Intrahepatic cholestasis of pregnancy: Molecular pathogenesis, diagnosis and management

Department of Internal Medicine III, Aachen University of Technology RWTH, Germany.
Journal of Hepatology (Impact Factor: 11.34). 01/2001; 33(6):1012-21. DOI: 10.1016/S0168-8278(00)80139-7
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Available from: Frank Lammert, Apr 25, 2015
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    • "In addition, serum TBS increase upon food intake, thereby increasing variation, unless serum is collected upon fasting. Elevated serum transaminases during the 3rd trimester of pregnancy are seen in women with HELLP-syndrome (hemolysis, elevated liver enzymes and low platelet count), pre-eclampsia, acute fatty liver of pregnancy and other non-pregnancy-related liver disorders, including obesity [1] [2] [6]. These women also hold an increased risk for fetal adverse outcomes, but have an etiology that differs from women with ICP. "
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    ABSTRACT: Background & aims: Intrahepatic cholestasis of pregnancy (ICP) is defined by pruritus, elevated total fasting serum bile salts (TBS) and transaminases, and an increased risk of adverse fetal outcome. An accurate diagnostic marker is needed. Increased serum autotaxin correlates with cholestasis-associated pruritus. We aimed at unraveling the diagnostic accuracy of autotaxin in ICP. Methods: Serum samples and placental tissue were collected from 44 women with uncomplicated pregnancies and 105 with pruritus and/or elevated serum transaminases. Autotaxin serum levels were quantified enzymatically and by Western blotting, autotaxin gene expression by quantitative PCR. Results: Serum autotaxin was increased in ICP (mean ± SD: 43.5 ± 18.2 nmol ml(-1)min(-1), n=55, p<0.0001) compared to other pruritic disorders of pregnancy (16.8 ± 6.7 nmol ml(-1)min(-1), n=33), pre-eclampsia complicated by HELLP-syndrome (16.8 ± 8.9 nmol ml(-1)min(-1), n=17), and pregnant controls (19.6 ± 5.7 nmol ml(-1)min(-1), n=44). Longitudinal analysis during pregnancy revealed a marked rise in serum autotaxin with onset of ICP-related pruritus. Serum autotaxin was increased in women taking oral contraceptives. Increased serum autotaxin during ICP was not associated with increased autotaxin mRNA in placenta. With a cut-off value of 27.0 nmol ml(-1)min(-1), autotaxin had an excellent sensitivity and specificity in distinguishing ICP from other pruritic disorders or pre-eclampsia/HELLP-syndrome. Serum autotaxin displayed no circadian rhythm and was not influenced by food intake. Conclusions: Increased serum autotaxin activity represents a highly sensitive, specific and robust diagnostic marker of ICP, distinguishing ICP from other pruritic disorders of pregnancy and pregnancy-related liver diseases. Pregnancy and oral contraception increase serum autotaxin to a much lesser extent than ICP.
    Full-text · Article · Nov 2014 · Journal of Hepatology
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    • "It is characterized by elevated serum bile acids (SBA) and/or transaminases and pruritis. Genetic predisposition, ethnicity, raised steroid hormone levels, and environmental factors have been proposed to play a role in the pathogenesis of ICP [7] [16] . ICP has been found to be associated with an increased risk of adverse pregnancy outcomes, such as preterm delivery , meconium staining, low APGAR scores, increased neonatal unit admission, intrauterine fetal death (IUFD), gestational diabetes mellitus, and preeclampsia [1] [5] [27] . "
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    ABSTRACT: Abstract Aim: Our aim was to investigate whether any hematological changes readily detectable by simple complete blood count (CBC), as well as fasting and postprandial total serum bile acid (SBA) levels, have diagnostic values for the prediction of adverse pregnancy outcomes in intrahepatic cholestasis of pregnancy (ICP). Methods: A prospective, case control study was carried out including 217 pregnant women (117 women with ICP and 100 healthy controls). The main outcome measures investigated were preterm delivery, APGAR scores, and neonatal unit admission. A multivariate logistic regression model was used to identify the independent risk factors of adverse pregnancy outcomes. Results: Compared with controls, women with ICP had significantly higher mean platelet volume (MPV) (mean 10.2±1.0 vs. 11.0±1.3; P<0.001) and platelet distribution width (PDW) (mean 13.1±2.3 vs. 14.7±2.8; P<0.001) values. Analysis with logistic regression revealed that the probability of preterm delivery did not increase until MPV levels exceeded 11.2 fL [odds ratio (OR)=2.68, 95% confidence interval (CI)=1.13-6.32, P=0.025], and total bilirubin levels exceeded 0.6 mg/dL (OR=3.13, 95% CI=1.21-8.09, P=0.019). Considering the low APGAR scores, only increased postprandial total SBA levels of ≥51 μmol/L were found to be predictive significantly (OR=3.02, 95% CI=1.07-8.53, P=0.037). Conclusions: Our study suggests that increased MPV and total bilirubin levels are associated with preterm delivery, and increased postprandial total SBA levels are predictive for low APGAR in ICP patients.
    Full-text · Article · Oct 2014 · Journal of Perinatal Medicine
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    • "It seems to be a multifactorial disease. The pathogenesis of ICP involves many factors, including genetic, hormonal, and environmental factors [3]. As yet, the pathogenesis and etiology of ICP remain elusive and incompletely understood. "
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    ABSTRACT: Objective To investigate differences in the placental proteomes of women with intrahepatic cholestasis of pregnancy (ICP) and those with a normal pregnancy. Methods Ten pregnant women diagnosed with ICP were recruited at the First People’s Hospital of Yuhang District from October 2011 to September 2012; 10 age-matched healthy pregnant women acted as controls. Total placental proteins were extracted and subjected to two-dimensional polyacrylamide gel electrophoresis followed by mass spectrometry to identify proteins that were differentially expressed in the two groups. Results In total, 37 protein spots with differentially expressed proteins were found. These comprised proteins involved in cytoskeleton activity, blood coagulation, and platelet activation as well as chaperones, heat shock proteins, RNA-binding and calcium-binding proteins, and various enzymes. Conclusion The placentas of women with ICP displayed significant proteome differences compared with women with a normal pregnancy. The results indicate that a variety of mechanisms and proteins may contribute to the development of ICP. Further verification and research are required to elucidate the exact roles of these proteins in ICP pathogenesis.
    Full-text · Article · Sep 2014 · International Journal of Gynecology & Obstetrics
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