALD 58 has been developed for men regularly drinking 30-60 g/day on average and women drinking 20-50 g/day on average (Figure 1).The diagnosis of ALD is reserved for men regularly drinking >60 g/day on average and women drinking >50 g/day on average.The risk factors of heavy alcohol use and metabolic syndrome are frequently observed in the same individual in the general population.The prevalence of type 2 diabetes mellitus (T2DM) and metabolic syndrome in ALD patients in an analysis of the NHANES database (1999-2004) was reported as 19% and 37%, respectively. 59

| Heavy alcohol use and obesity or metabolic risk factors
The prevalence of steatosis increases synergistically with increasing body mass index (BMI) and heavy alcohol intake.This was demonstrated in the Study of Health in Pomerania where hepatic steatosis was examined by ultrasonography. 60The incidence of cirrhosis also increases synergistically with BMI and heavy alcohol intake.In the UK Million Women Study, the incidence of cirrhosis increased synergistically with obesity and heavy alcohol intake ≥150 g/week. 61In the Midspan prospective cohort study, participants were stratified by BMI (<25, 25 to <30, and obese ≥30) and alcohol consumption (none, 10-140, and ≥150 g/week).The relative risk contribution to liver-related mortality was 1.29 (.60-2.80) for BMI, 3.66 (4.98-18.2) for alcohol, and 9.53 (4.98-18.2) for both BMI and alcohol. 62The Finnish population-based Health 2000 Study enrolled 6366 subjects and followed until 2013 for liver-related admission, mortality, and liver cancer.The hazard ratios for metabolic syndrome were 2.03 (1.18-3.47),weekly binging 2.28 (.76-6.71), and 4.61 (2.04-10.4),respectively. 63In a Taiwanese population-level prospective study of 23 712 residents with liver disease followed for 11.6 years, a total of 305 cases of incident HCC were observed. 64

| Moderate alcohol use and obesity or metabolic risk factors
The potential benefits of moderate alcohol consumption (10-29.9gm/d) on liver disease are more ambivalent compared to the data on overall mortality.Many modest alcohol consumption studies compared the prevalence or risk of MASLD in the general population.These studies are not directly applicable to patients who have existing MASLD.In a meta-analysis 65 of 43 175 individuals, moderate alcohol consumption was associated with lower prevalence of MASLD.Similar protective benefit of moderate alcohol use on MASLD was shown in a Japanese cohort of 5297 employees. 66Of note, this study showed findings opposite to the Kangbuk Samsung Health Study on 58 927 participants followed for 347 925 personyears (sum of everyone's follow-up period), which showed fibrosis progression as assessed by FIB-4. 67It should be noted that fatty liver at baseline was present in only 8% in the first study but was universally observed in everyone in the latter study.
We also learned from MASH CRN cohort that modest alcohol consumption is associated with lower prevalence of MASH and less fibrosis.It compared lifetime non-drinkers to modest drinkers consuming up to 20 g/day.A dose-response was also observed: those who drink more frequently are more protected. 68A subsequent cohort study of the same patients showed that modest alcohol consumption is associated with less steatohepatitis resolution but a similar improvement in fibrosis as non-drinkers. 69Other crosssectional liver biopsy study in MASLD patients similarly showed that modest alcohol consumption is associated with lower prevalence of MASH and less fibrosis. 70Gene expression analysis in liver biopsy revealed a marked inhibition of immune response pathway in modest drinkers compared to the non-drinkers, which may account for the lowering of liver fibrosis and hepatocellular injury. 71 evaluate the cumulative lifetime exposure of moderate alcohol consumption on histological outcomes and to address the lack of a randomized control trial in modest alcohol consumption, Sookoian 72 conducted a Mendelian randomization study using a genetic variant (rs1229984 A;G) in the alcohol dehydrogenase (ADH1B) gene where the A allele carrier corresponds to on average 6 g/day less alcohol consumption.The ADH1B gene is not directly linked to the pathophysiology of MASH, and excessive alcohol (>30 g/day for men, >20 g/day for women) has been excluded by history; therefore, ADH1B gene serves as a valid instrument for instrumental analysis of moderate alcohol consumption.The study found that moderate alcohol consumption is associated with a higher NAFLD Activity Score among 466 patients with biopsyproven MASLD.

| Safe alcohol use in obesity or metabolic risk factors
In NHANES III, NAFLD is defined by Hepatic Steatosis Index and 4568 participants with MASLD were included.Modest alcohol consumption of 5-15 g/day on average was protective (HR = .59,95% CI: .40-.85) against overall mortality. 73The exact amount of alcohol consumption associated with decreased overall mortality and liver-related mortality compared to non-drinkers, known as the J curve, has been reported in many studies that focus on patients with existing metabolic risk factors.The FINRISK studies 1992-2012 enrolled 41 260 participants without liver disease and had 355 liverrelated events occurred in 12.4 years of follow-up.A J curve was only observed in the lowest waist-to-hip WHR tertile, and the nadir was at 5 g of alcohol per day for the lowest WHR tertile group.For the highest WHR tertile group, the hazard ratio increased sharply starting at 5 g/day. 74Another analysis of the FINRISK study included only patients with MASLD based on by Hepatic Steatosis Index.
There was a J curve for overall mortality at 5 g/day, but not for mortality due to advanced liver disease. 75

