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Dufford MT, Fleischer TC, Sommerville LJ, Badsha MB, Polpitiya AD, Logan J, Fox AC, Rust SR, Cox CB, Garite TJ, Boniface JJ, Kearney PE. Clock Proteins Have the Potential to Improve Term Delivery Date Prediction: A Proof-of-Concept Study. Life (Basel) 2025; 15:224. [PMID: 40003633 PMCID: PMC11856609 DOI: 10.3390/life15020224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 01/23/2025] [Accepted: 01/31/2025] [Indexed: 02/27/2025] Open
Abstract
Our ability to accurately predict the delivery date of term pregnancies is limited by shortcomings of modern-day clinical tools and due date estimation methods. The pregnancy clock is a series of coordinated and harmonized signals between mother, fetus, and placenta that regulate the length of gestation. Clock proteins are thought to be important mediators of these signals, yet few studies have investigated their potential utility as predictors of term delivery date. In this study, we performed a cross-sectional proteome analysis of 2648 serum samples collected between 18 and 28 weeks of gestation from mothers who delivered at term. The cohort included pregnancies both with and without complications. A total of 15 proteins of diverse functionalities were shown to have a direct association with time to birth (TTB), 11 of which have not been previously linked to gestational age. The protein A Distintegrin and Metalloproteinase 12 (ADA12) was one of the 15 proteins shown to have an association with TTB. Mothers who expressed the highest levels of ADA12 in the cohort (90th percentile) gave birth earlier than mothers who expressed the lowest levels of ADA12 (10th percentile) at a statistically significant rate (median gestational age at birth 390/7 weeks vs. 393/7 weeks, p < 0.001). Altogether, these findings suggest that ADA12, as well as potentially other clock proteins, have the potential to serve as clinical predictors of term delivery date in uncomplicated pregnancies and represent an important step towards characterizing the role(s) of clock proteins in mediating pregnancy length.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Paul E. Kearney
- Sera Prognostics, Inc., Salt Lake City, UT 84109, USA (T.C.F.); (A.C.F.); (T.J.G.)
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Hahnefeld L, Hackel J, Trautmann S, Angioni C, Schreiber Y, Gurke R, Thomas D, Wicker S, Geisslinger G, Tegeder I. Healthy plasma lipidomic signatures depend on sex, age, body mass index, and contraceptives but not perceived stress. Am J Physiol Cell Physiol 2024; 327:C1462-C1480. [PMID: 39437447 DOI: 10.1152/ajpcell.00630.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 10/14/2024] [Accepted: 10/14/2024] [Indexed: 10/25/2024]
Abstract
Perceived stress is thought to contribute to the pathogenesis of metabolic, vascular, mental, and immune diseases, with different susceptibilities in women and men. The present study investigated if and how perceived stress and/or demographic variables, including sex, age, body mass index, regular prescription drugs, occasional analgesics, or dietary supplements, manifested in plasma lipidomic profiles obtained by targeted and untargeted mass spectrometry analyses. The study included 217 healthy women and 108 healthy men, aged 18-68 yr, who were recruited in a 2:1 female:male ratio to account for women with/without contraceptives. As expected, dehydroepiandrosterone sulfate (DHEAS) and ceramides were higher in men than women, and DHEAS decreased with age, whereas ceramides increased. Contrary to expectations, neither DHEAS nor ceramides were associated with perceived stress [Perceived Stress Questionnaire with 30 questions (PSQ30 questionnaire)], which was, however, associated with BMI in men but not in women. None of the lipid species or classes showed a similar "age × sex × BMI" interaction, but the endocannabinoid palmitoylethanolamide (PEA) correlated with body mass index (BMI) and hypertension. Independent of perceived stress, lysophosphatidylcholines (LPCs) were lower in women than men, whereas LPC metabolites, lysophosphatidic acids (LPAs), were higher in women. The LPA:LPC ratio was particularly high in women using oral contraceptives, suggesting a strong hormone-induced extracellular conversion of LPCs to LPAs, which is catalyzed by the phospholipase D, autotaxin. The results reveal complex sex differences in perceived stress and lipidomic profiles, the latter being exacerbated by contraceptive use, but perceived stress and lipids were not directly correlated.NEW & NOTEWORTHY Perceived stress (PSQ questionnaire) depends on the interaction of "sex × age × BMI." Plasma lipid profiles depend on sex and age. Natural sex differences are exacerbated by the use of contraceptives. Perceived stress is not correlated with specific plasma lipids or lipidomic profiles. Women have high LPA:LPC ratios in association with high levels of autotaxin.
