Etiology Of Intrahepatic Cholestasis Of Pregnancy Research Articles

Current understanding of autophagy in intrahepatic cholestasis of pregnancy.

Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disease during pregnancy. Manifested with pruritus and elevation in bile acids, the etiology of ICP is still poorly understood. Although ICP is considered relatively benign for the mother, increased rates of adverse fetal outcomes including sudden fetal demise are possible devastating outcomes associated with ICP. Limited understanding of the underlying mechanisms restricted treatment options and managements of ICP. In recent decades, evolving evidence indicated the significance of autophagy in pregnancy and pregnancy complications. Autophagy is an ancient self-defense mechanism which is essential for cell survival, differentiation and development. Autophagy has pivotal roles in embryogenesis, implantation, and maintenance of pregnancy, and is involved in the orchestration of diverse physiological and pathological cellular responses in patients with pregnancy complications. Recent advances in these research fields provide tantalizing targets on autophagy to improve the care of pregnant women. This review summarizes recent advances in understanding autophagy in ICP and its possible roles in the causation and prevention of ICP.

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

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder which typically commences in the late second or third trimester and resolves within 48 hours after delivery. It is characterized by mild to severe pruritus, without any specific dermatologic features, elevated liver enzymes and increased serum bile acids (BA). The etiology of ICP is still not completely explicit. Pathogenesis includes a combination of hormonal and environmental factors superimposing on a genetic predisposition. During recent years increasingly ICP is recognized to be associated with an abnormal metabolic profile, including glucose intolerance and dyslipidemia, although it is considered to be secondary to maternal aberrant BA homeostasis. This article reviews the recent literature data and current concepts for ICP, with emphasis on a possibility of metabolic disorders being primary causative factors in ICP pathogenesis.

Intrahepatic cholestasis of pregnancy : Rare but important

Intrahepatic cholestasis of pregnancy (ICP) is aliver-specific disorder occurring in approximately 0.5-2.0% of all pregnancies with aconsiderable variation in certain ethnic groups. ICP usually runs abenign course for the mother and is characterized by maternal pruritus mainly in the third trimester, elevated transaminases and fasting total serum bile salts and increased fetal adverse events. The etiology of ICP is only partially understood but seems to be multifactorial. Cholestasis-inducing effects of certain female sex hormones and their metabolites play an important role in genetically susceptible women. The mechanisms resulting in fetal complications such as spontaneous preterm labour, antepartum passage of meconium, asphyxia events, still birth and fetal death are not well understood. Certain sulfated progesterone metabolites are likely to play arole in the pathogenesis of pruritus in ICP. In contrast to pregnancy-related dermatoses, pruritus does not present with primary skin alterations. However, intense scratching may cause secondary skin changes such as abrasions, excoriations and sometimes prurigo nodularis. Treatment is based on ursodeoxycholate treatment to reduce pruritus and hepatic impairment as well as elective delivery between gestation week 37-38 to pre-empt potential stillbirths. This article reviews clinical symptoms, diagnosis, treatment and in particular pathogenesis of pruritus in ICP.

Intrahepatic cholestasis of pregnancy and fetal outcomes. Mini review

Intrahepatic cholestasis of pregnancy (ICP), a pregnancy-related liver disease, leads to complications for both mother and fetus. It is the most common liver disease in pregnant women. The incidence of ICP has varied widely in different reports (ranging from 0.1 to 15.6%), for reasons that are incompletely understood. Hormonal, immunologic, genetic, environmental and alimentary factors have been implicated in the etiology of ICP. Although a clear correlation between elevated levels of maternal serum bile acids and deficient fetal outcome has been established in clinical practice, the underlying mechanisms remain elusive. Here we present a mini literature review about intrahepatic cholestasis of pregnancy and fetal outcomes.