| S TR ATEG IE S TO REDUCE ALD BURDEN
Strategies to reduce the burden of ALD are essential in addressing this significant global public health concern.As the drinking amount and pattern of alcohol consumption are associated with the risk of cirrhosis, 76 it becomes critical to control alcohol consumption to improve health at population level.This is especially critical since ALD is the 11th most preventable cause of mortality worldwide, 20 contributing to approximately 4% of global deaths.The direct and indirect economic consequences of alcohol misuse, such as workforce productivity loss and healthcare costs, further emphasize the need for effective public health policies (PHP) at global, regional, and national levels. 77The World Health Organization categorizes PHP into eight key areas: national plans to combat alcohol's harmful consequences, control of alcohol production and sale, taxation and pricing policies, limiting drinking age, restrictions on alcohol access, driving-related alcohol policies, control over advertising and promotion, and government monitoring systems. 49udies have demonstrated that PHP can significantly reduce alcohol use and negative consequences including alcohol-associated mortality. 49,78A strong, multifaceted intervention approach is necessary to effectively decrease the burden of ALD.For example, national alcohol policies, though less implemented, have shown a strong association between lower ALD mortality and alcohol use disorder prevalence. 78The control of alcohol production and sale through licensing and regulating outlet density, along with restrictions on sale days and hours, has proven effective in reducing alcohol consumption and related harm.Taxation strategies, including alcohol volumetric tax and setting minimum unit price (MUP), are particularly effective in reducing acute and chronic alcohol-related harms.Such measures not only diminish consumption but also generate revenue for health-related programmes. 79The benefit of MUP policy has recently been shown in Scotland with implementation of £.50 per unit of alcohol in 2018.This policy resulted in improved population-level health in Scotland as evidenced by a 13.4% reduction in alcoholrelated deaths as compared to England. 80Furthermore, maximum benefit was observed in individuals from low socio-economic groups, which is critical in bridging health disparities. 81dressing alcohol consumption at a young age is crucial, as early alcohol use predicts the development of cirrhosis in adults. 82licies that increase the minimum drinking age and restrict alcohol access to young people can significantly reduce alcohol-related injuries and fatalities.Similarly, driving-related alcohol policies, such as sobriety checkpoints and lower legal blood alcohol concentrations, have effectively reduced drunk-driving incidents.Control over alcohol advertising and promotion is essential, especially with the influence of mainstream media and internet-based marketing on youth drinking patterns.Stronger regulations and international agreements are needed to counteract the impact of alcohol marketing on young people. 78Societal changes, such as sharing roles and increased workforce participation, have led to shifts in alcohol consumption patterns.Additionally, the rising stress levels associated with juggling family and work responsibilities may drive some women to use alcohol as a coping mechanism. 83Alcohol advertising targeted towards women has also played a role in normalizing and promoting alcohol consumption. 49,77stricting alcohol access through national licensing and selling is another effective strategy.This includes managing the density of alcohol sales centres and regulating sale times, which can reduce alcohol-related crimes, emergency visits, and homicides.However, the effective implementation of PHP requires governmental oversight and the overcoming of barriers such as lack of political will and contradictions between alcohol industry efforts and public health strategies. 78Furthermore, to reduce ethnic disparities on alcohol use and severity of ALD, data are needed on the social determinants of health.The clinic approach should also address cultural backgrounds associated with alcohol use and high-risk patterns. In

FU N D I N G I N FO R M ATI O N
The study is not funded by any financial support.

CO N FLI C T O F I NTE R E S T S TATE M E NT
The authors do not have any disclosures to report.

O RCI D
Juan P Arab https://orcid.org/0000-0002-8561-396X Alcohol use and obesity emerged as risk factors for HCC development in addition to six other factors.In a multivariable-adjusted model, synergy between BMI ≥ 30 and alcohol use increased the risk of HCC by 3.82-fold (95% CI: 1.94-7.52)vs. non-drinkers with BMI < 30.F I G U R E 1 New nomenclature identifying phenotype of individuals with both the risk factors of metabolic syndrome at risky alcohol use (MetALD).

Furthermore, we need 7 |
to recognize that ALD and AUD frequently co-exist.Hence, efforts should be made to manage the dual pathology of alcohol use disorder and liver disease.Strategies are needed to overcome barriers of AUD treatment in ALD patients at the level of clinicians (lack of time and adequate training to manage addiction component of the disease), patients (stigma attached to ALD, lack of awareness and insight, fear of being looked down by the society and family), and system/administration (lack of adequate resources and staff, clinic space and billing, financial constraints, and unique issues in ALD patients [lack of insurance, social support, and transportation]).In this sense, a multidisciplinary clinic with addiction counsellor, social worker, psychiatrist, hepatologist, and clinic nurse aiming to provide holistic, collocated, comprehensive care for ALD patients should be promoted and implemented.26In summary, reducing the burden of ALD requires a comprehensive approach involving a combination of national policies, regulation of alcohol production and sale, taxation and pricing strategies, age restrictions, driving-related policies, control of advertising, and clinical interventions.Each of these components contributes to a multifaceted strategy aimed at mitigating the adverse health and economic impacts of alcohol misuse.SUMMARY AND FUTURE PROS PEC TSIn summary, global alcohol consumption varies across regions in terms of quantity, type, and patterns.There are ethnic groups who are particularly affected, such as Hispanics, Native Americans, Asians, and blacks.Potential explanations are related to differences in genetics, cultural background, socio-economic status, access to health care, and obesity-undernutrition.Potential solutions start from recognizing the problem, integrating cultural aspects into ALD clinics, to a whole society approach with the implementation of public health policies.By addressing these challenges and promoting awareness, we can strive to reduce the burden of ALD, especially in high-risk demographic groups to improve their long-term health outcomes.Future research should delve deeper into these factors to develop targeted interventions aimed at reducing harmful drinking behaviours in these special populations.