Abstract
Background & Aims
Alcohol consumption is a well-established risk factor for hepatocellular carcinoma (HCC), although its impact may vary across different age groups. Accordingly, we aimed to investigate the association between alcohol consumption and the risk of HCC across different age groups.
Methods
We included 4,234,445 participants aged ≥20 years who underwent a national health examination in 2009. Cox proportional hazards regression models were used to investigate the association of alcohol consumption with the risk of HCC across age groups.
Results
Among 3,869,084 participants, 20,475 individuals were newly diagnosed with HCC during a median follow-up of 11.3 years. When stratified by 20-years age groups, increasing alcohol consumption was significantly associated with an increased risk of HCC in the ≥60-years age group compared with no alcohol consumption (p for trend <0.001). Heavy alcohol consumption was significantly associated with an increased risk of HCC in the 40–59-years and ≥60-years age groups, with larger effect estimates observed at older ages (adjusted hazard ratio, 1.11; 95% CI, 1.05–1.18 for the 40–59-years age group; adjusted hazard ratio, 1.47; 95% CI, 1.38–1.57 for the ≥60-years age group).
Conclusions
Our findings indicate that the association between alcohol consumption and the risk of HCC differs across age groups, with the most pronounced risk increase observed among older individuals. These findings may inform age-tailored HCC risk assessment and prevention strategies, particularly by identifying middle-aged and older heavy drinkers who may benefit from more careful risk stratification.
Impact and implications
Alcohol consumption is a well-established risk factor for HCC, but its age-specific impact remains insufficiently defined. In this nationwide cohort of 3,869,084 adults, heavy alcohol consumption was associated with increased HCC risk in the 40–59-years and ≥60-years age groups, with the strongest association and highest 10-year cumulative risk observed among heavy drinkers aged ≥60 years. These findings may help refine age-tailored HCC risk assessment by supporting the consideration of heavy alcohol consumption alongside established liver-related risk factors, particularly in middle-aged and older adults.
Keywords: Age, Alcohol, Hepatocellular carcinoma
Graphical abstract
Highlights
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The association between alcohol consumption and the risk of HCC differs across age groups.
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Heavy drinking increased risk of HCC in the 40–59-years and ≥60-years age groups.
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Our findings support age-tailored HCC risk stratification in heavy drinkers.
Introduction
Hepatocellular carcinoma (HCC) is one of the most common cancers and cancer-related mortality.1,2 As a result of improved vaccination and the development of antiviral agents, risk factors for HCC have shifted from viral to non-viral liver diseases, which has implications for primary and secondary prevention (including HCC surveillance) and treatment.[3], [4], [5] Thus, modifying preventable HCC risk factors, such as alcohol consumption, obesity, and diabetes, is an important strategy for prevention of HCC.
Alcohol consumption is a widely recognized risk factor for HCC, and accounts for 50% of mortality caused by cirrhosis.6,7 The relationship between alcohol consumption and risk of HCC involves complex mechanisms, including liver injury caused by acetaldehyde and DNA damage caused by oxidative stress.[8], [9], [10], [11] Chronic excessive alcohol consumption can lead to alcoholic liver disease (ALD), which spans the clinical spectrum from simple steatosis to alcoholic hepatitis, fibrosis, cirrhosis, and ultimately HCC.12,13 However, although the quantity and duration of alcohol consumption are associated with ALD progression14 and increased risk of HCC,15 progression to ALD is influenced by complex interactions between consumption and a constellation of host factors, leading to the development of cirrhosis and HCC in only a subset of patients.
The association between alcohol consumption and the risk of HCC may vary by age. Metabolic and physiological changes across different life stages can significantly influence the impact of alcohol on the liver.16 The liver's capacity to metabolize alcohol and regenerate itself changes with age, potentially affecting the threshold for alcohol-related liver damage. Furthermore, age-related changes in liver function, regenerative capacity, inflammation, fibrosis, and the potential accumulation of alcohol-related liver injury may contribute to differences in alcohol-associated HCC risk across age groups.
Accordingly, we conducted a large-scale, nationwide cohort study of more than 3 million individuals to investigate the association between alcohol consumption and the risk of HCC across different age groups.
Patients and methods
Data source
We used data from the South Korean National Health Insurance Service (KNHIS) database. The KNHIS, a national health insurance system managed by the government, covers ∼97% of the total population. The KNHIS claims database contains information on demographics, medical treatment, procedures, prescription drugs, diagnostic codes, healthcare utilization, and national health screening results. The KNHIS provides a standardized national health screening program every 2 years for all insured individuals.17,18 This national health screening includes a self-administered questionnaire covering medical history and lifestyle habits, anthropometric measurements, and laboratory tests.19 The Institutional Review Board (IRB) of Severance Hospital, Seoul, Republic of Korea (IRB No. 4-2024-0673) and the National Health Insurance Service (NHIS) Big Data Steering Department approved this study. The requirement for written informed consent was waived, as the KNHIS dataset was anonymized and constructed in accordance with strict confidentiality guidelines. This study was conducted in accordance with the principles of the Declaration of Helsinki.
