Intrahepatic cholestasis of pregnancy: Recent advances

doi:10.1016/j.clindermatol.2016.02.004

Clinics in Dermatology

Volume 34, Issue 3, May–June 2016, Pages 327-334

https://doi.org/10.1016/j.clindermatol.2016.02.004 Get rights and content

Abstract

Intrahepatic cholestasis of pregnancy, also known as obstetric cholestasis, is a pruritic condition of pregnancy characterized by an underlying elevation in circulating bile acids and liver derangement, and associated with adverse fetal outcomes, such as preterm labor and stillbirth. Limited understanding of the underlying pathophysiology and mechanisms involved in adverse outcomes has previously restricted treatment options and pregnancy management. Recent advances in these research fields provide tantalizing targets to improve the care of pregnant women affected by this condition.

Introduction

Intrahepatic cholestasis of pregnancy (ICP), also called obstetric cholestasis, is a liver condition of pregnancy characterized by pruritus and the biochemical finding of elevated serum bile acids, often in the presence of other signs of liver dysfunction. By definition, ICP is confined to pregnancy and the peripartum period and is diagnosed after exclusion of other causes of cholestasis. In addition to the maternal symptomatology, ICP can be associated with adverse fetal outcomes, such as spontaneous preterm birth, meconium staining of the amniotic fluid, and stillbirth¹; hence, appropriate recognition and management are significant.

The incidence of ICP varies and is dependent on geographic location and ethnicity. For example, the incidence is 4% in Chile²; in the United Kingdom it is 0.7%, but is higher in women of Indian or Pakistani origin,³ whereas the incidence in China has recently been estimated at 1.2%, based on more than 100,000 hospital births.⁴ Within the Californian population, genetic ancestry mapping has indicated higher levels of ICP in women of Native American ethnicity.⁵

ICP is more common in women with preexisting hepatitis C and gallstone disease; hence, the benefit of serum screening and liver ultrasound in all women diagnosed with the condition.⁶ Its incidence is also higher in women with multiple gestation pregnancies⁷ and in those who conceived using assisted reproduction.⁸

Section snippets

Symptoms

The hallmark symptom of ICP is pruritus—that is, “itching in the absence of an eruption;” yet, scratching can often lead to secondary skin changes. Traditionally, pruritus is described on the palms and soles, but ICP-associated pruritus can be generalized.⁹ Itching ranges from mild to debilitating and intense, and it is typically worse at night. Excoriated lesions (Figure 1) can become complicated by secondary infection. The onset of pruritus often precedes biochemical derangement,¹⁰ making the

Pruritus in pregnancy and ICP

The cause of pruritus in ICP is not fully understood, although a number of possible pruritogens have been identified. It has long been established that bile acids can elicit itch when applied to the skin,¹³ and the lowering of serum bile acids with the use of ursodeoxycholic acid (UDCA) treatment for ICP is mirrored by a reduction in itch intensity.¹⁴ There is some experimental evidence for a role of bile acids in pruritus because the secondary bile acid deoxycholic acid has been found to

Maternal disease

The etiology of ICP is influenced by a combination of genetic, endocrine, and environmental factors. Evidence for a genetic etiology includes an increased risk in first-degree relatives,²² the presence of mutations in biliary transporters, such as the bile salt export pump (BSEP/ABCB11) and multi-drug resistance protein 3 (MDR3/ABCB4),[23], [24] and polymorphisms that confer susceptibility in these genes and the principal nuclear receptor influencing bile acid homeostasis, farnesoid X receptor

Management

The drugs for which placebo-controlled studies have been performed in the treatment of ICP are summarized in Table 1. UDCA has the most experimental data to support its use. It is a hydrophilic bile acid that improves bile acid profiles in cholestatic liver disorders via multiple mechanisms, including enhanced biliary excretion (reviewed by Lazaridis⁶⁰). It also reduces the extent of the elevation of fetal bile acids in ICP.⁶¹ UDCA is the most widely prescribed pharmacologic treatment for ICP,