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Affiliation(s)
- Lisa Hahnefeld
- Faculty of Medicine, Institute of Clinical Pharmacology, Goethe University Frankfurt, Frankfurt am Main, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP and Fraunhofer Cluster of Excellence for Immune Mediated Diseases CIMD, Frankfurt am Main, Germany
| | - Juliane Hackel
- Faculty of Medicine, Institute of Clinical Pharmacology, Goethe University Frankfurt, Frankfurt am Main, Germany
| | - Sandra Trautmann
- Faculty of Medicine, Institute of Clinical Pharmacology, Goethe University Frankfurt, Frankfurt am Main, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP and Fraunhofer Cluster of Excellence for Immune Mediated Diseases CIMD, Frankfurt am Main, Germany
| | - Carlo Angioni
- Faculty of Medicine, Institute of Clinical Pharmacology, Goethe University Frankfurt, Frankfurt am Main, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP and Fraunhofer Cluster of Excellence for Immune Mediated Diseases CIMD, Frankfurt am Main, Germany
| | - Yannick Schreiber
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP and Fraunhofer Cluster of Excellence for Immune Mediated Diseases CIMD, Frankfurt am Main, Germany
| | - Robert Gurke
- Faculty of Medicine, Institute of Clinical Pharmacology, Goethe University Frankfurt, Frankfurt am Main, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP and Fraunhofer Cluster of Excellence for Immune Mediated Diseases CIMD, Frankfurt am Main, Germany
| | - Dominique Thomas
- Faculty of Medicine, Institute of Clinical Pharmacology, Goethe University Frankfurt, Frankfurt am Main, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP and Fraunhofer Cluster of Excellence for Immune Mediated Diseases CIMD, Frankfurt am Main, Germany
| | - Sabine Wicker
- Goethe-University Frankfurt, University Hospital, Occupational Health Service, Frankfurt am Main, Germany
| | - Gerd Geisslinger
- Faculty of Medicine, Institute of Clinical Pharmacology, Goethe University Frankfurt, Frankfurt am Main, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP and Fraunhofer Cluster of Excellence for Immune Mediated Diseases CIMD, Frankfurt am Main, Germany
| | - Irmgard Tegeder
- Faculty of Medicine, Institute of Clinical Pharmacology, Goethe University Frankfurt, Frankfurt am Main, Germany
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3
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Hague WB, Williamson C, Beuers U. Intrahepatic cholestasis of pregnancy: Introduction and overview 2024. Obstet Med 2024; 17:138-143. [PMID: 39262909 PMCID: PMC11384812 DOI: 10.1177/1753495x241265772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Accepted: 06/04/2024] [Indexed: 09/13/2024] Open
Abstract
Considerable progress has been made to explain the aetiology of intrahepatic cholestasis of pregnancy (ICP) and of the adverse pregnancy outcomes associated with high maternal total serum bile acids (TSBAs). The reported thresholds for non-fasting TSBA associated with the risk of stillbirth and spontaneous preterm birth can be used to identify pregnancies at risk of these adverse outcomes to decide on appropriate interventions and to give reassurance to women with lower concentrations of TSBA. Data also support the use of ursodeoxycholic acid to protect against the risk of spontaneous preterm birth. A previous history of ICP may be associated with higher rates of subsequent hepatobiliary disease: if there is a suspicion of underlying susceptibility, clinicians caring for women with ICP should screen for associated disorders or for genetic susceptibility and, where appropriate, refer for ongoing hepatology review.
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Affiliation(s)
- Wm Bill Hague
- Robinson Research Institute, The University of Adelaide, North Adelaide, Australia
| | | | - Ulrich Beuers
- Department of Gastroenterology and Hepatology and Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Centres, Amsterdam, Netherlands
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Liu W, Chen L, Wang W, Yue Z, Li J, Tan M, Gu Y, Zhu R, Zhang Y. A comprehensive review of novel biomarkers in the diagnosis of intrahepatic cholestasis of pregnancy. Biomark Med 2023; 17:509-521. [PMID: 37650679 DOI: 10.2217/bmm-2023-0190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/01/2023] Open
Abstract
Intrahepatic cholestasis of pregnancy (ICP) is a disease specific to pregnancy, featuring maternal itching and elevated serum bile acid levels. It leads to a series of adverse pregnancy outcomes as well as increased fetal mortality. Routine biochemical markers fail to fulfill the tremendous clinical requirements, thereby novel effective biomarkers are urgently desired. In our review, the potential novel biomarkers for ICP diagnosis are classified into four categories and elaborated in detail. The concrete diagnostic performances (sensitivity, specificity and area under the curve) of these biomarkers are demonstrated in tables. Moreover, the relationships between some biomarkers and ICP pathogenesis are briefly expounded. Nevertheless, only a few novel biomarkers are ideal, and their clinical applicability requires more evidence from larger multicenter trials.
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Affiliation(s)
- Weici Liu
- Wuxi Maternal & Child Health Hospital, Wuxi Medical Center of Nanjing Medical University, Wuxi, 214023, Jiangsu, China
- The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, 214023, Jiangsu, China
| | - Lingyan Chen
- Wuxi Maternal & Child Health Hospital, Wuxi Medical Center of Nanjing Medical University, Wuxi, 214023, Jiangsu, China
| | - Wenxiang Wang
- School of Basic Medical Sciences, Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Zhiran Yue
- Second Clinical Medical College of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Jingyang Li
- Wuxi Maternal & Child Health Hospital, Wuxi Medical Center of Nanjing Medical University, Wuxi, 214023, Jiangsu, China
| | - Mengjing Tan
- Department of Gynecology & Obstetrics, Anqing Hospital Affiliated to Anhui Medical University, Anqing, 246003, Anhui, China
| | - Ying Gu
- Wuxi Maternal & Child Health Hospital, Wuxi Medical Center of Nanjing Medical University, Wuxi, 214023, Jiangsu, China
| | - Ru Zhu
- Department of Gynecology & Obstetrics, Anqing Hospital Affiliated to Anhui Medical University, Anqing, 246003, Anhui, China
| | - Yan Zhang
- Wuxi Maternal & Child Health Hospital, Wuxi Medical Center of Nanjing Medical University, Wuxi, 214023, Jiangsu, China
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Yaginuma S, Omi J, Kano K, Aoki J. Lysophospholipids and their producing enzymes: Their pathological roles and potential as pathological biomarkers. Pharmacol Ther 2023; 246:108415. [PMID: 37061204 DOI: 10.1016/j.pharmthera.2023.108415] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 04/10/2023] [Accepted: 04/11/2023] [Indexed: 04/17/2023]
Abstract
Accumulating evidence suggests that lysophospholipids (LPL) serve as lipid mediators that exert their diverse pathophysiological functions via G protein-coupled receptors. These include lysophosphatidic acid (LPA), sphingosine 1-phosphate (S1P), lysophosphatidylserine (LysoPS) and lysophosphatidylinositol (LPI). Unlike S1P, which is produced intracellularly and secreted from various cell types, some LPLs, such as LPA, LysoPS and LPI, are produced in lesions, especially under pathological conditions, where they positively or negatively regulate disease progression through their autacoid-like actions. Although these LPLs are minor components of the cell membrane, recent developments in mass spectrometry techniques have made it possible to detect and quantify them in a variety of biological fluids, including plasma, serum, urine and cerebrospinal fluid. The synthetic enzymes of LPA and LysoPS are also present in these biological fluids, which also can be detected by antibody-based methods. Importantly, their levels have been found to dramatically increase during various pathological conditions. Thus, LPLs and their synthetic enzymes in these biological fluids are potential biomarkers. This review discusses the potential of these LPLs and LPL-related molecules as pathological biomarkers, including methods and problems in their measurement.