Study population
Fig. S1 shows the selection process for the study population. We included 4,234,445 participants aged ≥20 years who underwent a national health examination between January 1 and December 31, 2009. To minimize the confounding effects of pre-existing diseases, we excluded those with a prior diagnosis of cancer before cohort entry (n = 65,148). To minimize potential reverse causality, we further excluded participants who developed HCC or died within the first year of follow-up (n = 11,173). We also excluded those with missing data (n = 289,040). Finally, 3,869,084 participants were included and followed until HCC development, death, or December 31, 2021, whichever occurred first.
Ascertainment of alcohol consumption
Information on alcohol consumption was obtained from a standardized self-administered questionnaire administered as part of the national health screening program. The weekly frequency of alcohol consumption was reported as 0, 1–2, 3–4, and 5–7 days/week. In addition, the amount of alcohol consumed per occasion was expressed as the number of glasses consumed on a single occasion. Approximately 8 g of ethanol was estimated to be present per glass of each type of alcoholic beverage. The average daily amount of alcohol consumed was calculated using the weekly frequency of alcohol consumption and the amount of alcohol consumed per occasion. Participants were classified as non-drinkers, light-to-moderate drinkers (<30 g of alcohol per day for men, <20 g of alcohol per day for women), or heavy drinkers (≥30 g of alcohol per day for men, ≥20 g of alcohol per day for women).[20], [21], [22]
Diagnosis of HCC
We identified incident HCC cases based on the International Classification of Diseases 10th Revision Clinical Modification (ICD-10-CM) code C22.0 and the special reimbursement cancer code V193 between January 2009 and December 2021. The NHIS has implemented a national registration program with special reimbursement codes (called V codes) to lower the co-payment rate to 5% for intractable diseases, including cancers, since 2006. To receive the benefits of reduced payments for cancer-related management, all patients with such diseases are required to have their diagnosis certified by a physician and medical institution.
Clinical variables
Anthropometric data, including body weight, height, and waist circumference, were measured during health screening. BMI was calculated by dividing body weight (kilograms) by height (meters) squared. Systolic and diastolic blood pressures were measured in a seated position after at least 5 min of rest. Blood samples were collected after overnight fasting. Demographic and lifestyle data were collected via a self-report questionnaire. Smoking status was categorized as never, former, or current smoking. Participants performing strenuous physical activity for ≥20 min at least three times per week or moderate physical activity for ≥ 30 min at least five times per week were considered regular exercisers. The low-income group included people in the lowest income quartile. Diabetes was defined as a fasting plasma glucose level ≥126 mg/dl or at least one prescription per year for antidiabetic medication under the relevant ICD-10-CM codes (E11−E14). Hypertension was defined as systolic blood pressure ≥140, diastolic blood pressure ≥90 mmHg, or at least one prescription for an antihypertensive medication per year under ICD-10-CM codes I10–I13 and I15. Dyslipidemia was defined as a serum total cholesterol level ≥240 mg/dl or at least one prescription for a lipid-lowering medication per year under ICD-10-CM code E78. Chronic viral hepatitis was defined as ICD-10 code B18. Liver cirrhosis was defined as ICD-10 codes K703 and K746. Fatty liver was defined using the fatty liver index (FLI) as FLI ≥30.23
Statistical analysis
Baseline characteristics were compared using analysis of variance for continuous variables and the Χ2 test for categorical variables. HCC incidence rates were calculated by dividing the number of incident cases by total person-years and were expressed per 1,000 person-years in each category of exposure. Five-year and 10-year cumulative risks of HCC were estimated according to alcohol consumption level and age group. To improve clinical interpretability, 10-year cumulative risk differences were calculated using non-drinkers as the reference group within each age group, and the corresponding number needed to harm (NNH) was calculated as the inverse of the absolute 10-year cumulative risk difference. Multivariable Cox proportional hazards regression models were used to estimate the adjusted hazard ratios (aHRs) and 95% CIs to investigate the dose–response association of alcohol consumption with the risk of HCC according to age. Model 1 was adjusted for age, sex, smoking status, physical activity, and income. Model 2 was additionally adjusted for BMI, diabetes, chronic viral hepatitis, liver cirrhosis, and fatty liver. To compare age-specific HCC risk with another alcohol-related adverse outcome, we additionally evaluated the association between alcohol consumption and all-cause mortality. An additional analysis was performed to further evaluate the dose–response association between alcohol consumption and the risk of HCC among individuals who consumed alcohol, with the lowest exposure group as the reference group. In this analysis, light-to-moderate alcohol consumption were further categorized, with light consumption defined as ≤10 g of alcohol per day.
Several subgroup analyses stratified by sex, smoking status, obesity, diabetes, chronic viral hepatitis, and chronic liver disease (CLD, including fatty liver, chronic viral hepatitis, or liver cirrhosis) were performed. Multiplicative interactions between alcohol consumption category and each stratification variable were tested using interaction terms in the Cox proportional hazards regression models. As a sensitivity analysis, we performed a competing-risk analysis using Fine–Gray subdistribution hazard models to account for death as a competing event for incident HCC. Subdistribution hazard ratios (SHRs) and 95% CIs were estimated overall and according to 20-year age groups using the same covariate adjustment strategy as in the primary Cox models. As an additional sensitivity analysis, we evaluated changes in alcohol consumption between the 2009 baseline health examination and the 2011 follow-up health examination. Participants were classified according to alcohol consumption category at baseline and follow-up, and the association between changes in alcohol consumption and subsequent risk of HCC was assessed. To address potential sick-quitter bias, we repeated the primary analysis after excluding former drinkers from the non-drinking reference group. All statistical analyses were performed using SAS software (version 9.4; SAS Institute, Cary, NC, USA). Statistical significance was set at a two-sided p <0.05.
