Introduction
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a condition characterized by excess fat accumulation in the liver without traditional causes of liver disease. This dysfunction can lead to liver inflammation and may eventually progress to more severe conditions like metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis, and even hepatocellular carcinoma (HCC).
Prevalent worldwide, MAFLD affects between 6.3% to 33% of the population, with MASH occurring in 3% to 5% of cases. Associated conditions often include obesity, type 2 diabetes, hyperlipidemia, hypertension, and metabolic syndrome.
Impact of Statins and Aspirin
Research suggests that medications such as statins and aspirin can significantly reduce the risk of HCC. Aspirin, due to its anti-inflammatory and anti-platelet effects, can lower indices of liver fibrosis and has a chemopreventive role in chronic hepatitis B and C, as well as in MAFLD/MASH.
Similarly, statins have shown a preventive effect on chronic hepatitis B and C, and they have been linked to lower incidences of MAFLD and improved liver histology. Statin users have a 53% lower risk of developing HCC compared to non-users with MAFLD.
Notably, these medications may also help in reducing hepatic decompensation, mortality, and portal hypertension in patients with chronic liver disease.
The Role of Sarcopenia and Muscle Stem Cells
Sarcopenia, a condition characterized by loss of muscle mass, is closely linked to MAFLD, liver cirrhosis, and HCC. Studies indicate that patients on statins have a reduced likelihood of sarcopenia. This may be due to statins’ positive impact on muscle perfusion and maintenance of muscle function.
Research also highlights the role of muscle satellite cells (mSCs) in maintaining muscle health, suggesting that a decline in mSC pool could lead to accelerated muscle loss, especially in the elderly.
New studies are exploring the potential of combining statin and aspirin use to combat MAFLD/MASH. While aspirin use is associated with a 20% reduction in cancer incidence, the combination of both drugs may offer additional benefits in preventing cirrhosis.
Study Methodology
Ethics
The study adhered to ethical standards, receiving approval from the Chang Gung Medical Foundation’s Institutional Review Board (IRB).
Data Sources
Data were sourced from Taiwan’s National Health Insurance Research Database (NHIRD), which covers nearly the entire population. The study included over 735,000 patients diagnosed with MAFLD/MASH between 2009 and 2020.
Study Groups
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Table 1 Baseline Characteristics of Patients with MAFLD/MASH Across Cohorts of Non-Statin & Aspirin Use, Statin Use, Aspirin Use, and Statin & Aspirin Use |
Main Outcomes
The main outcomes studied were cirrhosis, HCC, and all-cause mortality. Conditions noted before the study start date were considered baseline comorbidities.
Statistical Analysis
Cox regression models were used to analyze the data. Proportional hazards assumptions were tested using Cox-Snell residuals, ensuring model validity.
Results
Cirrhosis
The combined use of statin and aspirin significantly lowered the risk of cirrhosis compared to using either drug alone. However, there was no significant difference between statin use alone and the combined use in reducing cirrhosis.
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Table 2 Incidences and Hazard Ratios of Cirrhosis in Patients with MAFLD/MASH Across Cohorts |
Hepatocellular Carcinoma
Both statin and aspirin use individually reduced the incidence of HCC, and their combined use did not offer additional benefits in HCC prevention.
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Table 3 Incidences and Hazard Ratios of Hepatocellular Carcinoma in Patients with MAFLD/MASH Across Cohorts |
Overall Mortality
Both statin and aspirin use reduced all-cause mortality. However, combining these medications did not show superior results in reducing mortality compared tostatin use alone.
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Table 4 Incidences and Hazard Ratios of All-Cause Mortality in Patients with MAFLD/MASH Across Cohorts |
Discussion
The study found that while both aspirin and statins reduce cirrhosis, HCC, and mortality, the combination of both drugs did not provide additional benefits in reducing HCC and mortality. Statins showed a more pronounced effect in reducing HCC incidence.
Advanced stages of non-cirrhotic HCC often show higher interleukin-6 levels, similar to cases with known etiologies. This similarity suggests that underlying mechanisms may be common to both conditions.
Aspirin’s anti-inflammatory effects are mediated through NF-κB inhibition, reducing levels of inflammatory markers. Similarly, statins reduce portal pressure, improve liver function, and offer protection against fibrosis.
Obesity and hyperlipidemia are significant risk factors for HCC development, and the study suggests that statin and aspirin use may have a stronger protective effect in high-risk populations.
Limitations
The study is limited by its retrospective design and reliance on administrative databases, which lack clinical examination results, detailed socioeconomic data, and lifestyle factors. These limitations make it challenging to fully understand the role of socioeconomic and behavioral factors in disease progression.
Conclusion
Both aspirin and statins are effective in reducing cirrhosis, HCC, and mortality in patients with MAFLD/MASH. While the combination of both drugs shows additional benefits in preventing cirrhosis, it does not offer incremental advantages in reducing HCC or mortality. Statins appear to have a more significant effect on reducing HCC incidence compared to aspirin.
This research underscores the importance of considering statin use alone for preventing HCC and mortality in MAFLD/MASH patients.
Data Sharing Statement
The data supporting the findings are available upon request.
Informed Consent Statement
Consent was waived due to the retrospective nature of the study.
Acknowledgments
The NHIRD and funding agencies supported this study.
Funding
Supported by grants from Chang Gung Memorial Hospital and the National Health Research Institute.
Disclosure
No conflicts of interest declared.
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