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Affiliation(s)
- Shun Yaginuma
- Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Japan
| | - Jumpei Omi
- Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Japan
| | - Kuniyuki Kano
- Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Japan
| | - Junken Aoki
- Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Japan.
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Mechanisms of pruritus in cholestasis: understanding and treating the itch. Nat Rev Gastroenterol Hepatol 2023; 20:26-36. [PMID: 36307649 DOI: 10.1038/s41575-022-00687-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/07/2022] [Indexed: 02/01/2023]
Abstract
Pruritus in cholestatic liver diseases can be a major burden and dramatically impair the quality of life of those affected. Here, we provide an update on the latest insights into the molecular pathogenesis of and novel therapeutic approaches for cholestasis-associated itch. Endogenous and exogenous small-molecule pruritogen candidates bind to their receptors on unmyelinated itch C-fibres in the skin. Candidate pruritogens in cholestasis include certain lysophospholipids and sulfated progesterone metabolites, among others, whereas total bile acid or bilirubin conjugates seem unlikely to have a dominant role in the pathogenesis of cholestasis-associated pruritus. Transmission of itch signals via primary, secondary and tertiary itch neurons to the postcentral gyrus and activation of scratch responses offer various targets for therapeutic intervention. At present, evidence-based treatment options for pruritus in fibrosing cholangiopathies, such as primary biliary cholangitis and primary sclerosing cholangitis, are the peroxisome proliferator-associated receptor (PPAR) agonist bezafibrate and the pregnane X receptor (PXR) agonist rifampicin. In pruritus of intrahepatic cholestasis of pregnancy, ursodeoxycholic acid is recommended and might be supported in the third trimester by rifampicin if needed. Alternatively, non-absorbable anion exchange resins, such as cholestyramine, can be administered, albeit with poor trial evidence. Liver transplantation for intolerable refractory pruritus has become an extremely rare therapeutic strategy.
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7
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Süzen Çaypınar S, Oğlak SC, Behram M, Gedik Özköse Z, Sezer S, Karakaş S. Serum autotaxin levels correlate with the severity of pruritus in intrahepatic cholestasis of pregnancy. J Obstet Gynaecol Res 2022; 48:3093-3102. [PMID: 36164271 DOI: 10.1111/jog.15444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 08/25/2022] [Accepted: 09/14/2022] [Indexed: 11/28/2022]
Abstract
PURPOSE This study aimed to examine autotaxin (ATX) concentrations in the serum of pregnant women complicated with intrahepatic cholestasis of pregnancy (ICP) and compare them with individuals with uncomplicated healthy pregnancies. METHODS This prospective case-control study took place with 83 pregnant women. The study group included 43 pregnant women presenting with a singleton pregnancy diagnosed with ICP in their third trimester of pregnancy. The diagnostic power of the ATX variable was examined by receiver operating characteristic analysis, and the cut-off value calculated according to the Youden index was summarized with the related sensitivity and specificity points. RESULTS The mean serum concentration of maternal ATX was significantly higher in the ICP cases (8.91 ± 2.69 pg/mL) compared to the pregnant women in the control group (3.59 ± 1.39 ng/mL, p < 0.001). According to the Youden index, a 5.80 ng/mL cut-off value of serum ATX concentrations can be used to diagnose ICP with 97.7% sensitivity and 97.5% specificity. A significant highly positive correlation was found between maternal serum ATX levels and maternal serum total bile acid levels (r = 0.633 and p < 0.001) and itch intensity, which was objectified by the visual analog scale score (r = 0.951 and p < 0.001). CONCLUSION Maternal serum ATX levels were significantly increased in ICP patients as compared with healthy pregnant women. Also, serum ATX activity was highly correlated with the itch intensity. We consider that ATX might represent a robust, accurate, and reliable circulating biomarker to diagnose ICP.
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Affiliation(s)
- Sema Süzen Çaypınar
- Department of Perinatology, Başakşehir Çam ve Sakura City Hospital, Istanbul, Turkey
| | - Süleyman Cemil Oğlak
- Department of Obstetrics and Gynecology, Health Sciences University, Gazi Yaşargil Training and Research Hospital, Diyarbakır, Turkey
| | - Mustafa Behram
- Department of Perinatology, Health Sciences University, Antalya Training and Research Hospital, Istanbul, Turkey
| | - Zeynep Gedik Özköse
- Department of Perinatology, Health Sciences University, Kanuni Sultan Süleyman Training and Research Hospital, Istanbul, Turkey
| | - Salim Sezer
- Department of Perinatology, Esenyurt University Hospital, Istanbul, Turkey
| | - Sema Karakaş
- Department of Gynecologic Oncology, Health Sciences University, Bakırköy Dr Sadi Konuk Training and Research Hospital, Istanbul, Turkey
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8
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Jurk SM, Kremer AE, Schleussner E. Intrahepatic Cholestasis of Pregnancy. Geburtshilfe Frauenheilkd 2021; 81:940-947. [PMID: 34393257 PMCID: PMC8354350 DOI: 10.1055/a-1522-5178] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Accepted: 06/02/2021] [Indexed: 12/29/2022] Open
Abstract
Intrahepatic cholestasis of pregnancy (ICP) is a rare but potentially serious complication of pregnancy, the main symptom of which is intense pruritus with elevated serum levels of bile acids. The elevated serum bile acid concentration is regarded as a predictor for poor perinatal outcome including intrauterine death. Ursodeoxycholic acid (UDCA) has become established as the treatment of choice in clinical management to achieve a significant improvement in symptoms and reduce the cholestasis. Pregnant women with severe intrahepatic cholestasis should always be managed in a perinatal centre with close interdisciplinary monitoring and treatment involving perinatologists and hepatologists to minimise the markedly increased perinatal morbidity and mortality as well as maternal symptoms.
