Coffee and fatty liver: Why are observational studies positive but clinical trials have not confirmed this?

Some epidemiological studies indicate that coffee drinkers have a lower rate of liver fibrosis. However, when scientists synthesized data from randomized controlled trials, the results did not show statistically significant improvements in two commonly monitored liver enzymes, ALT and AST. Are these two sets of results truly contradictory?

To answer this, it is necessary to distinguish between what observational studies can detect and what an interventional trial can prove. Coffee may be associated with certain liver health outcomes, but this association does not mean that drinking coffee can treat fatty liver disease.

Fatty liver disease is now referred to as MASLD.

In many older documents, fatty liver disease was commonly called NAFLD, an abbreviation for Non-Alcoholic Fatty Liver Disease. Since 2023, a group of international experts has agreed on a new terminology system, including the term MASLD – Metabolic Dysfunction-Associated Steatotic Liver Disease.

MASLD describes fatty liver conditions associated with metabolic dysfunction, with at least one accompanying metabolic risk factor. The disease spectrum may include hepatic fat accumulation, metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, and cirrhosis.

The renaming does not mean that older studies on NAFLD have lost their value. However, when reading research results, it is important to remember that diagnostic criteria and disease classification methods may differ across time periods.

What has been observed in observational studies?

In 2021, Ebadi and colleagues published a systematic review and meta-analysis in the journal Nutrients, focusing on the association between coffee consumption and the incidence of fatty liver disease and the risk of significant liver fibrosis.

The research team synthesized 11 articles, including:

• 2 case–control studies.
• 8 cross-sectional studies.
• 1 prospective cohort study.

The results did not show a statistically significant association between coffee consumption and the incidence or prevalence of NAFLD in the analyses performed.

A notable finding emerged in the subgroup of patients who already had NAFLD: higher coffee intake was associated with a lower risk of significant liver fibrosis. The pooled estimate reported was RR 0.65, with a 95% confidence interval from 0.54 to 0.78.

An important limitation is that most studies in this analysis were cross-sectional. They help identify associations between two phenomena at a single point in time, but make it difficult to determine which factor occurred first and whether coffee is the cause of the difference.

Clinical trials provide a more cautious answer

In 2025, Sayedi and colleagues published a systematic review and meta-analysis of clinical trials on the effects of coffee or coffee extracts on liver function indices in individuals with NAFLD.

The research team found only four studies, corresponding to five intervention-versus-placebo comparison pairs, that met the inclusion criteria for analysis.

The results did not record statistically significant changes in:

This is not evidence proving that coffee has no effect on the liver. It indicates that the aggregated intervention trials have not provided sufficient evidence to assert that coffee or coffee extract reduces ALT and AST levels in the studied patient groups.

The authors also emphasize the small number of trials, limited sample sizes, and short follow-up periods. These factors limit the ability to detect long-term effects.

ALT and AST are not comprehensive measures of liver fibrosis

This is an important detail when comparing the two study groups.

ALT and AST are enzymes used in blood tests to assess hepatocellular injury in a clinical context. However, the levels of these two enzymes do not fully reflect the degree of fibrosis or the overall progression of liver disease.

An individual with liver enzyme levels within the reference range may still have significant liver disease. Conversely, elevated ALT or AST does not automatically prove that the individual has liver fibrosis.

To assess fibrosis, physicians may use appropriate tools such as the FIB-4 index, liver stiffness measurement, or other diagnostic methods depending on the case.

Therefore, a trial that finds no change in ALT and AST cannot automatically refute any association between coffee and liver fibrosis observed in other studies.

What mechanisms might be involved with the compounds in coffee?

Coffee is a complex chemical mixture containing caffeine and many non-caffeine compounds such as chlorogenic acids, diterpenes, and other metabolites.

Some mechanisms proposed in preclinical studies and biological reviews include:

• Caffeine may act on adenosine receptors and signaling pathways related to liver cells.
• Certain phenolic compounds exhibit antioxidant activity in experimental systems.
• Cafestol and kahweol have been studied for their ability to modulate certain inflammatory responses and oxidative stress.

However, a plausible biological mechanism does not equate to proven clinical efficacy. A compound that is active in cells or animal models does not necessarily produce similar results when humans consume coffee in real-life settings.

Furthermore, the composition of coffee varies by variety, origin, roast level, and brewing method. One cannot take the results from a single extract and apply them unchanged to every cup of coffee.

What do professional guidelines say?

The 2024 Clinical Practice Guidelines on MASLD from EASL, EASD, and EASO note that coffee is associated with improved liver damage and reduced some liver-related clinical outcomes in observational studies.

However, the guidelines also caution that observational studies are prone to confounding factors; randomized trials on the impact of coffee on the liver are scarce and results are inconsistent. Therefore, it is not possible to draw a definitive conclusion about the causal effect of coffee consumption.

This is a much more cautious approach than popular headlines such as 'coffee cures fatty liver' or 'drinking coffee helps liver recovery'.

A key area of interest in future research is the need for large-scale trials, long-term follow-up, and measurement of liver-related outcomes directly, rather than relying solely on liver enzymes. Studies should also distinguish between caffeinated and decaf coffee, brewing methods, and the presence of additives.

At present, the most reasonable interpretation is that coffee has a positive signal related to some liver health outcomes in observational studies, particularly fibrosis; however, the effectiveness of coffee as a therapeutic intervention has not been definitively confirmed.

References

1. Ebadi, M., Ip, S., Bhanji, R. A., & Montano-Loza, A. J. (2021). Effect of Coffee Consumption on Non-Alcoholic Fatty Liver Disease Incidence, Prevalence and Risk of Significant Liver Fibrosis: Systematic Review with Meta-Analysis of Observational Studies. Nutrients, 13(9), 3042. https://doi.org/10.3390/nu13093042
2. Sayedi, M., Chaghazardi, Z., & Sharifi, A. (2025). Effect of coffee and coffee extract on liver function test in non-alcoholic fatty liver disease patients, a systematic review and meta-analysis. Gastroenterology and Hepatology from Bed to Bench, 18(4), 373–379. https://doi.org/10.22037/ghfbb.v18i4.3123
3. European Association for the Study of the Liver, European Association for the Study of Diabetes, & European Association for the Study of Obesity. (2024). Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). Journal of Hepatology, 81(3), 492–542. https://doi.org/10.1016/j.jhep.2024.04.031
4. Rinella, M. E. et al. (2023). A multisociety Delphi consensus statement on new fatty liver disease nomenclature. Journal of Hepatology, 79(6), 1542–1556. https://doi.org/10.1016/j.jhep.2023.06.003
5. Dranoff, J. A. (2023). Coffee as chemoprotectant in fatty liver disease: caffeine-dependent and caffeine-independent effects. American Journal of Physiology-Gastrointestinal and Liver Physiology. https://doi.org/10.1152/ajpgi.00026.2023