# Risk of Esophageal and Gastric Cancer by Histologic Subtype in Steatotic Liver Disease: A UK Biobank Study

## TL;DR

This study shows that alcohol consumption combined with fatty liver disease increases the risk of certain stomach and esophageal cancers.

## Contribution

The study identifies specific cancer subtypes linked to alcohol-related fatty liver disease subtypes, revealing alcohol's modifying role in cancer risk.

## Key findings

- Alcohol-exposed fatty liver disease subtypes are strongly linked to esophageal adenocarcinoma and intestinal-type gastric cancer.
- Minimal alcohol consumption in fatty liver disease patients significantly elevates cancer risk compared to purely metabolic cases.
- Non-intestinal gastric and squamous esophageal cancers show no significant association with fatty liver disease.

## Abstract

Steatotic liver disease (SLD), formerly known as fatty liver disease, affects over 30% of the global population and has been linked to cancers outside of the liver. The recently updated classification system distinguishes between SLD subtypes based on alcohol consumption patterns. While previous studies have reported a relationship between these refined SLD classifications and extrahepatic cancer risk, the specific histologic cancer subtypes were unclear. This study’s findings revealed that alcohol consumption significantly modifies cancer risk in SLD patients. Those with combined metabolic dysfunction and alcohol exposure showed the highest risk of esophageal adenocarcinoma and intestinal-type gastric cancer. Other subtypes, such as squamous esophageal cancer and non-intestinal gastric cancer, did not show a clear association with SLD. Furthermore, purely metabolic SLD without alcohol consumption was associated with minimal cancer risk elevation, whereas even minimal alcohol consumption substantially increased risk in SLD patients.

Aim: The recently updated steatotic liver disease (SLD) nomenclature provides a refined classification accounting for both metabolic dysfunction and alcohol exposure. However, the relationship between SLD subtypes and upper gastrointestinal (UGI) cancer risk remains unclear. Methods: We analyzed 456,367 UK Biobank participants, categorizing them into non-SLD, metabolic dysfunction-associated steatotic liver disease with no alcohol (MASLD1), MASLD with minimal alcohol use (MASLD2), metabolic dysfunction-associated alcohol-related liver disease (MetALD), and alcohol-associated liver disease (ALD) groups. Cox proportional hazards models estimated cancer risks over a median 13-year follow-up, with histologic subtype-specific analyses. Results: Compared to non-SLD, esophageal cancer risk was significantly elevated in all SLD groups with any alcohol consumption (MASLD2, MetALD, and ALD), but not in purely metabolic SLD without alcohol (MASLD1). This association was driven by adenocarcinoma subtype, with hazard ratios ranging from 1.67 to 1.80 in alcohol-exposed SLD groups. For gastric cancer, elevated risk was observed primarily in ALD and MetALD groups, affecting intestinal-type cancers. Squamous cell esophageal cancer and non-intestinal gastric cancer showed no significant associations. Conclusions: Upper GI cancer risk in SLD patients is significantly modified by alcohol consumption, with combined metabolic dysfunction and alcohol exposure conferring the highest risks for esophageal adenocarcinoma and intestinal-type gastric cancer. Clinically, these findings suggest that SLD patients with any level of alcohol consumption require heightened cancer surveillance. Even minimal alcohol intake substantially increases cancer risk in metabolically compromised individuals, supporting alcohol reduction as a key preventive strategy.