Hepatic exposome as an emerging contributor to metabolic dysfunction-associated steatotic liver disease

Table 2 Key challenges and proposed solutions for advancing the hepatic exposome in clinical hepatology

Challenge	Description	Proposed solution/future direction
Exposure measurement	Single biomarkers poorly capture lifetime exposure; non-persistent chemicals fluctuate, persistent ones bioaccumulate	Serial biomonitoring within prospective cohorts; couple to untargeted exposomics-metabolomics to read biological response
Reverse causation and confounding	Diseased liver alters chemical handling and serum levels; diet and socioeconomics co-vary	Prospective designs establishing temporality; pre-diagnostic biospecimens; careful covariate control
Inconsistent and heterogeneous evidence	Meta-analyses show robust associations for some chemicals but null/inverse for others; unstable sensitivity analyses	Harmonized exposure and outcome definitions; individual-participant-data pooling; transparent reporting
Chemical mixtures	Humans are exposed to dynamic combinations with additive, synergistic, or antagonistic effects	Mixture-aware statistical methods; nutrient-toxicant and exposure-exposure interaction studies
Susceptibility and sex differences	Hepatic response is host-dependent; women and early-life windows show heightened risk	Sex-stratified analyses adequately powered; life-course and developmental cohort designs
Causal inference	Much evidence is observational and mechanistic data often single-chemical/high-dose	Human liver organoids and microphysiological models; Mendelian-randomization-style and quasi-experimental approaches
Clinical translation	No validated tools to detect or stratify exposome-associated liver injury	Develop and validate a hepatic exposome biomarker panel of exposure and effect; integrate exposure history into care
Prevention and regulation	Exposures are largely involuntary and ubiquitous	Upstream regulatory action on water, air, and food packaging; surveillance of regrettable substitution