MASLD, MetALD Linked to Increased Risk of Liver, Gastrointestinal Cancers

Gi-Ae Kim, MD

Credit: Kyung Hee University

New research is providing clinicians with an overview of the association between steatotic liver disease (SLD) and cancer, with study findings suggesting an increased risk of certain cancers in metabolic dysfunction-associated steatotic liver disease (MASLD) and MASLD with increased alcohol intake (MetALD).¹

Results showed that compared with those without SLD, patients with MASLD, MetALD, and other combination etiology had a greater risk of developing liver cancer and extrahepatic cancer, particularly gastrointestinal cancer. Findings bridge previous nonalcoholic fatty liver disease (NAFLD) research to MASLD to expand the understanding of cancer risk in this patient population, suggesting the value of proper MASLD management and alcohol consumption modification for reducing cancer risk.¹

In 2023, new liver disease nomenclature from a multi-society consensus was recently proposed and accepted to encourage a better understanding of liver disease etiologies and pathophysiology as well as avoid stigmatization. With this updated nomenclature, NAFLD became MASLD, and MetALD was introduced as a new subtype of SLD to encompass those who consume greater amounts of alcohol.²

“With the new nomenclature presenting a challenge to broaden our knowledge, it is worth investigating the precise cancer risk of patients by the newly suggested subtypes,” Gi-Ae Kim, MD, an assistant professor in the department of internal medicine at Kyung Hee University School of Medicine in Korea, and colleagues wrote.¹ “As for the newly suggested subtype of MetALD, little data regarding its cancer risk are available.”

To investigate the risk of cancers in SLD subtypes, investigators conducted a nationwide cohort study of patients from the National Health Insurance Service (NHIS) database in the Republic of Korea. NHIS offers a standardized national health screening program to all insured individuals every 2 years with a participation rate of approximately 76%, and the NHIS database encompasses almost the entire population of the Republic of Korea.¹

From the NHIS database, a total of 3,705,386 subjects aged 40–69 years and who had health screening from January 1, 2011, to December 31, 2011, were recruited. Investigators excluded those with a history of cancer, transplantation, liver cirrhosis, and death before December 31, 2011. In total, 3,596,709 participants were included in the analysis.¹

Investigators defined SLD as a fatty liver index (FLI) ≥ 30, calculated using triglyceride, body mass index (BMI), gamma-glutamyl transferase (GGT), and waist circumference. MASLD was defined as the presence of SLD with ≥ 1 of the following cardiometabolic risk factors:

• BMI ≥23 kg/m2 or waist circumference >90 cm for men and >80 cm for women
• Fasting blood glucose ≥100 mg/dL, type 2 diabetes or reported use of diabetes medication
• Blood pressure ≥130/85 mmHg or reported use of hypertensive medication
• Triglyceride ≥150 mg/dL or reported use of medication
• High-density lipoprotein (HDL) cholesterol ≤40 mg/dL for men and ≤50 mg/dL for women, or reported use of medication.

Additionally, MetALD was defined as having MASLD with moderate alcohol intake (30–60 g/day for men and 20–50 g/day for women), and other combination etiology was defined as having SLD with ≥ 1 of the cardiometabolic risk factors accompanied by excessive alcohol intake (>60 g/day for men and >50 g/day for women) or the concomitant liver disease.¹

The primary outcome was the development of cancer during the follow-up, defined as the presence of ICD-10 codes for primary cancer accompanied by a cancer-specific insurance claim code. Participants were followed up until the development of cancer, death, or December 31, 2021.¹

Participants with SLD comprised 39.3% (n = 1,415,255) of the cohort. Patients with cardiometabolic risk factors had MASLD (n = 1,102,225), MetALD (n = 166,359), and other combination etiology (n = 137,710). Compared with no SLD (n = 2,181,454), investigators noted MASLD, MetALD, and other combination etiology groups were more likely to be male, have diabetes, and have hypertension.¹

During 33.9 million patient-years (PYs) of follow-up, 285,845 (7.9%) participants developed cancer. The annual incidence rate of all cancer was greater in MASLD (9.1 per 1000 PYs), MetALD (8.4 per 1000 PYs), and other combination etiology (12.2 per 1000 PYs) than in no SLD (7.8 per 1000 PYs). When death was treated as a competing risk and other variables were adjusted, the risk escalated from no SLD to MASLD (subdistribution hazard ratio [SHR], 1.02; 95% CI, 1.01–1.03), MetALD (SHR, 1.07; 95% CI, 1.05–1.09) and other combination etiology (SHR, 1.40; 95% CI, 1.37–1.43).¹

Investigators pointed out the annual incidence rate of liver cancer was greater in MASLD (0.58 per 1000 PYs), MetALD (0.76 per 1000 PYs), and other combination etiology (2.91 per 1000 PYs) than in no SLD (0.37 per 1000 PYs). In the multivariable-adjusted analyses, the risk of developing liver cancer was higher in MASLD (adjusted hazard ratio [aHR], 1.18; 95% CI, 1.13–1.22), MetALD (aHR, 2.09; 95% CI, 1.95–2.24), and other combination etiology (aHR, 8.35; 95% CI, 7.93–8.80) than no SLD, and when death was treated as a competing risk, liver cancer risk escalated from no SLD to MASLD (SHR, 1.16; 95% CI, 1.12–1.21), MetALD (SHR, 2.06; 95% CI, 1.92–2.20) and other combination etiology (SHR, 8.16; 95% CI, 7.69–8.67).¹

Similarly, the risk of gastrointestinal cancers increased in MASLD (SHR, 1.13; 95% CI, 1.11–1.15), MetALD (SHR, 1.17; 95% CI, 1.14–1.21), and other combination etiology (SHR, 1.09; 95% CI, 1.05–1.13) compared to no SLD. The risk of esophagus, stomach, colorectal, and biliary cancers was also higher in MASLD, MetALD, and other combination etiology, although investigators noted the risk of pancreas cancer did not show significant differences among the study groups.¹

Results also showed an increased risk of lung cancer in MASLD (SHR, 1.07; 95% CI, 1.04–1.10) and other combination etiology (SHR, 1.16; 95% CI, 1.09–1.24) compared with no SLD. The risk of hormone-sensitive cancer including breast, uterus, and ovary cancer was modestly higher in MASLD (SHR, 1.07; 95% CI, 1.04–1.11) compared with no SLD.¹

Investigators acknowledged multiple limitations to these findings, including the use of FLI rather than hepatic steatosis identified by imaging or biopsy to diagnose SLD and the potential lack of generalizability to other patient populations since all participants in the present study were Korean.¹

“Our study generated novel knowledge for the newly created SLD subtype of MetALD and bridged the previous findings of NAFLD to MASLD expanding the understanding of their cancer risk for not only liver cancer but also extrahepatic cancer,” investigators concluded.¹ “The findings suggest that managing MASLD properly and modifying alcohol consumption can serve as a preventative strategy against cancer risk.”

References

1. ^{Park Y, Jung J, Han S, Kim GA. Metabolic dysfunction-associated steatotic liver disease and MetALD increases the risk of liver cancer and gastrointestinal cancer: A nationwide cohort study. Alimentary Pharmacology and Therapeutics. https://doi.org/10.1111/apt.18286}
2. ^{Brooks, A. From NAFLD to MASLD: 2023 Brings New Liver Disease Nomenclature. HCPLive. December 13, 2023. Accessed September 27, 2024. https://www.hcplive.com/view/from-nafld-to-masld-2023-new-liver-disease-nomenclature}