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Affiliation(s)
| | - Andreas E Kremer
- Medizinische Klinik 1, Universitätsklinikum Erlangen, Erlangen, Germany.,Klinik für Gastroenterologie und Hepatologie, Universitätsspital Zürich, Zürich, Switzerland
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9
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Hagenbeck C, Hamza A, Kehl S, Maul H, Lammert F, Keitel V, Hütten MC, Pecks U. Management of Intrahepatic Cholestasis of Pregnancy: Recommendations of the Working Group on Obstetrics and Prenatal Medicine - Section on Maternal Disorders. Geburtshilfe Frauenheilkd 2021; 81:922-939. [PMID: 34393256 PMCID: PMC8354365 DOI: 10.1055/a-1386-3912] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 02/05/2021] [Indexed: 02/07/2023] Open
Abstract
Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disease specific to pregnancy. The cardinal symptom of pruritus and a concomitant elevated level of bile acids in the serum and/or alanine aminotransferase (ALT) are suggestive for the diagnosis. Overall, the maternal prognosis is good. The fetal outcome depends on the bile acid level. ICP is associated with increased risks for adverse perinatal outcomes, including preterm delivery, meconium-stained amniotic fluid, and stillbirth. Acute fetal asphyxia and not chronic uteroplacental dysfunction leads to stillbirth. Therefore, predictive fetal monitoring is not possible. While medication with ursodeoxycholic acid (UDCA) improves pruritus, it has not been shown to affect fetal outcome. The indication for induction of labour depends on bile acid levels and gestational age. There is a high risk of recurrence in subsequent pregnancies.
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Affiliation(s)
| | - Amr Hamza
- Universitätsklinikum des Saarlandes, Klinik für Frauenheilkunde, Geburtshilfe und Reproduktionsmedizin, Homburg, Germany
- Kantonsspital Baden AG, Baden, Switzerland
| | - Sven Kehl
- Frauenklinik, Friedrich Alexander University Erlangen Nuremberg, Faculty of Medicine, Erlangen, Germany
| | - Holger Maul
- Section of Prenatal Disgnostics and Therapy, Asklepios Klinik Barmbek, Hamburg, Germany
| | - Frank Lammert
- Klinik für Innere Medizin II, Universitätsklinikum des Saarlandes und Medizinische Fakultät der Universität des Saarlandes, Homburg, Germany
| | - Verena Keitel
- Universitätsklinikum Düsseldorf, Klinik für Gastroenterologie, Hepatologie und Infektiologie, Düsseldorf, Germany
| | - Matthias C. Hütten
- Clinique E2 Neonatology, Maastricht Universitair Medisch Centrum+, Maastricht, Netherlands
| | - Ulrich Pecks
- Universitätsklinikum Schleswig-Holstein, Campus Kiel, Klinik für Gynäkologie und Geburtshilfe, Kiel, Germany
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10
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Lysophosphatidic acid activates nociceptors and causes pain or itch depending on the application mode in human skin. Pain 2021; 163:445-460. [PMID: 34166323 DOI: 10.1097/j.pain.0000000000002363] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Accepted: 04/13/2021] [Indexed: 11/26/2022]
Abstract
ABSTRACT Lysophosphatidic acid (LPA) is involved in the pathophysiology of cholestatic pruritus and neuropathic pain. Slowly conducting peripheral afferent C-nerve fibers are crucial in the sensations of itch and pain. In animal studies, specialized neurons ("pruriceptors") have been described, expressing specific receptors e.g. from the Mrgpr family. Human nerve fibers involved in pain signaling ("nociceptors") can elicit itch if activated by focalized stimuli such as cowhage spicules.In this study, we scrutinized the effects of LPA in humans by two different application modes on the level of psychophysics and single nerve fiber recordings (microneurography). In healthy human subjects, intracutaneous LPA microinjections elicited burning pain, whereas LPA application via inactivated cowhage spicules evoked a moderate itch sensation. LPA microinjections induced heat hyperalgesia and hypersensitivity to higher electrical stimulus frequencies. Pharmacological blockade of TRPA1 or TRPV1 reduced heat hyperalgesia but not acute chemical pain. Microneurography revealed an application mode-dependent differential activation of mechano-sensitive (CM) and mechano-insensitive (CMi) C-fibers. LPA microinjections activated a greater proportion of CMi and more strongly than CM fibers; spicule-application of LPA activated CM and CMi fibers to a similar extent but excited CM more and CMi fibers less intensely than microinjections.In conclusion, we show for the first time in humans that LPA can cause pain as well as itch dependent on the mode of application and activates afferent human C-fibers. Itch may arise from focal activation of few nerve fibers with distinct spatial contrast to unexcited surrounding afferents, and a specific combination of activated fiber subclasses might contribute.