Results
Baseline characteristics of the study population
Among 3,869,084 participants, 20,475 were newly diagnosed with HCC during the median follow-up duration of 11.3 years (IQR, 11.1–11.6 years). Table 1 shows the baseline characteristics of the study population according to alcohol consumption levels. Non-drinkers, light-to-moderate drinkers, and heavy drinkers comprised 49.5%, 41.6%, and 8.9% of the total study population, respectively. Compared with non-drinkers, light-to-moderate and heavy drinkers were younger and were more likely to be male, current smokers, regular exercisers, and not in the low-income group. They also had higher BMI, waist circumference, blood pressure, and levels of aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transpeptidase, as well as a higher prevalence of fatty liver. Participants with chronic viral hepatitis were more likely to be non-drinkers, whereas heavy drinkers had the highest prevalence of liver cirrhosis and diabetes and the highest fasting blood glucose levels.
Table 1.
Baseline characteristics of the study population according to the alcohol consumption.
| Characteristics | Alcohol consumption∗ |
p value | ||
|---|---|---|---|---|
| Non-drinker (n = 1,914,909, 49.5%) | Light-to-moderate drinker (n = 1,609,635, 41.6%) | Heavy drinker (n = 344,540, 8.9%) | ||
| Demographic variables | ||||
| Age (years) | 51.3 ± 14.2 | 43.0 ± 12.7 | 44.1 ± 12.8 | <0.001 |
| Age group (years) | ||||
| 20–29 | 151,247 (7.9) | 265,712 (16.5) | 51,302 (14.9) | |
| 30–39 | 238,201 (12.4) | 418,420 (26.0) | 79,236 (23.0) | |
| 40–49 | 472,297 (24.7) | 450,898 (28.0) | 100,938 (29.3) | |
| 50–59 | 471,584 (24.6) | 285,218 (17.7) | 67,788 (19.7) | |
| 60–69 | 357,651 (18.7) | 136,641 (8.5) | 32,327 (9.4) | |
| ≥70 | 223,929 (11.7) | 52,746 (3.3) | 12,949 (3.8) | |
| Male | 632,516 (33.0) | 1,199,069 (74.5) | 301,599 (87.5) | <0.001 |
| BMI (kg/m2) | 23.6 ± 3.3 | 23.7 ± 3.2 | 24.3 ± 3.2 | <0.001 |
| Waist circumference (cm) | 79.2 ± 9.1 | 80.9 ± 8.9 | 83.5 ± 8.6 | <0.001 |
| Systolic BP (mmHg) | 121.9 ± 15.5 | 122.5 ± 14.4 | 126.2 ± 14.8 | <0.001 |
| Diastolic BP (mmHg) | 75.5 ± 10.1 | 76.8 ± 9.9 | 79.3 ± 10.2 | <0.001 |
| Lifestyle factors | ||||
| Smoking status | <0.001 | |||
| Never | 1,550,341 (81.0) | 665,242 (41.3) | 74,135 (21.5) | |
| Former | 151,217 (7.9) | 324,369 (20.2) | 77,950 (22.6) | |
| Current | 213,351 (11.1) | 620,024 (38.5) | 192,455 (55.9) | |
| Alcohol intake (g/day) | 0 | 10.2 ± 7.2 | 48.5 ± 25.3 | <0.001 |
| Regular exerciser | 321,740 (16.8) | 310,412 (19.3) | 70,265 (20.4) | <0.001 |
| Low income | 455,995 (23.8) | 311,966 (19.4) | 63,437 (18.4) | <0.001 |
| Comorbidities | ||||
| Chronic viral hepatitis | 149,764 (7.8) | 95,917 (6.0) | 22,517 (6.5) | <0.001 |
| Cirrhosis | 18,332 (1.0) | 10,488 (0.7) | 3,886 (1.1) | <0.001 |
| Fatty liver (fatty liver index ≥30) | 556,393 (29.1) | 670,853 (41.7) | 211,551 (61.4) | <0.001 |
| Hypertension | 579,823 (30.3) | 364,191 (22.6) | 104,147 (30.2) | <0.001 |
| Diabetes | 189,272 (9.9) | 114,254 (7.1) | 36,073 (10.5) | <0.001 |
| Dyslipidemia | 413,056 (21.6) | 238,526 (14.8) | 58,509 (17.0) | <0.001 |
| Laboratory variables | ||||
| Fasting blood glucose, mg/dl | 97.2 ± 24.0 | 96.7 ± 22.8 | 101.2 ± 27.9 | <0.001 |
| Aspartate aminotransferase, IU/L | 24.3 ± 13.8 | 25.7 ± 16.2 | 30.8 ± 24.7 | <0.001 |
| Alanine aminotransferase, IU/L | 23.5 ± 20.0 | 26.6 ± 22.8 | 31.2 ± 26.8 | <0.001 |
| Gamma-glutamyl transpeptidase, IU/L | 26.6 ± 30.5 | 42.0 ± 51.2 | 75.5 ± 93.6 | <0.001 |
Data are presented as mean ± SD or n (%). ∗Light-to-moderate: >0 and <30 g alcohol/day for men, >0 and <20 g alcohol/day for women; heavy ≥30 g alcohol/day for men, ≥20 g alcohol/day for women. p values were calculated using analysis of variance for continuous variables and the Χ2 test for categorical variables. Statistical significance was defined as a two-sided p <0.05.
