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Interaction between alcohol consumption and metabolic syndrome in predicting severe liver disease in the general population
Abstract
The metabolic syndrome and alcohol risk use are both associated with a high prevalence of hepatic steatosis, but only a minority develop liver failure or liver cancer. Few general population studies have analyzed metabolic predictors of such severe liver complications. We studied which metabolic factors best predict severe liver complications, stratified by alcohol consumption, in 6732 individuals without baseline liver disease who participated in the Finnish population-based Health 2000 Study (2000-2001), a nationally representative cohort. Follow-up data from national registers until 2013 were analyzed for liver-related admissions, mortality, and liver cancer. Baseline alcohol use and metabolic factors were analyzed by backward stepwise Cox regression analysis. Eighty-four subjects experienced a severe liver event during follow-up. In the final multivariate model, factors predictive of liver events were age (hazard ratio [HR], 1.02; 95% confidence interval [CI], 1.004-1.04), sex (women: HR, 0.55; 95% CI, 0.34-0.91), alcohol use (HR, 1.002; 95% CI, 1.001-1.002), diabetes (HR, 2.73; 95% CI, 1.55-4.81), low-density lipoprotein (LDL) cholesterol (HR, 0.74; 95% CI, 0.58-0.93), and homeostasis model assessment of insulin resistance (HOMA-IR) (HR, 1.01; 95% CI, 1.004-1.02). Among alcohol risk users (≥210 g/week for men, ≥ 140 g/week for women), diabetes (HR, 6.79; 95% CI, 3.18-14.5) was the only significant predictor. Among nonrisk drinkers, age, alcohol use, smoking, waist circumference, low LDL cholesterol and HOMA-IR were significant independent predictors. The total-to-LDL cholesterol ratio and waist circumference-to-body mass index ratio emerged as additional independent predictors. CONCLUSION: Multiple components of the metabolic syndrome independently affected the risk for severe liver disease. Alcohol was significant even when average alcohol consumption was within the limits currently defining nonalcoholic fatty liver disease. (Hepatology 2018;67:2141-2149).
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“Equally important may be the possible synergy between alcohol consumption and the presence of metabolic risk factors for liver disease progression, 75,83 with the strongest effect for central obesity.”
From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [84]
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Tobari, M., Hashimoto, E., Taniai, M., Kodama, K., Kogiso, T., Tokushige, K., Yamamoto, M., Nishino, T., Katagiri, S., & Tatsuo, A. (2020) · Journal of Gastroenterology and Hepatology · doi:10.1111/jgh.14867 · Cited by 51
Díaz, L. A., Lazarus, J. V., Fuentes–López, E., Idalsoaga, F. J., Ayares, G., Desaleng, H., Danpanichkul, P., Cotter, T. G., Dunn, W., Francisco Barrera, M., et al. (2024) · Communications Medicine · doi:10.1038/s43856-024-00649-x · Cited by 55
Gwin, R. M., Warren, J. K., Samuelson, D. A., & Gum, G. G. (1983) · PubMed · Cited by 55
Rehm, J. T., Patra, J., Brennan, A., Buckley, C. M., Greenfield, T. K., Kerr, W. C., Manthey, J., Purshouse, R. C., Rovira, P., Shuper, P. A., et al. (2021) · Drug and Alcohol Review · doi:10.1111/dar.13286 · Cited by 58
“In fact, alcohol use plays a role in all types of liver disease, including in metabolic dysfunction [15], and even in so-called non-alcoholic liver disease [16,17].”