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11
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Hagenbeck C, Pecks U, Lammert F, Hütten MC, Borgmeier F, Fehm T, Schleußner E, Maul H, Kehl S, Hamza A, Keitel V. [Intrahepatic cholestasis of pregnancy]. DER GYNAKOLOGE 2021; 54:341-356. [PMID: 33896963 PMCID: PMC8056200 DOI: 10.1007/s00129-021-04787-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Accepted: 03/08/2021] [Indexed: 12/19/2022]
Abstract
Intrahepatic cholestasis of pregnancy (ICP) is the most frequent pregnancy-specific liver disease. It is characterized by pruritus and an accompanying elevation of serum bile acid concentrations and/or alanine aminotransferase (ALT), which are the key parameters in the diagnosis. Despite good maternal prognosis, elevated bile acid concentration in maternal blood is an influencing factor to advers fetal outcome. The ICP is associated with increased rates of preterm birth, neonatal unit admission and stillbirth. This is the result of acute fetal asphyxia as opposed to a chronic uteroplacental insufficiency. Reliable monitoring or predictive tools (e.g. cardiotocography (CTG) or ultrasound) that help to prevent advers events are yet to be explored. Medicinal treatment with ursodeoxycholic acid (UDCA) does not demonstrably reduce adverse perinatal outcomes but does improve pruritus and liver function test results. Bile acid concentrations and gestational age should be used as indications to determine delivery. There is a high risk of recurrence in subsequent pregnancies.
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Affiliation(s)
- Carsten Hagenbeck
- Klinik für Frauenheilkunde und Geburtshilfe, Universität Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, Deutschland
| | - Ulrich Pecks
- Klinik für Gynäkologie und Geburtshilfe, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel, Deutschland
| | - Frank Lammert
- Klinik für Innere Medizin II, Universitätsklinikum des Saarlandes, Universität des Saarlandes, Homburg, Deutschland
| | - Matthias C. Hütten
- Neonatologie, Maastricht Universitair Medisch Centrum+, Maastricht, Niederlande
| | - Felix Borgmeier
- Klinik für Frauenheilkunde und Geburtshilfe, Universität Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, Deutschland
| | - Tanja Fehm
- Klinik für Frauenheilkunde und Geburtshilfe, Universität Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, Deutschland
| | | | - Holger Maul
- Frauenklinik, Asklepios Kliniken Barmbek, Wandsbek und Nord-Heidberg, Hamburg, Deutschland
| | - Sven Kehl
- Frauenklinik, Universitätsklinikum Erlangen, Erlangen, Deutschland
| | - Amr Hamza
- Kantonsspital Baden, Baden, Schweiz
- Klinikum für Frauenheilkunde, Geburtshilfe und Reproduktionsmedizin, Universität des Saarlandes, Homburg, Deutschland
| | - Verena Keitel
- Klinik für Gastroenterologie, Hepatologie und Infektiologie, Universität Düsseldorf, Düsseldorf, Deutschland
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12
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Yule CS, Holcomb DS, Kraus AC, Brown CEL, McIntire DD, Nelson DB. Cholestasis: A Prospective Study of Perinatal Outcomes and Time to Symptom Improvement. Am J Perinatol 2021; 38:414-420. [PMID: 32971564 DOI: 10.1055/s-0040-1717076] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OBJECTIVE Although intrahepatic cholestasis of pregnancy (ICP) remains poorly understood, there are several perinatal complications associated with this condition. This study aimed to examine perinatal outcomes of women with ICP, evaluate outcomes according to severity of disease, and monitor time to symptom improvement following diagnosis. STUDY DESIGN It involves a prospective, observational study of women with ICP at a single institution. Women with new-onset pruritus without rash were referred to a high-risk obstetrics clinic and evaluated with fasting total bile acids (TBA). Laboratory-confirmed ICP was defined as fasting TBA ≥10 µmol/L. Following diagnosis, a standardized protocol was utilized, including treatment with ursodeoxycholic acid (UDCA). Perinatal outcomes were compared amongst those with and without ICP, and to the general population. Women with ICP were further analyzed based on maximum TBA: 10 to 39, 40 to 99, and ≥100 µmol/L. A Kaplan-Meier survival curve was used to analyze time to symptom improvement. RESULTS A total of 404 patients were evaluated and 212 (52%) were diagnosed with ICP. The mean gestational age at diagnosis was 34.1 ± 3.3 weeks. When comparing those with ICP to those not confirmed, and to the general population, there were no differences in age, parity, mode of delivery, preeclampsia, or stillbirth (p > 0.05). Preterm birth was significantly associated with ICP (p < 0.01). This relationship was significant across increasing severity of TBA (p < 0.01) and persisted when examining rates of spontaneous preterm birth (p < 0.01). All women with fasting TBA ≥40 µmol/L delivered preterm due to premature rupture of membranes or spontaneous labor. Time to symptom improvement after diagnosis was over 2 weeks on average; however, this time increased with worsening severity of disease. CONCLUSION Despite treatment with UDCA, women with ICP are at increased risk for spontaneous preterm birth, and this risk significantly increased with severity of disease. Although not significant, a trend exists between increasing time to symptom improvement and worsening severity of disease. KEY POINTS · Preterm birth is significantly increased in patients diagnosed with intrahepatic cholestasis of pregnancy.. · The risk of preterm birth in women with ICP increases across increasing strata of disease.. · Following initiation of treatment in patients with ICP, symptom improvement takes more than 2 weeks..