Associated conditions

Bile acids have traditionally been viewed as detergent molecules that aid digestion of fats, secondary to their hydrophobic properties; however, they have important roles in metabolism, with multiple signaling effects on downstream organs, such as the pancreas and adipose tissue. The two major bile acid receptors currently recognized are the nuclear receptor FXR and the G-protein coupled cell surface receptor TGR5. Bile acid binding of these receptors results in multiple downstream metabolic

Long-term implications

Women with ICP have slightly higher long-term risks of cancer of the liver and biliary tree (HR 3.61; 95% CI 1.68-7.77, and 2.62; 95% CI 1.26-5.46, respectively),⁷⁸ as well as higher rates of other hepatobiliary diseases, most commonly cholelithiasis.⁶ In addition, a Swedish population-based study using national disease databases also found mildly elevated rates of diabetes mellitus, thyroid disease, psoriasis, inflammatory polyarthropathies, Crohn's disease, and cardiovascular disease.⁷⁸ Women

Future directions

As further insights are gained into the etiology of ICP, improvements in the management of patients affected by the condition become possible. Understanding the underlying pathophysiology will certainly enable us to do the following:

•
Develop predictive biomarkers enabling targeted obstetric care to women at risk of developing ICP from early pregnancy onwards. Putative biomarkers, such as autotaxin¹⁸ and the sulfated progesterone metabolites,²¹ have been suggested and are promising for future

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Cited by (57)