Association between alcohol consumption and the risk of HCC according to age
Among the total population, increasing alcohol consumption was significantly associated with an increased risk of HCC compared with no alcohol consumption (p for trend <0.001). Among heavy drinkers, the HCC incidence rate increased markedly with age, from 0.12 per 1,000 person-years in individuals aged 20–39 years to 0.84 per 1,000 person-years in those aged 40–59 years and 2.64 per 1,000 person-years in those aged ≥60 years. Heavy alcohol consumption was significantly associated with an increased risk of HCC (aHR, 1.28; 95% CI, 1.22–1.34), whereas light-to-moderate alcohol consumption was not, compared with no alcohol consumption (Table 2). The risk of HCC according to alcohol consumption level, stratified by 20-year age groups, is shown in Table 2 and Fig. 1A.
Table 2.
Dose–response association between alcohol consumption and the risk of hepatocellular carcinoma according to age group.
| Alcohol consumption | No. | HCC no. | Person-years | Incidence rate | Hazard ratio (95% CI) |
||
|---|---|---|---|---|---|---|---|
| Unadjusted | Model 1 | Model 2 | |||||
| Total | |||||||
| No | 1,914,909 | 9,809 | 21,044,273.1 | 0.47 | 1 (reference) | 1 (reference) | 1 (reference) |
| Light-to-moderate | 1,609,635 | 7,722 | 17,920,752.1 | 0.43 | 0.92 (0.90–0.95) | 0.92 (0.89–0.96) | 0.98 (0.95–1.02) |
| Heavy | 344,540 | 2,944 | 3,790,942.9 | 0.78 | 1.67 (1.60–1.74) | 1.37 (1.31–1.44) | 1.28 (1.22–1.34) |
| p for trend | <0.001 | <0.001 | <0.001 | ||||
| 20–year age groups | |||||||
| Age 20–39 years | |||||||
| No | 389,448 | 291 | 4,392,196.4 | 0.07 | 1 (reference) | 1 (reference) | 1 (reference) |
| Light-to-moderate | 684,132 | 642 | 7,721,959.7 | 0.08 | 1.26 (1.09–1.44) | 0.88 (0.76–1.01) | 0.93 (0.81–1.07) |
| Heavy | 130,538 | 183 | 1,469,500.0 | 0.12 | 1.88 (1.56–2.26) | 1.16 (0.96–1.39) | 1.17 (0.97–1.40) |
| p for trend | <0.001 | 0.838 | 0.725 | ||||
| Age 40–59 years | |||||||
| No | 943,881 | 4,141 | 10,599,937.2 | 0.39 | 1 (reference) | 1 (reference) | 1 (reference) |
| Light-to-moderate | 736,116 | 4,288 | 8,234,082.2 | 0.52 | 1.33 (1.28–1.39) | 0.84 (0.81–0.88) | 0.92 (0.88–0.96) |
| Heavy | 168,726 | 1,563 | 1,868,511.9 | 0.84 | 2.14 (2.02–2.27) | 1.14 (1.08–1.22) | 1.11 (1.05–1.18) |
| p for trend | <0.001 | 0.233 | 0.0501 | ||||
| Age ≥60 years | |||||||
| No | 581,580 | 5,377 | 6,052,139.5 | 0.89 | 1 (reference) | 1 (reference) | 1 (reference) |
| Light-to-moderate | 189,387 | 2,792 | 1,964,710.1 | 1.42 | 1.60 (1.53–1.68) | 0.99 (0.95–1.04) | 1.05 (0.998–1.10) |
| Heavy | 45,276 | 1,198 | 452,931.0 | 2.64 | 2.99 (2.81–3.18) | 1.63 (1.53–1.74) | 1.47 (1.38–1.57) |
| p for trend | <0.001 | <0.001 | <0.001 | ||||
Model 1 was adjusted for age, sex, smoking status, physical activity, and income. Model 2 was adjusted for age, sex, BMI, smoking status, physical activity, income, chronic viral hepatitis, liver cirrhosis, fatty liver, and diabetes. Incidence rate per 1,000 person-years. Hazard ratios and 95% CIs were estimated using Cox proportional hazards regression models. p for trend was calculated by modeling alcohol consumption categories as an ordinal variable. Statistical significance was defined as a two-sided p <0.05.
Fig. 1.
Dose–response association between alcohol consumption and the risk of hepatocellular carcinoma according to age group.
(A) level of alcohol consumption, (B) frequency of alcohol consumption (days per week), and (C) amount of alcohol consumption (glasses per occasion). Points indicate adjusted hazard ratios and error bars indicate 95% CIs. Hazard ratios were estimated using multivariable Cox proportional hazards regression models.