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Affiliation(s)
- Casey S Yule
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Denisse S Holcomb
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Alexandria C Kraus
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Charles E L Brown
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Donald D McIntire
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - David B Nelson
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas
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Roediger R, Fleckenstein J. Intrahepatic Cholestasis of Pregnancy: Natural History and Current Management. Semin Liver Dis 2021; 41:103-108. [PMID: 33764488 DOI: 10.1055/s-0040-1722264] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Intrahepatic cholestasis of pregnancy (ICP) is a common disorder in the second half of pregnancy characterized by pruritus and elevated serum bile acids (BAs) with spontaneous resolution after delivery. ICP carries a risk of adverse effects on the fetus which correlates with the degree of BA elevation. ICP occurs in genetically susceptible women as the reproductive hormones increase during pregnancy. Ursodeoxycholic acid is still considered the first-line treatment for ICP though it is of unproven benefit in preventing adverse effects on the fetus. Fetal complications, such as stillbirth, increase with gestational age, so preterm delivery is generally performed in cases of severe ICP, defined as BA levels above 40 μmol/L. ICP may recur in future pregnancies and is associated with an increased risk for future hepatobiliary, immune mediated, and cardiovascular diseases. Children born of mothers with ICP have normal development but may have a risk for subsequent metabolic disease.
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Affiliation(s)
- Rebecca Roediger
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri
| | - Jaquelyn Fleckenstein
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri
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Cifci S, Irak K, Bayram M, Ekmen N, Kazezoglu C, Acar Z, Sasani H. Relationship between pruritus and autotaxin in intrahepatic cholestasis of pregnancy. GASTROENTEROLOGIA Y HEPATOLOGIA 2020; 44:96-102. [PMID: 33010963 DOI: 10.1016/j.gastrohep.2020.08.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Revised: 08/10/2020] [Accepted: 08/16/2020] [Indexed: 12/20/2022]
Abstract
OBJECTIVE Intrahepatic cholestasis of pregnancy is a temporary, pregnancy-specific disease that resolves with delivery, characterized by itching (pruritus), as well as high transaminase and serum bile acid levels in the third trimester of pregnancy. Due to the effects of Autotaxin on the physiology of pregnancy, we aimed to investigate Autotaxin activity in patients with intrahepatic cholestasis of pregnancy. PATIENTS AND METHODS Sixty-nine patients diagnosed with intrahepatic cholestasis of pregnancy and 20 healthy pregnant women were enrolled in the study. Fasting serum bile acid, pruritus intensity, serum parameters, gestational week of the patients at the time of diagnosis were recorded, and birth week and birth weight were monitored. Autotaxin serum level was measured enzymatically. RESULTS The mean serum bile acid level (n=69; 38.74±35.92μmol/L) in patients with intrahepatic cholestasis of pregnancy (n=69) was detected to be higher than healthy pregnant women (n=20; 5.05±1.88μmol/L) (p<0.001). Weak correlation was detected between serum bile acid level and itch intensity (p=0.014, r=0.295), while no relation was detected between Autotaxin and itch intensity (p=0.446, r=0.09). Although mean Autotaxin (intrahepatic cholestasis of pregnancy: 678.10±424.42pg/mL, control: 535.16±256.47pg/mL) levels were high in patients with intrahepatic cholestasis of pregnancy, it was not statistically significant (p=0.157). CONCLUSION In our study, we observed that the serum Autotaxin level did not make a significant difference in patients with intrahepatic cholestasis of pregnancy compared to healthy pregnant women. These findings suggest that larger clinical studies are required to reveal the physio-pathological effects of Autotaxin on pregnancy.
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Affiliation(s)
- Sami Cifci
- Basaksehir Cam and Sakura City Hospital, Department of Gastroenterology, Istanbul, Turkey
| | - Kader Irak
- SBU Istanbul Kanuni Sultan Süleyman Training and Research Hospital, Department of Gastroenterology, Istanbul, Turkey
| | - Mehmet Bayram
- SBU Istanbul Kanuni Sultan Süleyman Training and Research Hospital, Department of Gastroenterology, Istanbul, Turkey
| | - Nergiz Ekmen
- Gazi University Medical Faculty, Department of Gastroenterology, Ankara, Turkey.
| | - Cemal Kazezoglu
- SBU Istanbul Kanuni Sultan Süleyman Training and Research Hospital, Department of Biochemistry, Istanbul, Turkey
| | - Zuat Acar
- SBU Sarıyer Hamidiye Etfal Training and Research Hospital, Department of Perinatology, Istanbul, Turkey
| | - Hadi Sasani
- Tekirdag Namık Kemal University, Faculty of Medicine, Department of Radiology, Tekirdag, Turkey
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Sanjel B, Shim WS. Recent advances in understanding the molecular mechanisms of cholestatic pruritus: A review. Biochim Biophys Acta Mol Basis Dis 2020; 1866:165958. [PMID: 32896605 DOI: 10.1016/j.bbadis.2020.165958] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 08/21/2020] [Accepted: 09/01/2020] [Indexed: 02/06/2023]
Abstract
Cholestasis, a condition characterized by an abnormal decrease in bile flow, is accompanied by various symptoms such as pruritus. Although cholestatic pruritus is a prominent condition, its precise mechanisms have largely been elusive. Recently, advancements have been made for understanding the etiology and pathogenesis of cholestatic pruritus. The current review therefore focuses on summarizing the overall progress made in the elucidation of its molecular mechanisms. We have reviewed the available animal models on cholestasis to compare the differences between them, characterized potential pruritogens involved in cholestatic pruritus, and have summarized the receptor and ion channels implicated in the condition. Finally, we have discussed the available treatment options for alleviation of cholestatic pruritus. As our understanding of the mechanisms of cholestatic pruritus deepens, novel strategies to cure this condition are awaited.
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Affiliation(s)
- Babina Sanjel
- College of Pharmacy, Gachon University, Hambakmoero 191, Yeonsu-gu, Incheon 21936, Republic of Korea; Gachon Institute of Pharmaceutical Sciences, Hambakmoero 191, Yeonsu-gu, Incheon 21936, Republic of Korea
| | - Won-Sik Shim
- College of Pharmacy, Gachon University, Hambakmoero 191, Yeonsu-gu, Incheon 21936, Republic of Korea; Gachon Institute of Pharmaceutical Sciences, Hambakmoero 191, Yeonsu-gu, Incheon 21936, Republic of Korea.