BackgroundThorhauge, K. H., Semmler, G., Johansen, S., Lindvig, K. P., Kjærgaard, M., Hansen, J. K., Torp, N., Hansen, C. D., Andersen, P., Hofer, B., et al. (2024) · Journal of Hepatology · doi:10.1016/j.jhep.2024.02.019 · Cited by 52
Bariatric surgery and the risk of alcohol‐related cirrhosis and alcohol misuse
Mellinger, J. L., Shedden, K., Winder, G. S., Fernandez, A. C., Lee, B. P., Waljee, J. F., Fontana, R. J., Volk, M. L., Blow, F. C., & Lok, A. S.-F. (2021) · Liver International · doi:10.1111/liv.14805 · Cited by 56
Management of alcohol use disorder in patients with chronic liver disease
Mellinger, J. L., Fernandez, A. C., & Winder, G. S. (2023) · Hepatology Communications · doi:10.1097/hc9.0000000000000145 · Cited by 52
Alcohol use disorder in community management of chronic liver diseases
Leggio, L., & Mellinger, J. L. (2022) · Hepatology · doi:10.1002/hep.32531 · Cited by 51
“In a large study from northern Europe, drinking more than 1 glass of alcohol per day for women and 2 per day for men produced nearly 7‐fold increases in incidence of severe liver disease among those with greater central adiposity.[93] Among those with diabetes, the increases were nearly 20‐fold compared to those witho…”
BackgroundJohnston, M. P., Patel, J. A., & Byrne, C. D. (2020) · Current Pharmaceutical Design · doi:10.2174/1381612826666200128094231 · Cited by 49
Alcohol-associated liver disease: Natural history, management and novel targeted therapies
Alvarado‐Tápias, E., Pose, E., Gratacós‐Ginès, J., Clemente, A. P. G., López‐Pelayo, H., & Bataller, R. A. (2024) · Clinical and Molecular Hepatology · doi:10.3350/cmh.2024.0709 · Cited by 55
Future Trends in Demand for Liver Transplant: Birth Cohort Effects Among Patients With NASH and HCC
Shingina, A., DeWitt, P. E., Dodge, J. L., Biggins, S. W., Gralla, J., Sprague, D., & Bambha, K. M. (2018) · Transplantation · doi:10.1097/tp.0000000000002497 · Cited by 47
Fouad, Y. M., Esmat, G., Elwakil, R., Zakaria, S., Yosry, A., Waked, I. A., El-Razky, M., Doss, W. H., El‐Serafy, M., Mostafa, E., et al. (2022) · Saudi Journal of Gastroenterology · doi:10.4103/sjg.sjg_357_21 · Cited by 49
“MAFLD patients with cirrhosis should be considered for surveillance for varices and HCC. Multiple gaps in our knowledge on MAFLD are identified, and a joint effort by various stakeholders for gathering more evidence is the only way forward for the full adoption of these recommendations and tackling this growing burden.”
BackgroundInfluentialNrf2 Pathway and Oxidative Stress as a Common Target for Treatment of Diabetes and Its Comorbidities
Yi, M., Cisneros, L., Cho, E. J., Alexander, M., Kimelman, F. A., Swentek, L., Ferrey, A., Tantisattamo, E., & Ichii, H. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25020821 · Cited by 46
“The severity of liver disease is significantly increased with alcohol consumption in synergy with insulin resistance and total-to-LDL cholesterol ratio [131].”
BackgroundAlcohol-associated liver cancer
Fu, Y., Maccioni, L., Wang, X. W., Greten, T. F., & Gao, B. (2024) · Hepatology · doi:10.1097/hep.0000000000000890 · Cited by 50
Wang, Y., Chuang, Y., Wu, C., Jan, M., Wu, W., Lin, C., Liu, C., Yang, Y., Chen, P., Lin, S., et al. (2018) · Hepatology · doi:10.1002/hep.30339 · Cited by 46
“However, only approximately 10% of our study subjects consumed alcohol ≥140 g/week, defined as alcohol risk use.(31) The effect of smoking remained even after adjustment for amount of ethanol consumed.”
BackgroundPal, P., Palui, R., & Ray, S. (2021) · World Journal of Hepatology · doi:10.4254/wjh.v13.i11.1584 · Cited by 51
Sripongpun, P., Kaewdech, A., Udompap, P., & Kim, W. R. (2024) · JHEP Reports · doi:10.1016/j.jhepr.2024.101127 · Cited by 45
“14 It is increasingly recognized that no level of alcohol intake is safe, 11,15,16 whereas abstaining from alcohol could mitigate its harmful effects.”