We additionally estimated 5-year and 10-year cumulative HCC risks according to alcohol consumption level and age group; the full estimates are presented in Table S1. In the total population, the 5-year cumulative risks were 0.22%, 0.20%, and 0.34% among non-drinkers, light-to-moderate drinkers, and heavy drinkers, respectively; the corresponding 10-year cumulative risks were 0.46%, 0.42%, and 0.76%, respectively. In age-stratified analyses, the 10-year cumulative risks among non-drinkers, light-to-moderate drinkers, and heavy drinkers were 0.08%, 0.06%, and 0.07% in individuals aged 20–39 years; 0.35%, 0.45%, and 0.73% in those aged 40–59 years; and 0.88%, 1.32%, and 2.51% in those aged ≥ 60 years, respectively. These findings indicate that the cumulative risk of HCC increased markedly with age and was highest among heavy drinkers aged ≥60 years.
In the ≥60-years age group, increasing alcohol consumption was significantly associated with an increased risk of HCC compared with no alcohol consumption (p for trend <0.001), whereas no significant association was found in the 20–39-years and 40–59-years age groups (p for trend = 0.725 for the 20–39-years age group; p for trend = 0.0501 for the 40–59-years age group), with the latter showing a borderline non-significant trend. Heavy alcohol consumption was significantly associated with increased risks of HCC in the 40–59-years and ≥60-years age groups, with larger effect estimates observed at older ages (aHR, 1.11; 95% CI, 1.05–1.18 for the 40–59-years age group; aHR, 1.47; 95% CI, 1.38–1.57 for ≥ 60-years age group). By contrast, light-to-moderate alcohol consumption was not significantly associated with increased HCC risk in the total population or in any age group after adjustment for potential confounders.
Association between frequency of alcohol consumption and the risk of HCC according to age
In the total population and in 20-year stratified age groups, increasing frequency of alcohol consumption was significantly associated with an increased risk of HCC compared with no alcohol consumption (all p for trend <0.05) (Table 2). Alcohol consumption of ≥3 days/week was significantly associated with an increased risk of HCC, with the risk showing a gradual rise as the frequency of consumption increased (aHR, 1.16; 95% CI, 1.11–1.21 for 3-4 days/week; aHR, 1.42; 95% CI, 1.35–1.49 for ≥5 days/week) compared with no alcohol consumption. Age-stratified analyses of drinking frequency showed that alcohol consumption of ≥3 days/week was significantly associated with an increased risk of HCC in all age groups, although the association for 3–4 days/week in the 40–59-years age group did not reach statistical significance (Fig. 1B and Table S2).
Association between the amount of alcohol consumed on a single occasion and the risk of HCC according to age
In the total population, an increasing amount of alcohol consumed on a single occasion was significantly associated with an increased risk of HCC compared with no alcohol consumption (p for trend <0.001) (Table S2). Alcohol consumption of more than five glasses/occasion was significantly associated with an increased risk of HCC (aHR, 1.08; 95% CI, 1.04–1.12) compared with no alcohol consumption. In age-stratified analyses, consumption of more than five glasses/occasion was significantly associated with an increased risk of HCC (aHR, 1.23; 95% CI, 1.17–1.30) compared with no alcohol consumption, in the ≥60-years age group (Fig. 1C and Table S2).
Association between alcohol consumption and the risk of mortality according to age
To compare the age-specific association between alcohol consumption and HCC risk with another clinically relevant alcohol-related harm, we additionally evaluated all-cause mortality according to alcohol consumption category and age group. Overall, heavy alcohol consumption was associated with increased all-cause mortality compared with non-drinking (aHR, 1.07; 95% CI, 1.05–1.09). In age-stratified analyses, heavy alcohol consumption was associated with increased mortality among individuals aged 20–39 years and 40–59 years, with aHRs of 1.14 (95% CI, 1.05–1.24) and 1.23 (95% CI, 1.19–1.27), respectively. However, among individuals aged ≥60 years, the association between heavy alcohol consumption and all-cause mortality was attenuated and no longer statistically significant (aHR, 1.001; 95% CI, 0.98–1.03). Light-to-moderate alcohol consumption was associated with lower all-cause mortality than non-drinking across all age groups, although this finding should be interpreted cautiously given the possibility of residual confounding and abstainer/sick-quitter bias. These results are presented in Table S3.
Association between alcohol consumption and the risk of HCC after excluding non-drinkers
The risk of HCC was analyzed in individuals after excluding non-drinkers. The risk of HCC increased linearly as alcohol consumption increased in the total population (p for trend <0.001, aHR, 1.15, 95% CI, 1.10–1.21, for moderate alcohol drinkers; aHR, 1.39; 95% CI, 1.32–1.46, for heavy drinkers) compared with light drinkers (Fig. 2 and Table S4). When stratified by 20-years age groups, similar dose–response patterns were observed across all age groups. Among individuals aged 20–39 and 40–59 years, both moderate and heavy alcohol consumption were associated with progressively increased risks of HCC compared with light consumption (all p for trend <0.05). Among individuals aged ≥60 years, a clearer dose–response association was observed. Compared with light alcohol consumption, moderate and heavy alcohol consumption were associated with an increased risk of HCC (p for trend <0.001; aHR, 1.21; 95% CI, 1.12–1.30 for moderate alcohol consumption; aHR, 1.55; 95% CI, 1.43–1.68 for heavy alcohol consumption) (Table S4).
Fig. 2.
Dose–response association between alcohol consumption and the risk of hepatocellular carcinoma according to age group after excluding non-drinkers.
Light alcohol consumption was used as the reference group. Points indicate adjusted hazard ratios and error bars indicate 95% CIs. Hazard ratios were estimated using multivariable Cox proportional hazards regression models.