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Walker KF, Chappell LC, Hague WM, Middleton P, Thornton JG. Pharmacological interventions for treating intrahepatic cholestasis of pregnancy. Cochrane Database Syst Rev 2020; 7:CD000493. [PMID: 32716060 PMCID: PMC7389072 DOI: 10.1002/14651858.cd000493.pub3] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
BACKGROUND Intrahepatic cholestasis of pregnancy (ICP) is a liver disorder that can develop in pregnancy. It occurs when there is a build-up of bile acids in the maternal blood. It has been linked to adverse maternal and fetal/neonatal outcomes. As the pathophysiology is poorly understood, therapies have been largely empiric. As ICP is an uncommon condition (incidence less than 2% a year), many trials have been small. Synthesis, including recent larger trials, will provide more evidence to guide clinical practice. This review is an update of a review first published in 2001 and last updated in 2013. OBJECTIVES To assess the effects of pharmacological interventions to treat women with intrahepatic cholestasis of pregnancy, on maternal, fetal and neonatal outcomes. SEARCH METHODS For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (13 December 2019), and reference lists of retrieved studies. SELECTION CRITERIA Randomised or quasi-randomised controlled trials, including cluster-randomised trials and trials published in abstract form only, that compared any drug with placebo or no treatment, or two drug intervention strategies, for women with a clinical diagnosis of intrahepatic cholestasis of pregnancy. DATA COLLECTION AND ANALYSIS The review authors independently assessed trials for eligibility and risks of bias. We independently extracted data and checked these for accuracy. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS We included 26 trials involving 2007 women. They were mostly at unclear to high risk of bias. They assessed nine different pharmacological interventions, resulting in 14 different comparisons. We judged two placebo-controlled trials of ursodeoxycholic acid (UDCA) in 715 women to be at low risk of bias. The ten different pharmacological interventions were: agents believed to detoxify bile acids (UCDA) and S-adenosylmethionine (SAMe); agents used to bind bile acids in the intestine (activated charcoal, guar gum, cholestyramine); Chinese herbal medicines (yinchenghao decoction (YCHD), salvia, Yiganling and Danxioling pill (DXLP)), and agents aimed to reduce bile acid production (dexamethasone) Compared with placebo, UDCA probably results in a small improvement in pruritus score measured on a 100 mm visual analogue scale (VAS) (mean difference (MD) -7.64 points, 95% confidence interval (CI) -9.69 to -5.60 points; 2 trials, 715 women; GRADE moderate certainty), where a score of zero indicates no itch and a score of 100 indicates severe itching. The evidence for fetal distress and stillbirth were uncertain, due to serious limitations in study design and imprecision (risk ratio (RR) 0.70, 95% CI 0.35 to 1.40; 6 trials, 944 women; RR 0.33, 95% CI 0.08 to 1.37; 6 trials, 955 women; GRADE very low certainty). We found very few differences for the other comparisons included in this review. There is insufficient evidence to indicate if SAMe, guar gum, activated charcoal, dexamethasone, cholestyramine, Salvia, Yinchenghao decoction, Danxioling and Yiganling, or Yiganling alone or in combination are effective in treating women with intrahepatic cholestasis of pregnancy. AUTHORS' CONCLUSIONS When compared with placebo, UDCA administered to women with ICP probably shows a reduction in pruritus. However the size of the effect is small and for most pregnant women and clinicians, the reduction may fall below the minimum clinically worthwhile effect. The evidence was unclear for other adverse fetal outcomes, due to very low-certainty evidence. There is insufficient evidence to indicate that SAMe, guar gum, activated charcoal, dexamethasone, cholestyramine, YCHD, DXLP, Salvia, Yiganling alone or in combination are effective in treating women with cholestasis of pregnancy. There are no trials of the efficacy of topical emollients. Further high-quality trials of other interventions are needed in order to identify effective treatments for maternal itching and preventing adverse perinatal outcomes. It would also be helpful to identify those women who are mostly likely to respond to UDCA (for example, whether bile acid concentrations affect how women with ICP respond to treatment with UDCA).
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Affiliation(s)
- Kate F Walker
- Division of Child Health, Obstetrics and Gynaecology, School of Medicine, University of Nottingham, Nottingham, UK
| | - Lucy C Chappell
- Department of Women and Children's Health, King's College London, London, UK
| | - William M Hague
- Women's and Children's Hospital, North Adelaide, Australia
- Robinson Research Institute, The University of Adelaide, North Adelaide, Australia
| | - Philippa Middleton
- Healthy Mothers, Babies and Children, South Australian Health and Medical Research Institute, Adelaide, Australia
| | - Jim G Thornton
- Division of Child Health, Obstetrics and Gynaecology, School of Medicine, University of Nottingham, Nottingham, UK
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Signalling by lysophosphatidate and its health implications. Essays Biochem 2020; 64:547-563. [DOI: 10.1042/ebc20190088] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Revised: 05/11/2020] [Accepted: 05/12/2020] [Indexed: 02/06/2023]
Abstract
AbstractExtracellular lysophosphatidate (LPA) signalling is regulated by the balance of LPA formation by autotaxin (ATX) versus LPA degradation by lipid phosphate phosphatases (LPP) and by the relative expressions of six G-protein-coupled LPA receptors. These receptors increase cell proliferation, migration, survival and angiogenesis. Acute inflammation produced by tissue damage stimulates ATX production and LPA signalling as a component of wound healing. If inflammation does not resolve, LPA signalling becomes maladaptive in conditions including arthritis, neurologic pain, obesity and cancers. Furthermore, LPA signalling through LPA1 receptors promotes fibrosis in skin, liver, kidneys and lungs. LPA also promotes the spread of tumours to other organs (metastasis) and the pro-survival properties of LPA explain why LPA counteracts the effects of chemotherapeutic agents and radiotherapy. ATX is secreted in response to radiation-induced DNA damage during cancer treatments and this together with increased LPA1 receptor expression leads to radiation-induced fibrosis. The anti-inflammatory agent, dexamethasone, decreases levels of inflammatory cytokines/chemokines. This is linked to a coordinated decrease in the production of ATX and LPA1/2 receptors and increased LPA degradation through LPP1. These effects explain why dexamethasone attenuates radiation-induced fibrosis. Increased LPA signalling is also associated with cardiovascular disease including atherosclerosis and deranged LPA signalling is associated with pregnancy complications including preeclampsia and intrahepatic cholestasis of pregnancy. LPA contributes to chronic inflammation because it stimulates the secretion of inflammatory cytokines/chemokines, which increase further ATX production and LPA signalling. Attenuating maladaptive LPA signalling provides a novel means of treating inflammatory diseases that underlie so many important medical conditions.
