DDW 2024: Parental Obesity at Pregnancy with Risk of Metabolic-Dysfunction
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease globally, with rising prevalence linked to increasing obesity, diabetes, and cardiovascular disease. MASLD affects about 15% of children and over 30% of adults. The disease spectrum includes a fibroinflammatory phenotype termed metabolic dysfunction-associated steatohepatitis (MASH). By 2030, the incidence of hepatic decompensation, hepatocellular carcinoma, and MASH-related cirrhosis is expected to increase two- to three-fold. MASH cirrhosis is the leading cause of liver transplantation in women and individuals over 65, matching alcohol-related liver disease. New vocabulary for steatotic liver diseases includes cardiometabolic risk factors and hepatic steatosis, assessed through imaging or biopsy in children and adults. Despite the disease burden, there are no widespread screening protocols for early detection in younger patients. MASLD often remains asymptomatic until advanced stages, possibly due to developmental origins or early triggers. Prior animal studies suggest transgenerational priming for metabolic dysfunction, but clinical studies have been mostly cross-sectional with inconsistent definitions of MASLD and NAFLD.
A notable birth cohort study from Australia examined around 1,100 adolescents and found significant correlations between steatosis and maternal factors such as pre-pregnancy obesity, shorter breastfeeding duration, and increased gestational weight gain. This study aims to investigate how childhood growth patterns might mediate adult MASLD risk using the new MASLD definition. Data from the UK-based Avon Longitudinal Study of Parents and Children (ALSPAC) assessed offspring at age 24 using transient elastography to diagnose hepatic steatosis and fibrosis. Statistical analyses included logistic regression models and causal mediation analyses, adjusting for factors like offspring sex, alcohol consumption, socioeconomic status, and parental ages at delivery. Of the initial 10,000 offspring, around 4,000 attended the Focus at 24 clinics.
The study observed an 18.3% MASLD prevalence among 24-year-old offspring, with a higher proportion of males and elevated BMI among those with MASLD. Significant associations were found between parental pre-pregnancy BMI and offspring MASLD risk, with a 55% increase per five-unit increase in maternal BMI and a 44% increase per five-unit increase in paternal BMI. Causal mediation analysis showed that childhood BMI trajectories accounted for a small proportion of the total effect. At the same time, cumulative overweight exposure explained nearly 80% of the impact of biparental overweight/obesity on offspring MASLD risk.
In conclusion, parental BMI around pregnancy is significantly associated with MASLD risk in offspring, with maternal obesity having a stronger effect and an additive risk observed with biparental overweight. Childhood BMI trajectory is a weak mediator, but cumulative overweight exposure significantly mediates the relationship between biparental overweight and offspring MASLD risk. Incorporating a family history of obesity, particularly parental obesity before pregnancy, into the risk stratification of younger patients with MASLD is crucial. Early interventions to reduce the duration and severity of childhood obesity exposure may significantly mitigate MASLD risk later in life, though effective and lasting strategies remain elusive. Future research should focus on modifiable early-life and childhood risk factors, using life-course analyses to understand early-onset gastrointestinal cancers. Given the current cohort's predominantly white, Western European descent, investigations involving larger and more diverse populations are necessary. The impact of pre-pregnancy parental weight loss on offspring MASLD risk is unknown, raising questions about whether the generational risk is fixed or adjustable through successful obesity interventions like GLP-1 agonists. Additionally, the relationship between early developmental exposures and long-term MASLD outcomes needs further exploration.
Digestive Disease Week (DDW) 2024, May 18-21, 2024, Washington, D.C.
