Targeting Nonalcoholic Fatty Liver Disease during the reproductive period to improve women's health outcomes

Weill Medical Coll Of Cornell Univ, New York NY

Investigators

Abstract

Metabolic dysfunction associated steatotic liver disease (MASLD), previously known as nonalcoholic fatty liver disease (NAFLD), and its progressive form, metabolic dysfunction associated steatohepatitis (MASH), is the leading cause of cirrhosis and liver transplantation in women, yet it is often undiagnosed until overt complications have developed. Non-invasive tests can now identify “at-risk” MASH, defined as having the highest risk for liver disease progression. Women of reproductive age commonly engage with healthcare systems during their pregnancy care, providing a unique opportunity to identify “at-risk” MASH early, particularly because metabolic changes in pregnancy may initiate and/ or worsen MASLD progression. As such, we first conducted a multidisciplinary protocol to screen for MASLD in pregnant individuals, Fatty Liver in Pregnancy (FLIP) I, in which we identified 1) a 14% overall prevalence of MASLD in pregnant individuals, 2) Hispanic ethnicity and pre-pregnancy weight as key predictors of MASLD in pregnancy, and 3) in a pilot study of postpartum assessment, found that 83% of individuals had worsening MASLD grade post-delivery. Given that hepatic lipid metabolism dysregulation plays a central role in MASLD initiation and progression, in a preliminary lipidomics analysis in FLIP I participants, we identified distinct lipidomic profiles in individuals with MASLD in pregnancy (compared to non-pregnant individuals with MASLD), and clustering of polyunsaturated fatty acid-derived oxidized fatty acids in individuals with MASLD, gestational hypertension and preeclampsia, emphasizing the potential shared role of these lipid pathways in the pathogenesis of MASLD and these adverse pregnancy outcomes (APOs). With our findings from FLIP I, we are now poised to study the longitudinal influence of MASLD in pregnancy, and associated lipid parameters, on women's health. In the proposed FLIP II study, we seek to evaluate the evolution of MASLD in pregnancy and its influence on pregnancy outcomes, identify predictors for the development of “at-risk” MASH after pregnancy, and evaluate the MASLD driven lipid based mechanisms that predict these events. We will prospectively screen 1540 pregnant individuals for MASLD (by ultrasound and Fibroscan) in early pregnancy and enroll them for longitudinal follow up for up to one year postpartum. We will administer detailed questionnaires collecting sociodemographic, dietary, and clinical data and collect and bank serum specimens for analysis. Our specific aims are 1) To determine the association between MASLD in pregnancy and APOs; 2) To evaluate antepartum factors that predispose to “at-risk” MASH post-pregnancy; and 3) To investigate the lipidomics-based mechanisms underlying MASLD in pregnancy and its association with post-delivery “at-risk” MASH. By uncovering novel insights into the natural history of MAFLD/ MASH in women in the pregnancy/ postpartum period, our study will help stratify risk factors for MASH progression and provide valuable information for future targeted interventions in this subgroup. Ultimately, this research will enhance our understanding of how MAFLD influences both the course of pregnancy and the subsequent progression of maternal liver disease.