Roles of PPARγ/NF-κB Signaling Pathway in the Pathogenesis of Intrahepatic Cholestasis of Pregnancy

BackgroundIntrahepatic cholestasis of pregnancy (ICP) is the most prevalent pregnancy specific liver disease. However, the pathogenesis and etiology of ICP is poorly understood.AimTo assess the expression of peroxisome proliferator-activated receptorγ (PPARγ) and nuclear factor kappa B (NF-κB) in placenta and HTR-8/SVneo cell, and evaluate the serum levels of cytokines, bile acids, hepatic function and lipids in control and ICP patients and the fetal outcome, in order to explore the role of PPARγ/NF-κB signaling pathway in the possible mechanism of ICP.MethodsClinical data of the pregnant women were collected and serum levels of cytokines, bile acids, hepatic function and lipids were measured. Expressions of PPARγ and NF-κB in placenta and HTR-8/SVneo cell were determined. The new-born information was collected to demonstrate the relationship between PPARγ/NF-κB signaling pathway and ICP.ResultsThe serum levels of bile acids, hepatic function, triglycerides (TG), total cholesterol (TC), IL-6, IL-12 and TNF-α in ICP group were significantly increased (P<0.01), and serum level of IL-4 was significantly decreased (P<0.01). PPARγ and NF-κB staining were found in the membrane and cytoplasm of placental trophoblast cell. The expression of PPARγ and NF-κB were significantly higher in ICP group and taurocholate acid (TCA) treated HTR-8/SVneo cell (P<0.01). The new-born information in severe ICP group were significantly different as compared to that in control group (P<0.05), and part of information in mild ICP group were also difference to that in control group (P<0.05).ConclusionsThe higher expressions of PPARγ and NF-κB in ICP placenta and TCA treated HTR-8/SVneo cell, together with the abnormal serum levels of cytokines, might induced by the imbalance of inflammatory and immune reaction, and then disturb placental bile acid and serum lipids transportation, finally result in fatal cholestasis which probably be one of the mechanism of ICP.

Immune mechanisms and the role of oxidative stress in intrahepatic cholestasis of pregnancy.

IntroductionThe purpose of this study was to investigate levels of inflammatory cytokines such as interleukin 6 (IL-6), tumor necrosis factor α (TNF-α) and neopterin and oxidative stress status in patients with intrahepatic cholestasis of pregnancy (ICP) as well as their potential role in the pathophysiology.Material and methodsThirty patients with ICP (Group 1) and 30 healthy pregnant women (Group 2) were included in this prospective case-control study. Levels of IL-6, TNF-α and neopterin were determined in both of the groups. Total anti-oxidant status (TAS) and total oxidative stress (TOS) levels were determined by means of a fully automated Erel method. Oxidative stress index (OSI) was calculated as the ratio of TOS to TAS.ResultsThere was no significant difference between the groups in IL-6 and TNF-α levels (p = 0.105 and p = 0.722, respectively). The mean neopterin level was significantly higher in Group 1 compared to Group 2 (2.34 ±0.77 and 1.57 ±0.38, respectively, p = 0.001). In addition, TAS, TOS and OSI levels were significantly higher in Group 1 (p = 0.004, p = 0.001 and p = 0.001, respectively) compared to Group 2.DiscussionIntrahepatic cholestasis of pregnancy is an inflammatory disorder in which maternal immune reaction may play a role. Interleukin 6 and TNF-α, which are some of the markers of humoral reaction, act as an indicator of abnormal reaction rather than acute-phase reaction in ICP. Further clinical trials and supportive placental findings are needed on the role of cytokines in cellular and humoral immune reactions during the symptomatic period and delivery to better understand the role of immune mechanisms in the aetiology of ICP.

Intrahepatic cholestasis of pregnancy

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder characterized by maternal pruritus in the third trimester, raised serum bile acids and increased rates of adverse fetal outcomes. The etiology of ICP is complex and not fully understood, but it is likely to result from the cholestatic effects of reproductive hormones and their metabolites in genetically susceptible women. Equally unclear are the mechanisms by which the fetal complications occur. This article reviews the epidemiology, clinical features, diagnosis, etiology and management of ICP.