Subgroup analyses
To further examine whether the association between alcohol consumption and HCC risk differed according to clinically relevant modifiers, we performed stratified analyses by sex, smoking status, obesity, diabetes, chronic viral hepatitis, and CLD, with additional stratification by 20-years age groups. Significant interactions were observed between alcohol consumption and sex, smoking status, diabetes, chronic viral hepatitis, and CLD, whereas the interaction with obesity was not statistically significant. These findings are presented in Table S5–S10.
Among men, heavy alcohol consumption was associated with an increased risk of HCC overall and across age groups, whereas this association was not evident among women. The interaction between alcohol consumption and sex was statistically significant (p for interaction = 0.0003) (Table S5). Similarly, the association between alcohol consumption and HCC risk differed by smoking status, with heavy drinking showing stronger associations among current smokers than among non- or former smokers (p for interaction <0.001) (Table S6). In analyses stratified by diabetes, both light-to-moderate and heavy alcohol consumption were associated with increased HCC risk among individuals with diabetes, particularly in older age groups, and the interaction between alcohol consumption and diabetes was significant (p for interaction <0.001) (Table S7). By contrast, the interaction with obesity was not statistically significant (p for interaction = 0.130) (Table S8).
In analyses stratified by chronic viral hepatitis, heavy alcohol consumption was associated with a markedly increased risk of HCC among individuals without chronic viral hepatitis, whereas the corresponding adjusted hazard ratios were attenuated among those with chronic viral hepatitis, despite higher absolute incidence rates in this group (p for interaction <0.001) (Table S9). Similar effect modification was observed according to the presence of CLD (p for interaction <0.001) (Table S10).
Sensitivity analyses
In a competing-risk analysis using the Fine–Gray subdistribution hazard model, the overall pattern of association remained similar to that observed in the primary Cox models. Compared with no alcohol consumption, heavy alcohol consumption was associated with a higher risk of HCC in the total population (SHR, 1.29; 95% CI, 1.23–1.35), whereas light-to-moderate alcohol consumption was not associated with an increased risk (SHR, 0.998; 95% CI, 0.97–1.03). In age-stratified analyses, heavy alcohol consumption remained associated with increased risk of HCC among individuals aged 40–59 years (SHR, 1.11; 95% CI, 1.05–1.18) and those aged ≥60 years (SHR, 1.47; 95% CI, 1.38–1.58), whereas the association among individuals aged 20–39 years was not statistically significant (SHR, 1.17; 95% CI, 0.97–1.41) (Table S11).
To address potential sick-quitter bias, we performed a sensitivity analysis after excluding former drinkers from the non-drinking reference group. In this analysis, heavy alcohol consumption remained associated with an increased risk of HCC in the total population (aHR, 1.38; 95% CI, 1.30–1.47). In age-stratified analyses, the association was strongest among individuals aged ≥60 years (aHR, 1.61; 95% CI, 1.48–1.75), followed by those aged 40–59 years (aHR, 1.16; 95% CI, 1.06–1.27). Among individuals aged 20–39 years, heavy alcohol consumption showed a positive but statistically non-significant association with HCC risk (aHR, 1.17; 95% CI, 0.93–1.50). These findings were broadly consistent with the main analysis and are presented in Table S12. In the sensitivity analysis incorporating changes in alcohol consumption between 2009 and 2011, increased alcohol consumption was associated with higher HCC risk. Among baseline non-drinkers, progression to heavy drinking was associated with increased HCC risk compared with persistent non-drinking (aHR, 1.66; 95% CI, 1.39–1.97). Among baseline light-to-moderate drinkers, progression to heavy drinking was also associated with increased risk compared with persistent light-to-moderate drinking (aHR, 1.29; 95% CI, 1.17–1.42). Conversely, among baseline heavy drinkers, reduction to light-to-moderate drinking was associated with lower HCC risk compared with persistent heavy drinking (aHR, 0.81; 95% CI, 0.73–0.91) (Table S13).
Discussion
In this nationwide cohort of over 3,800,000 individuals, increasing alcohol consumption was significantly associated with an increased risk of HCC in individuals 60 years and older after adjusting for potential confounders. The relationship between alcohol consumption and the risk of HCC was not uniform across age groups. The effect of alcohol consumption was less pronounced in younger age groups, whereas the risk increased significantly in older populations.
Previous studies on the association between alcohol consumption and the risk of HCC have highlighted the complexity of this relationship. Although excessive alcohol consumption is a well-known risk factor for HCC,6 there are inconsistent results regarding the association between mild-to-moderate alcohol consumption and the risk of HCC. Research has shown a dose-dependent increase in the risk of HCC with higher alcohol intake.24 Conversely, other studies have suggested that moderate alcohol consumption does not significantly increase the risk of HCC and may even confer protective effects against liver cancer.16,25,26 These findings underline the importance of individual differences, which could modulate susceptibility to alcohol-related liver damage. Our study is the first to investigate the association between alcohol consumption and the risk of HCC across distinct age groups. By stratifying participants by age, we were able to clearly delineate how the impact of alcohol on the risk of HCC differs across life stages. Notably, the association between increasing alcohol consumption and the risk of HCC was most evident in individuals aged ≥60 years. These age-dependent patterns emphasize the need for age-tailored risk assessment and prevention strategies.
