Immunological basis in the pathogenesis of intrahepatic cholestasis of pregnancy

Abstract

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.

Keywords: S-adenosylmethionine; T-lymphocytes; bile acids; intrahepatic cholestasis of pregnancy; ursodeoxycholic acid.

Figure 1. The risks and effects of intrahepatic cholestasis of pregnancy

Risk factors, diagnostic criteria and effects of intrahepatic cholestasis of pregnancy on the fetus and mother are shown above. Short term effects of ICP on the mother occur from the onset of intrahepatic cholestasis of pregnancy until the delivery of the placenta while long term effects are those that occur a significant time later. AST: Aspartate aminotransferase; ALT: Alanine transaminase

Figure 2. Immunologic changes occurring in intrahepatic cholestasis of pregnancy

The rise in estradiol and progesterone in the third trimester of pregnancy modulates immune cells including macrophages, CD4+ T cells, neutrophils and NK cells via increases in bile acids. The increase in bile acid levels lead to increased activation of alveolar macrophages which have been implicated in infant respiratory distress syndrome, one of the fetal risks involved this disorder. Changes occur in the differentiation of CD4+ T cells. TH1 cell proliferation becomes increased and secrete pro-inflammatory cytokines such as IFN-γ and TNF-α that cause placental damage. TH2 cells which secrete anti-inflammatory IL-4 and IL-10 are decreased along with T-regulatory cells which have been shown to decrease the incidence of labor complications. Meanwhile TH17 cells produce IL-17 which induces the production of IL-6, a cytokine shown to cause preterm birth and recurrent miscarriage when at increased levels. Neutrophils, which are increased, create ROS that cause cellular injury. Finally, NK and uNK cells secrete VEGF, a factor that causes angiogenesis. While VEGF is increased in ICP, other angiogenic factors are decreased thus questioning the role of angiogenesis in intrahepatic cholestasis of pregnancy. BSEP: Bile Salt Export Pump; NATP: Na+/taurocholate co-transporter; OATP: Organic anion transporting polypeptides; iRDS: Infant respiratory distress syndrome; Treg: T-regulatory cells; ROS: Reactive oxygen species; NK: Natural killer cells; uNK: Uterine natural killer cells; VEGF: Vascular endothelial growth factor.

Figure 3. Mechanisms of treatment for intrahepatic cholestasis of pregnancy

In parts A, B and C, the effects of treatments are shown in hepatocytes; D shows PPC’s effects occurring in immune cells such as leukocytes. UDCA, as shown in A, treats intrahepatic cholestasis of pregnancy in part by decreasing bile acid via higher protein levels of the canalicular transporters BSEP and MDR3 and the basolateral MRP4 protein. In B, Rifampicin increases expression of CYP3A4 through binding of PXR to RXR which activates its transcription. CYP3A4 converts bile acids to 6α-hydroxylated bile acids that are later glucuronidated and exported into the blood via MRP3. The elimination of bilirubin is also increased with rifampicin through increased UGT1A1 which converts bilirubin to bilirubin diglucuronide that is then excreted through MRP2, a canalicular exporter. In C, SAMe’s effect on GSH is shown. It increases levels of GSH, which protects hepatocytes by scavenging free radicals, detoxifying electrophiles and modulating critical cell processes such as DNA synthesis. GSH also controls the generation of ROS in mitochondria. This production can be induced by the binding of TNF-α to its receptor TNFR1 to cause apoptosis. Finally, PPC in D acts by increasing activation of PPARα which inhibits the NF-κB and thus the production of pro-inflammatory cytokines in cells such as macrophages and lymphocytes. UDCA: ursodeoxycholic acid; BSEP: Bile salt export pump; MDR3: multidrug resistance protein 3; MRP2, 3, 4: Multidrug resistance associated protein 2, 3, 4; UGT1A1: UDP glucuronosyltransferase 1A1; PXR: Pregnane X receptor; RXR: 9-cis retinoic acid receptor; CYP3A4: Cytochrome P450 3A4; SAMe: S-adenosylmethionine; GSH: Glutathione; ROS: Reactive oxygen species; TNFR1: Tumor necrosis factor receptor type 1; PPC: Polyunsaturated phosphatidylcholine; PPARα: Peroxisome proliferator-activated receptor α.