Metabolic Dysfunction-Associated Steatotic Liver Disease and the Role of Persistent Organic Pollutants

Steatotic liver disease (SLD) is the most common liver disease globally. Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with increased morbidity and mortality, with risks rising alongside disease severity. Many persistent organic pollutants (POPs) have been associated with SLD. This dissertation aimed to generate updated prevalence estimates for SLD and SLD subtypes in the United States (US) adult population and to compare reliability of multiple non-invasive metrics to assess steatosis and fibrosis. Additionally, it set out to evaluate both cross-sectional and longitudinal associations of POPs with MASLD prevalence, incidence and progression among a population of US Hispanic/Latino Adults; a group commonly reporting highest SLD risk. All analyses were conducted in a sex-specific manner a priori, and both traditional as well as experimental chemical mixture methods were applied to examine the POPs-MASLD relationships. The National Health and Nutrition Examination Survey (NHANES) data from the 2017-2020 cycle (Males N=1627, Females N=1611) were used for estimating disease prevalence and assessing tool performance in the general US population. An ancillary study population from the Hispanic Community Health Study / Study of Latinos (HCHS / SOL) was used to explore POPs-MASLD relationships at baseline (Males = 895, Females = 1066) and 6-year follow-up (Males N = 669, Females N = 871). Findings suggest the prevalence of MASLD in the adult US population is higher than many historic estimates, with current projections of 46% of females and 51% of males with MASLD, 5.5% of females and 7% of males likely having metabolic dysfunction-associated steatohepatitis (MASH), specifically. The Fatty Liver Index (FLI) appears to be a reliable non-invasive tool for detection of steatosis, but the choice metric for fibrosis is less clear. The fibrosis-4 index (FIB-4) and NAFLD fibrosis score (NFS) are potentially preferable, particularly in Mexican Americans. Among Hispanics/Latinos at baseline, Males showed consistent positive associations for POPs and prevalence of low risk and increased risk MASLD, FLI score, and FIB-4 score. FLI score was especially strongly positively correlated with POPs in males. Females showed less uniform findings but indicated positive associations for POPs and more severe disease/fibrosis metrics. Upon follow-up, incidence and progression of MASLD was common in both males and females, even among those without traditional risk factors. 18.4% of females and 11.9% of males without MASLD (‘Healthy’) at Visit 1 developed suspected fibrosis at Visit 2 with no evidence of steatosis. Chemical mixture methods showed baseline POPs levels were significantly positively associated with increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) liver enzymes at follow-up among females classified as Low Risk MASLD at Visit 1. In sum, the global burden of MASLD is immense and education and screening are lacking. Performance of non-invasive tools for liver disease detection differs meaningfully by subgroup including race/ethnicity, sex, and reproductive status. This research suggests the FLI is a reliable tool to flag patients in need of further testing and staging for MASLD. However, there is a need to re-evaluate guidance and cut points for non-invasive liver metrics, especially by sex and reproductive status. Females tended to show greater associations between POPs and incidence or progression of MASLD, particularly for progression to a fibrotic state. Menopause is an especially vulnerable time for the liver in females, and POPs may aggravate the progression and/or development of more severe liver disease and fibrosis. The role of hormones along with POPs requires further study, and the drastic change in risk profile from pre- to post-menopausal status for women deserves greater attention.