The stronger association between heavy alcohol consumption and the risk of HCC among older adults may reflect several possible explanations. First, older adults may have accumulated alcohol-related liver injury over a longer period, although lifetime drinking patterns were not directly measured in this study. Second, aging itself may increase susceptibility to alcohol-related hepatocarcinogenesis through reduced hepatic regenerative capacity, increased oxidative stress, chronic inflammation, and a greater burden of comorbid liver or metabolic conditions.[27], [28], [29] Third, selection or survivor effects may have influenced the observed age-specific associations, because individuals who continue heavy drinking into older age may represent a selected population with distinct health characteristics.30,31 Therefore, our findings should be interpreted as age-specific associations based on baseline alcohol consumption rather than direct evidence that cumulative lifetime alcohol exposure explains the increased risk of HCC in older adults.
We also evaluated all-cause mortality as an additional comparator for alcohol-related harm. Heavy alcohol consumption was associated with increased all-cause mortality in the total population, particularly among individuals aged 20–39 years and 40–59 years, supporting the broader clinical relevance of heavy drinking beyond HCC risk. The attenuated association among individuals aged ≥60 years may reflect survivor bias, competing health risks, or residual confounding. Future studies incorporating other alcohol-associated outcomes, including colorectal cancer, stroke, and accidents, may provide a more comprehensive assessment of the age-specific burden of alcohol consumption.
Although some analyses suggested that light-to-moderate alcohol consumption was associated with a lower risk of HCC compared with no alcohol consumption, this pattern does not indicate a true protective effect of alcohol. Rather, in the drinker-only analysis using light alcohol consumption as the reference group, the risk of HCC increased with moderate and heavy alcohol consumption across age groups, supporting a dose–response pattern. This discrepancy likely reflects differences in the composition of the non-drinker reference group, including former drinkers or individuals with underlying health conditions, and the generally healthier profile of the light alcohol consumption group. To minimize potential sick-quitter bias, we additionally repeated the analysis after excluding former drinkers from the non-drinking reference group. The association between heavy alcohol consumption and increased HCC risk persisted after this exclusion, particularly among individuals aged 40–59 years and those aged ≥60 years. This supports the robustness of our main findings and suggests that the observed association between heavy alcohol consumption and HCC risk was unlikely to be explained solely by misclassification of former drinkers as non-drinkers. Nevertheless, light-to-moderate alcohol consumption should be interpreted cautiously because residual confounding, differences in baseline health status, and changes in drinking behavior over time may still influence the observed associations.
The additional stratified analyses suggested that the association between alcohol consumption and HCC risk may be modified by several clinical and lifestyle factors. Heavy alcohol consumption was more clearly associated with increased HCC risk among men, current smokers, individuals with diabetes, and older adults. Interestingly, the relative association between alcohol consumption and HCC risk appeared attenuated among individuals with chronic viral hepatitis, despite their substantially higher absolute incidence rates. This may reflect the high baseline risk conferred by chronic viral hepatitis, whereby the relative contribution of alcohol consumption is less apparent on the hazard ratio scale. Therefore, these results should not be interpreted as indicating that alcohol is safe in patients with chronic viral hepatitis; rather, both absolute and relative risks should be considered when interpreting subgroup-specific associations. Because these subgroup analyses were exploratory and based on multiplicative interaction tests, further studies are warranted to clarify whether alcohol consumption has additive or synergistic effects with viral, metabolic, and lifestyle risk factors on HCC development.
The combined impact of alcohol consumption and metabolic dysfunction is increasingly recognized in the context of metabolic dysfunction-associated alcohol-related liver disease (MetALD).32,33 Recent studies have also suggested that MetALD has clinical relevance beyond the liver, including esophageal squamous cell carcinoma recurrence34 and reflux esophagitis.35 Although our study was not originally designed to classify participants according to formal MetALD criteria, our additional analyses stratified by obesity and diabetes provide clinically relevant insight into whether selected metabolic factors modify alcohol-associated HCC risk. In these analyses, diabetes significantly modified the association between alcohol consumption and HCC risk, whereas obesity did not show a statistically significant interaction. These findings suggest that the combined effect of alcohol and metabolic dysfunction may differ according to the specific metabolic component. Biologically, alcohol consumption and metabolic dysfunction may jointly contribute to hepatocarcinogenesis through overlapping pathways, including insulin resistance, hepatic steatosis, oxidative stress, chronic inflammation, and fibrosis progression. Further studies using formal MetALD definitions and longitudinal metabolic profiles are warranted.
Translating these findings into clinical practice requires moving beyond relative hazard ratios to absolute and cumulative measures of risk. Compared with non-drinkers within each age group, heavy drinkers did not show an increased 10-year cumulative risk difference in the 20–39-years age group, whereas the 10-year cumulative risk differences were 0.38% in the 40–59-years age group and 1.63% in the ≥60-years age group, corresponding to NNH values of 263 and 61, respectively. The 10-year cumulative HCC risk was highest among heavy drinkers aged ≥60 years at 2.51%; however, this remains a population-level estimate rather than an individualized surveillance threshold. Therefore, alcohol consumption alone should not be considered sufficient to determine HCC surveillance eligibility. Consistent with prior work in alcohol-related cirrhosis, surveillance-related implications should be interpreted in the context of absolute and cumulative HCC risk, cirrhosis or advanced fibrosis, underlying liver disease status, competing mortality, and cost-effectiveness, rather than relative risk alone.36,37 Accordingly, our findings are best interpreted as supporting age-tailored risk stratification and prevention rather than direct expansion of surveillance eligibility based solely on alcohol consumption.
