Alcoholic and non-alcoholic fatty liver disease (NAFLD) are well-known risk factors for colorectal cancer (CRC). NAFLD has emerged as a heterogenous disease tightly linked to metabolic dysfunction and has been redefined under the umbrella term 'steatotic liver disease' (SLD). However, CRC risk variations across different SLD subgroups remain unknown. Now, researchers from Japan have discovered that the risk of CRC varies significantly among SLD subgroups, with patients with alcoholic liver disease being at higher risk.
Lifestyle-related disorders have become increasingly prevalent, representing a major health crisis. Non-alcoholic fatty liver disease (NAFLD), in particular, affects over a quarter of the world's population. In addition, it is closely linked to diabetes, obesity, and metabolic disorders, and constitutes a major risk for severe complications, including liver cancer and cardiovascular disease.
While alcohol consumption and obesity are established risk factors for colorectal cancer (CRC), a leading cause of cancer-related morbidity and mortality, mounting evidence supports the association between NAFLD and CRC. However, NAFLD is now being recognized as a multifaceted disease tightly associated with metabolic dysfunction and has been redefined under the umbrella term 'steatotic liver disease' (SLD). SLD is classified based on alcohol intake into three subgroups namely, metabolic dysfunction-associated SLD (MASLD), MASLD with increased alcohol intake (MetALD), and alcohol-associated liver disease (ALD). Due to the emerging heterogeneity of liver diseases, CRC risk variations across different SLD subgroups remain unknown.
To bridge this gap, a research team led by Dr. Takefumi Kimura from the Division of Gastroenterology, Department of Medicine, Shinshu University School of Medicine, Japan, along with Dr. Nobuharu Tamaki from Musashino Red Cross Hospital, Japan and Dr. Shun-Ichi Wakabayashi from Shinshu University School of Medicine, Japan, conducted a nationwide population-based study to compare the risk and incidence of CRC across patients with SLD. Their study was published online in Clinical Gastroenterology and Hepatology on January 30, 2025.
Explaining the rationale behind their study, Dr. Kimura states, "Identifying and screening patients with SLD at a higher risk of developing colorectal cancer can enable early detection and improve patient outcomes. Physicians can raise awareness among patients with SLD about their increased CRC risk, promoting regular screening."
The study included patients with SLD and individuals without known liver disease for comparative analyses. The incidence and risk of CRC were compared among the SLD subgroups. It was observed that 0.19% of patients were diagnosed with CRC over the 4.5-year follow-up period. In addition, the risk of CRC varied significantly among patients with SLD, with the highest CRC risk observed in patients with ALD (1.73 times higher), followed by MetALD (1.36 times), and MASLD (1.28 times).
Overall, the study highlights differences in CRC risk across patients with different subgroups of SLD, underscoring the need for comprehensive CRC screening and risk stratification based on the new consensus-based definitions of liver disease.
The differences in CRC risk across the different subgroups may be attributed to their underlying pathology and interactions with other comorbidities. Mechanistically, alcohol may trigger CRC development through the production of toxic metabolites, oxidative stress, and DNA damage. MASLD/NAFLD, on the other hand, is associated with increased inflammation, metabolic dysfunction, and insulin resistance, which in turn, elevates the risk of CRC.
"Our findings are based on data from approximately 6.38 million individuals, providing robust evidence of the individual and synergistic effects of alcohol and metabolic dysfunction on CRC risks. Enhanced and targeted screening programs for high-risk groups, such as ALD and MetALD patients, are crucial for early CRC detection and reducing CRC-related deaths," concludes Dr. Kimura.
