Development of an adverse outcome pathway for intrahepatic cholestasis of pregnancy

Abstract

Adverse Outcome Pathways (AOPs) are a research synthesis tool, used primarily by toxicologists for numerous applications including: hypothesis generation, data integration, biomarker determination, and identification of gaps in current knowledge. The AOP model provides a means for evaluating critical interactions between stressors and biological systems which result in adversity, meaning there is significant potential value in using this model in clinical research. However, AOPs have so far not been applied in this context, which may be attributable to the fact that the method is not yet streamlined with established practices in evidence-based medicine, such as systematic review. Here, we present one approach to developing a clinically focused AOP for intrahepatic cholestasis of pregnancy; aiming to enhance understanding of the mechanistic link between this common, gestational liver disease and its association with preterm birth. Mechanistic aspects of the disease pathogenesis, and use of AOPs to broaden inclusion and improve integration of in vitro and in vivo data in clinical research are discussed. We also demonstrate for the first time how central components of systematic review can be integrated into the development of an AOP.

Keywords: Adverse outcome pathway; Cholestasis; Pregnancy; Reproductive medicine.

Graphical abstract

Fig. 1

Proposed AOP: FXR inhibition leading to increased incidence of spontaneous preterm birth. 1a. Diagram to show basic structure of an AOP from Molecular Initiating Event (MIE) to Adverse Outcome (AO). 1b. Key Events (KE) and Key Event Relationships (KER) constituting the proposed AOP. 1c. Supporting information for the essentiality of each KE 1–5 (the extent to which there is evidence that blocking one KE prevents a later KE). 1d. The biological plausibility and empirical evidence for KERs 1–4. Evidence for each KE and KER is graded as high, moderate or low according to OECD guidance (OECD, 2018). Grading is indicated by the text box border: solid line (high), dashed line (moderate), dotted line (low).

Fig. 2

Literature search results. Results of the initial literature search for articles relevant to intrahepatic cholestasis of pregnancy. Stratification of these results and further analysis of articles to identify relevant records for each Key Event Relationship (KER) in the proposed Adverse Outcome Pathway: Farnesoid X receptor inhibition leading to spontaneous preterm birth are also shown. A secondary literature search for identifying articles of relevance to KER4 is also shown. The final result is the number of studies and study endpoints relevant to each KER 1–4. Abbreviations: ICP: intrahepatic cholestasis of pregnancy, KER: key event relationship, FXR: farnesoid X receptor.

Fig. 3

Suggested Adverse Outcome Pathway (AOP) Network for Intrahepatic Cholestasis of Pregnancy. Each box represents a Key Event (KE). Closed arrows indicate direct Key Event Relationships (KERs) and arrows with dotted lines indicate possible KERs (I.e. where there are knowledge gaps). Abbreviations: FXR = farnesoid X receptor, TGR5 = Takeda G-protein-coupled receptor 5.