From an implementation perspective, age-tailored prevention strategies may be particularly relevant in primary care, where alcohol use, metabolic risk factors, and routine liver biochemistry can be assessed together. The Nara Declaration proposes a collaborative pathway between primary care physicians and gastroenterologists or hepatologists using alanine aminotransferase (ALT) >30 U/L as a simple trigger for further evaluation of CLD, including viral hepatitis, metabolic dysfunction-associated steatotic liver disease, alcohol-related liver disease, and other etiologies.38 In this framework, non-invasive markers such as fibrosis 4 (FIB-4) or platelet count can be used to stratify fibrosis risk and guide referral to specialists when appropriate. In the context of our findings, this approach may be especially useful for individuals aged 40–59 years, in whom alcohol-associated HCC risk begins to emerge. For middle-aged adults with alcohol use and metabolic risk factors, even mildly elevated ALT may prompt alcohol reduction interventions, assessment of metabolic comorbidities, non-invasive fibrosis risk stratification, and referral to hepatology when appropriate.
Our study has several strengths. First, by analyzing data according to the age groups, we identified the life stages in which the association between alcohol consumption and the risk of HCC was most pronounced. Second, the large nationwide cohort increased the statistical power and reliability of our findings. Third, the long follow-up period allowed assessment of long-term HCC development after baseline alcohol exposure. Fourth, adjustment for multiple demographic, lifestyle, metabolic, and liver-related factors strengthened the robustness of the observed associations. Finally, the robustness of the main findings was supported by supplementary analyses, including a Fine–Gray competing-risk analysis treating death as a competing event, which yielded results broadly consistent with those of the primary Cox models.
Our study also has limitations. First, alcohol consumption was self-reported and assessed primarily at baseline, and data on lifetime drinking patterns before baseline were not available. Although we performed a sensitivity analysis using changes in alcohol consumption between the 2009 and 2011 health examinations, alcohol intake was not modeled as a continuously time-updated exposure throughout follow-up. Thus, residual exposure misclassification may remain, particularly among older adults whose drinking patterns may change over time, and we could not distinguish cumulative lifetime exposure from age-related susceptibility or selection/survivor effects. Second, residual confounding from unmeasured or incompletely measured factors cannot be excluded. The non-drinking reference group may also have included individuals with prior alcohol exposure or poorer baseline health status, although we performed a sensitivity analysis excluding former drinkers to reduce potential sick-quitter bias. Third, the absolute risk estimates, cumulative risk estimates, and NNH values presented in this study are population-level measures and should not be interpreted as causal effects or direct thresholds for HCC surveillance. Surveillance decisions require individualized consideration of cirrhosis or advanced fibrosis, underlying liver disease status, competing mortality, and cost-effectiveness. Fourth, our analyses of metabolic dysfunction were limited to selected factors, including obesity and diabetes, and formal MetALD criteria were not applied. Finally, although all-cause mortality was evaluated as an additional comparator, other alcohol-associated outcomes, including colorectal cancer, stroke, and accidents, were not analyzed.
In conclusion, our findings indicate that the association between alcohol consumption and the risk of HCC differs across age groups, with the most pronounced risk increase observed among older individuals. These findings may inform age-tailored HCC risk assessment and prevention strategies, particularly by identifying middle-aged and older heavy drinkers who may benefit from more careful risk stratification.
Abbreviations
aHR, adjusted hazard ratio; ALD, alcoholic liver disease; ALT, alanine aminotransferase; CLD, chronic liver disease; FIB-4, fibrosis 4; FLI, fatty liver index; HCC, hepatocellular carcinoma; ICD-10-CM, International Classification of Diseases 10th Revision Clinical Modification; IRB, Institutional Review Board; KNHIS, Korean National Health Insurance Service; MetALD, metabolic dysfunction-associated alcohol-related liver disease; NHIS, National Health Insurance Service; NNH, number needed to harm; SHR, subdistribution hazard ratio.
Authors’ contributions
Conception: MNK, KH. Study design: MNK, KH. Data analysis and interpretation: MNK, KH. Review of the results: all authors. Drafting of the manuscript: MNK. Overall study oversight and guarantor of the manuscript: MNK, KH, DYK. Reviewed the paper and approved the final version: all authors.
Data availability
The dataset used in this study is not publicly available because of privacy and ethical restrictions but can be accessed after approval by the relevant review committee.
Financial support
This study was supported by The Research Supporting Program of The Korean Association for the Study of the Liver and The Korean Liver Foundation.
Conflicts of interest
The authors declare no conflicts of interest pertaining to this manuscript.
Please refer to the accompanying ICMJE disclosure forms for further details.
Footnotes
Author names in bold designate shared co-first authorship
Supplementary data to this article can be found online at https://doi.org/10.1016/j.jhepr.2026.101975.
Contributor Information
Mi Na Kim, Email: minakim@yuhs.ac.
Kyungdo Han, Email: hkd917@naver.com.
Do Young Kim, Email: dyk@yuhs.ac.
Supplementary data
The following are the Supplementary data to this article:
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The dataset used in this study is not publicly available because of privacy and ethical restrictions but can be accessed after approval by the relevant review committee.