Combined Effects of Alcohol and Metabolic Disorders in Patients With Chronic Liver Disease
Åberg, F. O., Puukka, P. J., Salomaa, V. V., Männistö, S., Lundqvist, A., Valsta, L. M., Perola, M., Jula, A., & Färkkilä, M. A. (2019) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2019.06.036 · Cited by 44
NAFLD and autoimmune hepatitis: Do not judge a book by its cover
Dalekos, G. Ν., Gatselis, N., Zachou, K., & Koukoulis, G. Κ. (2020) · European Journal of Internal Medicine · doi:10.1016/j.ejim.2020.02.001 · Cited by 42
Hagström, H., Hegmar, H., & Moreno, C. (2024) · United European Gastroenterology Journal · doi:10.1002/ueg2.12524 · Cited by 40
“70 Longitudinal studies in a Finnish cohort reported an interaction between high waist circumference or high waist ‐ hip ratio and alcohol consumption over 210 g per week in men and over 140 g per week in women with an increased risk of liver ‐ related outcomes 26,29 (Table 1).”
BackgroundInfluentialSerum lipopolysaccharides predict advanced liver disease in the general population
Männistö, V., Färkkilä, M. A., Pussinen, P. J., Jula, A., Männistö, S., Lundqvist, A., Valsta, L. M., Salomaa, V. V., Perola, M., & Åberg, F. O. (2019) · JHEP Reports · doi:10.1016/j.jhepr.2019.09.001 · Cited by 41
“Current abstainer 349 (5) 120 (5) 108 (5) 121 (6)”
Decraecker, M., Dutartre, D., Hiriart, J., Irlès‐Depé, M., Grottes, H. M. D., Chermak, F., Foucher, J., Delamarre, A., & de Lédinghen, V. (2021) · Liver International · doi:10.1111/liv.15081 · Cited by 41
A public health perspective on mitigating the global burden of chronic liver disease
Balakrishnan, M., & Rehm, J. T. (2023) · Hepatology · doi:10.1097/hep.0000000000000679 · Cited by 41
“[4] This is finally a recognition that most risk factors, but in particular metabolic risk factors, and alcohol use interact, potentially synergistically, to produce liver damage, [33] even at low level to moderate level of alcohol consumption.”
BackgroundModerate Alcohol Intake in Non-Alcoholic Fatty Liver Disease: To Drink or Not to Drink?
Petroni, M. L., Brodosi, L., Marchignoli, F., Musio, A., & Marchesini, G. (2019) · Nutrients · doi:10.3390/nu11123048 · Cited by 42
“In prospective analyses even modest alcohol intake has been associated with possible disease progression [51] and, more significantly, with cancer development [8].”
BackgroundThe Changing Epidemiology of Alcohol-Associated Liver Disease: Gender, Race, and Risk Factors
Anouti, A., & Mellinger, J. L. (2022) · Seminars in Liver Disease · doi:10.1055/a-2000-6680 · Cited by 40
MetALD: Clinical aspects, pathophysiology and treatment
Gratacós‐Ginès, J., Ariño, S., Sancho‐Bru, P., Bataller, R. A., & Pose, E. (2024) · JHEP Reports · doi:10.1016/j.jhepr.2024.101250 · Cited by 45
“6,25,26,29,30,32,36 Importantly, the presence of diabetes markedly increases the risk of signi fi cant liver disease.”
InfluentialCelsa, C., Pennisi, G., Tulone, A., Ciancimino, G., Vaccaro, M., Pecorella, F., Maria, G. D., Enea, M., Midiri, F., Mantovani, A., et al. (2025) · The Lancet. Gastroenterology & hepatology · doi:10.1016/s2468-1253(25)00188-8 · Cited by 48
Charatcharoenwitthaya, P., Karaketklang, K., & Aekplakorn, W. (2020) · Frontiers in Medicine · doi:10.3389/fmed.2020.604919 · Cited by 39
“This finding is consistent with prospective studies that found even modest alcohol intake to be associated with possible disease progression (27), and more significantly, with cancer development in patients with NAFLD (28).”