Intrahepatic cholestasis of pregnancy: When should you look further?

Pruritus with abnormal liver function tests is the classical presentation of intrahepatic cholestasis of pregnancy (ICP), a condition associated with significant fetal complications. Although the etiology of ICP is unclear in many cases, certain features of the clinical presentation should alert the practitioner to the possibility of an underlying metabolic defect, which may not only affect subsequent pregnancies, but may be an indicator of more serious subsequent liver disease. We report a kindred of Anglo-Celtic descent, among whom many members present with ICP, gallstones or cholestasis related to use of oral contraception. Genetic studies revealed a novel mutation in the ABCB4 gene, which codes for a phospholipid transport protein. The clinical significance of this mutation and the importance of identifying such patients are discussed.

Sequencing and functional assessment of hPXR (NR1I2) variants in intrahepatic cholestasis of pregnancy

1. The purpose of this study was to evaluate the role of coding variation in hPXR (NR1I2) in intrahepatic cholestasis of pregnancy (ICP) and to functionally asses the response of PXR variants to ligands of interest in ICP.2. The coding region of hPXR was sequenced in a cohort of 121 Caucasian ICP patients and exon 2 was sequenced in an additional 226 cases. Reporter assays were used to evaluate the function of all known hPXR variants in response to the secondary bile acid lithocholic acid and therapeutic agents rifampicin, ursodeoxycholic acid and dexamethasone.3. Two coding single nucleotide polymorphisms (C79T and G106A) were detected in the ICP cohort at frequencies consistent with healthy populations. These do not alter hPXR function in response to ligands of interest to ICP. Analysis of all known coding hPXR variants demonstrates that while subtle changes in experimental design mask or may unveil the functional effects of genetic variation, these are not maintained in a standard functional assay.4. Coding genetic variation in hPXR does not contribute to the aetiology of ICP in Caucasian populations.

Relationship between asymptomatic hypercholanaemia of pregnancy and progesterone metabolism

The aim of this study was to identify a subgroup of pregnant women with asymptomatic hypercholanaemia of pregnancy (AHP), in which the relationship between alterations in the level and pattern of serum bile acids (BAs) and of progesterone plus progesterone metabolites could be investigated in the absence of overt impairment of hepatobiliary function. Cholanaemia and serum concentrations of progesterone were assayed by an enzymic technique and by ELISA respectively, while BA molecular species and progesterone metabolites were measured by GC-MS, in the serum of 411 healthy pregnant women. Samples were collected after an overnight fast in the final week of each trimester of gestation. Two pregnant women were excluded because of the suspicion of intrahepatic cholestasis of pregnancy (ICP). Cholanaemia was found to increase progressively throughout pregnancy, but with normal mean values lower than 3.0 microM. Thus in our series AHP was defined arbitrarily as the presence of serum total BA concentrations 2-fold higher than this value, i.e. 6 microM, in the absence of hepatobiliary disease or symptoms of ICP. The prevalence of this condition was observed to increase with gestational age. Changes in the pattern of serum BAs in AHP were also found. These were reflected in a marked increase in the proportion of cholic acid together with a decrease in that of deoxycholic acid, while the proportions of chenodeoxycholic acid and lithocholic acid changed only moderately. When groups at the same gestational age were compared, serum progesterone levels were always significantly lower, while those of progesterone metabolites were higher, in women with AHP. Our results suggest that AHP is a relatively common condition in our geographical location, where ICP is rarely diagnosed. Changes in the serum BA pattern in hypercholanaemia resemble these described in ICP. The simultaneous finding of lower serum total progesterone levels along with an increase in its metabolites supports the hypothesis that a primary defect in progesterone metabolism may be involved in the aetiology of ICP.