Immunological basis in the pathogenesis of intrahepatic cholestasis of pregnancy

Abstract

Summary Intrahepatic cholestasis of pregnancy poses a great risk to both maternal and fetal health. Despite extensive research, much of the pathogenesis of this disorder is unknown. The increase in bile acids observed in patients with intrahepatic cholestasis of pregnancy has been noted to cause a change in the immune system from the normally mediated TH2 response to one that is more oriented towards TH1. In this literature review, we have critically reviewed the current literature regarding the changes in the immune system and the potential effects of immunological changes in the management of the patient. The current treatment, ursodeoxycholic acid, is also discussed along with potential combination therapies and future directions for research.

The role of metabolic disorders in the pathogenesis of intrahepatic cholestasis of pregnancy

“…In the recent years the role of immune system abnormalities have been considered as an important etiological factor of ICP [28-30]. Zhang et al [31] presented the higher expressions of peroxisome proliferator-activated receptor γ (PPAR-γ) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in ICP placenta and then induced abnormal serum levels of cytokines interleukin 4 (IL-4), IL-6, IL-12 and tumor necrosis factor α (TNF-α).…”

Managing the challenge of drug-induced liver injury: a roadmap for the development and deployment of preclinical predictive models

“…For example, CsA and chlorpromazine exhibit concentration-dependent effects on mitochondrial membrane permeability and ER stress, respectively, which in turn may have longerterm implications on hepatobiliary transporter function. Advanced TIER 2 models, with incorporation of NPCs, would also permit more comprehensive mechanistic studies on the role of innate immune function in the initiation, adaptation and progression of changes in hepatobiliary transport functionand BA secretion by drugs; the association between indirect and direct effects on the role of transporters on BAs secretion and transport, and role of the immune system are well-described107,108 .Furthermore, technological advances in the development of in vitro models to explore the role of innate and adaptive immunity (TIER 3) in cholestasis is still required and remains an important focus for future research efforts to understand human DILI.…”

Beneficial and Deleterious Effects of Female Sex Hormones, Oral Contraceptives, and Phytoestrogens by Immunomodulation on the Liver

“…This is a highly conserved inducer of pro-inflammatory cytokines (e.g., TNF-α, IL-6, and IL-1β) released from Kupffer cells, activated sinusoidal cells, and cholangiocytes, which reduce the expression and the function of hepatocellular and cholangiocellular transporters and cause cholestasis as well as oxidative, mitochondrial, and endoplasmic reticulum stress [113,114]. Besides, the pro-inflammatory cytokines differently regulate hepatic transporters depending on the mechanism of cholestasis [97]; indeed, TNF-α and IL-1β downregulate the bile salt export pump (BSEP) and decrease BAs secretion [115].…”

“…Sulfated metabolites of P4 reduce NTCP function in a dose-dependent manner [126]. Currently, it has been proposed that during ICP the marked increase of E2 and P4 (also their metabolites) provoke cholestasis that negatively modify the immune balance by enhancing the activity of Th1/Th17 cells which release pro-inflammatory cytokines (TNF-α, IFN-γ, IL-17, and IL-6), while decreasing the activity of Th2/Treg cells which produce anti-inflammatory cytokines (IL-10 and IL-4), thus the outcome is multiple organ injury, the comprehensive review by Larson et al [115] is recommended.…”