ResultSynergistic and Detrimental Effects of Alcohol Intake on Progression of Liver Steatosis
Ciaula, A. D., Bonfrate, L., Krawczyk, M. J., Frühbeck, G., & Portincasa, P. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23052636 · Cited by 37
“In this scenario, metabolic risk might sensitize the liver to alcohol damage and vice versa [90,197,198,200].”
BackgroundInfluentialNomura, T., Ono, M., Kobayashi, K., Akaiwa, Y., Ayaki, M., Ogi, T., Ogi, M., Takahashi, H., Ishikawa, K., Morishita, A., et al. (2023) · Hepatology Research · doi:10.1111/hepr.13935 · Cited by 38
“Low or moderate alcohol use has been related to fibrosis progression in subjects with metabolic syndrome.(10) There remains a need for additional high‐quality longitudinal studies of liver outcomes among subjects with NAFLD who have moderate or lesser degrees of alcohol use.”
The steatotic liver disease burden paradox: unravelling the key role of alcohol
Torp, N., Israelsen, M. E., & Krag, A. A. (2024) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-024-01022-y · Cited by 39
“An analysis of the Finnish population-based Health 2000 study revealed that alcohol use, type 2 diabetes, LDL cholesterol and HOMA-IR were among the predictors of severe liver-related events 76 .”
Genetic and lifestyle risk factors for advanced liver disease among men and women
Sahlman, P., Nissinen, M. J., Puukka, P. J., Jula, A., Salomaa, V. V., Männistö, S., Lundqvist, A., Valsta, L. M., Perola, M., Färkkilä, M. A., et al. (2019) · Journal of Gastroenterology and Hepatology · doi:10.1111/jgh.14770 · Cited by 36
Yamamura, S., Kawaguchi, T., Nakano, D., Tomiyasu, Y., Yoshinaga, S., Doi, Y., Takahashi, H., Anzai, K., Eguchi, Y., Torimura, T., et al. (2019) · Hepatology Research · doi:10.1111/hepr.13436 · Cited by 36
Ullah, H., Filippis, A. D., Khan, H. Z., Xiao, J., & Daglia, M. (2020) · Food and Chemical Toxicology · doi:10.1016/j.fct.2020.111574 · Cited by 36
Metadata
- Authors
- Åberg, F., Helenius‐Hietala, J., Puukka, P., Färkkilä, M., & Jula, A.
- Affiliations
- University of Helsinki (FI)
- Department of Health,National Institute for Health and Welfare,Turku,Finland
- Corresponding author
- Åberg, Fredrik
- Venue
- Hepatology
- Published
- 2018-04-16
- Volume
- 67
- Issue
- 6
- Pages
- 2141-2149
- ISSN
- 0270-9139 (ISSN-L)
- 1527-3350
- OpenAlex
- W2770566262
- Cited by
- 267
- References
- 32
- Citations by year
- 2026: 20 · 2025: 32 · 2024: 46 · 2023: 28 · 2022: 30 · 2021: 31 · 2020: 34 · 2019: 26 · 2018: 16
- FWCI
- 16.75
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Finska Läkaresällskapet
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- alcohol consumption, metabolic syndrome, severe liver disease, liver failure, liver cancer, non-alcoholic fatty liver disease, diabetes mellitus, insulin resistance, HOMA-IR, LDL cholesterol, waist circumference, smoking, risk factors, liver-related mortality, general population, Finland, sex differences
- MeSH terms
- Alcohol Drinking, Female, Humans, Liver Diseases, Male, Middle Aged, Prognosis, Prospective Studies, Risk Factors, Severity of Illness Index, Metabolic Syndrome
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