The role of ERp29/FOS/EMT pathway in excessive apoptosis of placental trophoblast cells in intrahepatic cholestasis of pregnancy
2024, Placenta
Abnormal bile acid metabolism leading to changes in placental function during pregnancy. To determine whether endoplasmic reticulum protein 29 (ERp29) can mediate the pregnancy effects of cholestasis by altering the level of trophoblast cell apoptosis.
ERp29 in serum of 66 intrahepatic cholestasis of pregnancy (ICP) pregnant women and 74 healthy were detected by ELISA. Subcutaneous injection of ethinyl estradiol (E2) was used to induce ICP in pregnant rats. Taurocholic acid (TCA) was used to simulate the ICP environment, and TGF-β1 was added to induce the epithelial mesenchymal transformation (EMT) process. The scratch, migration, and invasion test were used to detect the EMT process. ERp29 overexpression/knockdown vector were constructed and transfected to verify the role of ERp29 in the EMT process. Downstream gene was obtained through RNA-seq.
Compared with the healthy pregnant women, the expression levels of ERp29 in serum of ICP pregnancy women were significantly increased (P < 0.001). ERp29 in the placenta tissue of the ICP pregnant rats increased significantly, and the level of apoptosis increased. The placental tissues of the ICP had high expression of E-cadherin and low expression of N-cadherin, snail1, vimentin. After HTR-8/SVneo cells were induced by TCA, EMT was inhibited, while the ERp29 increased. Cell and animal experiments showed that, knockdown of ERp29 reduced the inhibition of EMT, the ICP progress was alleviated. Overexpression of FOS salvaged the inhibitory effects of ERp29 on cell EMT.
The high level of ERp29 in placental trophoblast cells reduced FOS mRNA levels, inhibited the EMT process and aggravated the occurrence and development of ICP.
Gentamicin alleviates cholestatic liver injury by decreasing gut microbiota-associated bile salt hydrolase activity in rats
2023, European Journal of Pharmacology
Intrahepatic cholestasis lacks effective therapeutic drugs. The gut microbiota-associated bile salt hydrolases (BSH) may be a potential therapeutic target. In this study, oral administration of gentamicin (GEN) decreased the serum and hepatic levels of total bile acid in 17α-ethynylestradiol (EE)-induced cholestatic male rats, significantly improved the serum levels of hepatic biomarkers and reversed the histopathological changes in the liver. In healthy male rats, the serum and hepatic levels of total bile acid were also decreased by GEN, the ratio of primary to secondary bile acids, and conjugated to unconjugated bile acids was significantly increased, and the urinary excretion of total bile acid was elevated. 16S rDNA sequencing of the ileal contents revealed that GEN treatment substantially reduced the abundance of Lactobacillus and Bacteroides both of which expressed BSH. Consistently, BSH activity analysis by the generation of d5-chenodeoxycholic acid from d5-taurochenodeoxycholic acid in situ showed BSH was significantly inhibited in the ileal contents of rats treated with GEN. This finding led to an increased proportion of hydrophilic conjugated bile acids and facilitated the urinary excretion of total bile acids, thereby decreasing serum and hepatic total bile acids and reversing liver injury related to cholestasis. Our results provide important evidence that BSH can be a potential drug target for treating cholestasis.
Evaluation of Liver Disease in Pregnancy
2023, Clinics in Liver Disease
Citation Excerpt :
Associated fetal risks include preterm births, meconium-stained amniotic fluids, neonatal respiratory depression and asphyxia, and fetal death. These risks increase with increasing bile acid levels and most commonly occur when serum bile acid level is greater than 40 μmol/L.15 Proposed mechanisms include cardiotoxic effects of bile acids and vasoconstrictive effects of bile acids on placental veins.18 Therefore, the American College of Obstetricians and Gynecologists recommends delivery at 36 to 37 weeks or at diagnosis if diagnosed after 37 weeks.20
Specific fluorescence release based on synergistic activation of enzymes and position-dependent of electrophilic groups to diagnose intrahepatic cholestasis of pregnancy
2022, Chemical Engineering Journal
Citation Excerpt :
Intrahepatic cholestasis of pregnancy (ICP), the most frequent cause of hepatic disease in pregnancy, is associated with an increased risk for unexplained term stillbirth and preterm delivery. ICP is a clinical syndrome of unknown origin, initially is identified by persistent pruritus[8,9]. However, pruritus in pregnancy is reported in as many as 20% of women in early pregnancy[10], and the benign condition of pruritus gravidarum can be difficult to distinguish from a diagnosis of ICP.
The early diagnosis and effective treatment of disease have presented new challenges to today's researchers. Recently, an important direction of the development of the fluorescent probes field is to provide convenient detection tools for clinical diagnosis. Intrahepatic cholestasis of pregnancy (ICP), a pregnancy-specific liver disease associated with poor maternal and fetal outcome, lack biochemical diagnosis indicator with relatively high specificity. Glutathione S-transferases may be a potential candidate for ICP diagnosis owing to their high concentrations in the liver, however, fluorescent detection tool for GSTs with high selectivity is scarce, owing to the interference of high non-enzymatic reaction with GSH. In this work, a probe (MB5) through fine structure regulation for specific fluorescence response GSTs was obtained with synergistic activation of enzymes and position-dependent of electrophilic groups. Furthermore, overexpressed GSTs were visualized directly in cholestatic mice models through in vivo imaging, isolated organ imaging, and tissue slice analysis. More importantly, the serum samples of the ICP patients hold significantly high levels of GSTs concentrations, compared with healthy pregnant women. Therefore, a novel diagnostic tool and excellent detection method for ICP were provided, which will promote to the establishment of new biochemical markers of liver function in pregnancy.
Pregnancy-Associated Liver Diseases
2022, Gastroenterology
Citation Excerpt :
Rifampicin has been shown to improve cholestatic pruritus in nonpregnant individuals.81 There are reports of improved maternal itch or hypercholanemia with the use of s-adenosyl methionine, cholestyramine, and activated charcoal in small studies (reviewed in Ovadia and Williamson82), but none have reduced the rate of adverse perinatal outcomes. Topical emollients may soothe the skin for some women.
The liver disorders unique to pregnancy include hyperemesis gravidarum, intrahepatic cholestasis of pregnancy, acute fatty liver of pregnancy, and preeclampsia-associated hepatic impairment, specifically hemolysis, elevated liver enzymes, and low platelet count syndrome (HELLP). Their importance lies in the significant maternal and fetal/neonatal morbidity and mortality. Expeditious diagnosis and clinical evaluation is critical to ensure timely, appropriate care and minimize risks to the pregnant woman and her fetus/baby. A multidisciplinary approach is essential, including midwives, maternal-fetal-medicine specialists, anesthetists, neonatologists, and hepatologists.
Hepatitis B virus infection and intrahepatic cholestasis of pregnancy: a birth cohort study in Lanzhou, China
2024, Research Square

View all citing articles on Scopus

^☆: Research for this review was funded/supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy’s and St. Thomas' NHS Foundation Trust and King’s College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

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Intrahepatic cholestasis of pregnancy: Recent advances☆

Abstract

Introduction

Section snippets

Symptoms

Pruritus in pregnancy and ICP

Maternal disease

Management

Associated conditions

Long-term implications

Future directions

J Hepatol

Br J Obstet Gynaecol

Gastroenterology

J Clin Anesth

J Hepatol

Gastroenterology

J Biol Chem

J Hepatol

J Hepatol

Int J Gynaecol Obstet

J Hepatol

Gastroenterology

Eur J Obstet Gynecol Reprod Biol

J Hepatol

Gastroenterology

J Obstet Gynaecol Can

Sex Reprod Healthc

Eur J Obstet Gynecol Reprod Biol

J Hepatol

Int J Cardiol

Association of severe intrahepatic cholestasis of pregnancy with adverse pregnancy outcomes: A prospective population-based case-control study

Hepatology

Sex hormones and bile acids in intrahepatic cholestasis of pregnancy

Hepatology

Intrahepatic cholestasis of pregnancy: Prevalence and ethnic distribution

Ethn Health

Obstetrical disease spectrum in China: An epidemiological study of 111,767 cases in 2011

Chin Med J (Engl)

Intrahepatic cholestasis of pregnancy (ICP) in U.S. Latinas and Chileans: Clinical features, ancestry analysis, and admixture mapping

PLoS One

Intrahepatic cholestasis of pregnancy and associated hepatobiliary disease: A population-based cohort study

Hepatology

Association of assisted reproductive technology with adverse pregnancy outcomes

Iran J Reprod Med

Pruritus in pregnancy: A study of anatomical distribution and prevalence in relation to the development of obstetric cholestasis

Obstet Med

Pruritus induced by crude bile and purified bile acids. Experimental production of pruritus in human skin

Arch Dermatol

Ursodeoxycholic acid versus placebo, and early term delivery versus expectant management, in women with intrahepatic cholestasis of pregnancy: Semifactorial randomised clinical trial

BMJ

The TGR5 receptor mediates bile acid-induced itch and analgesia

J Clin Invest

Lysophosphatidic acid is a potential mediator of cholestatic pruritus

Gastroenterology

Serum autotaxin is increased in pruritus of cholestasis, but not of other origin, and responds to therapeutic interventions

Hepatology

Variant adiponutrin confers genetic protection against cholestatic itch

Sci Rep

Bile acids and progesterone metabolites in intrahepatic cholestasis of pregnancy

Ann Med

Prognostic and mechanistic potential of progesterone sulfates in intrahepatic cholestasis of pregnancy and pruritus gravidarum

Hepatology

Intrahepatic cholestasis of pregnancy is common among patients' first-degree relatives

Acta Obstet Gynecol Scand

Contribution of variant alleles of ABCB11 to susceptibility to intrahepatic cholestasis of pregnancy

Gut

A comprehensive analysis of common genetic variation around six candidate loci for intrahepatic cholestasis of pregnancy

Am J Gastroenterol

Promoter DNA methylation of farnesoid X receptor and pregnane X receptor modulates the intrahepatic cholestasis of pregnancy phenotype

PLoS One