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Abstract
Abstract
Purpose of Review
Chronic pruritus represents a burdensome symptom in cholestatic liver disease. This review recommends a stepwise therapeutic approach, alongside with providing information on epidemiology, pathophysiology, and novel drug targets.
Recent Findings
Current epidemiological data emphasize chronic itch as a major symptom in immune-mediated liver diseases such as primary biliary cholangitis affecting up to 70% of patients with a significant number suffering from long-lasting and severe pruritus. κ-opioid receptor (KOR) agonists, PPAR agonists, and ileal bile acid transporter (IBAT) inhibitors are currently investigated for their anti-pruritic efficacy in clinical trials. Future therapies may target the autotaxin-lysophosphatidic acid-axis or the Mas-related GPCR MRGPRX4.
Summary
Cholestatic pruritus still remains a challenging symptom for patients and physicians. Using a stepwise approach including cholestyramine, rifampicin, bezafibrate, naltrexone, and sertraline, pruritus is often adequately manageable. KOR agonists and IBAT inhibitors are currently the most promising anti-pruritic drugs for cholestatic pruritus in development.
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Reply to: "UDCA therapy in intrahepatic cholestasis of pregnancy?". J Hepatol 2020; 72:587-588. [PMID: 31892410 DOI: 10.1016/j.jhep.2019.11.018] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Accepted: 11/25/2019] [Indexed: 12/04/2022]
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Kremer AE. What are new treatment concepts in systemic itch? Exp Dermatol 2019; 28:1485-1492. [DOI: 10.1111/exd.14024] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2019] [Revised: 08/02/2019] [Accepted: 08/23/2019] [Indexed: 12/20/2022]
Affiliation(s)
- Andreas E. Kremer
- Department of Medicine 1 & Translational Research Center Friedrich‐Alexander‐University Erlangen‐Nürnberg Erlangen Germany
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Abstract
PURPOSE OF REVIEW Pruritus is a common extrahepatic symptom in various liver disorders, in particularly those with cholestatic features. This review summarizes epidemiology, pathophysiology, evidence-based therapeutic recommendations and currently investigated drugs for pruritus in hepatobiliary disorders. RECENT FINDINGS Recent epidemiological data suggest pruritus as a common and relevant symptom in immune-mediated liver diseases, i.e., primary biliary cholangitis (PBC) with over 70% affected patients, up to 56% suffering from chronic pruritus. The better pathophysiological understanding of hepatic pruritus has led to the identification of novel therapeutic targets, addressed in drug trials using KOR agonists, PPAR agonists, and ileal bile acid transporter inhibitors. Hepatic itch remains among the most agonizing symptoms for affected patients and a clinical challenge for physicians. Therapeutic recommendations include a guideline-based stepwise approach starting with cholestyramine, followed by rifampicin, naltrexone, and sertraline. Bezafibrate and ileal bile acid transporter inhibitors represent promising future anti-pruritic treatment options.
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Affiliation(s)
- Miriam M Düll
- Department of Medicine 1, Gastroenterology, Hepatology, Pneumology and Endocrinology, Friedrich-Alexander-University Erlangen-Nürnberg, Ulmenweg 18, D-91054, Erlangen, Germany
| | - Andreas E Kremer
- Department of Medicine 1, Gastroenterology, Hepatology, Pneumology and Endocrinology, Friedrich-Alexander-University Erlangen-Nürnberg, Ulmenweg 18, D-91054, Erlangen, Germany.
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Pleotropic Roles of Autotaxin in the Nervous System Present Opportunities for the Development of Novel Therapeutics for Neurological Diseases. Mol Neurobiol 2019; 57:372-392. [PMID: 31364025 DOI: 10.1007/s12035-019-01719-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Accepted: 07/23/2019] [Indexed: 12/23/2022]
Abstract
Autotaxin (ATX) is a soluble extracellular enzyme that is abundant in mammalian plasma and cerebrospinal fluid (CSF). It has two known enzymatic activities, acting as both a phosphodiesterase and a phospholipase. The majority of its biological effects have been associated with its ability to liberate lysophosphatidic acid (LPA) from its substrate, lysophosphatidylcholine (LPC). LPA has diverse pleiotropic effects in the central nervous system (CNS) and other tissues via the activation of a family of six cognate G protein-coupled receptors. These LPA receptors (LPARs) are expressed in some combination in all known cell types in the CNS where they mediate such fundamental cellular processes as proliferation, differentiation, migration, chronic inflammation, and cytoskeletal organization. As a result, dysregulation of LPA content may contribute to many CNS and PNS disorders such as chronic inflammatory or neuropathic pain, glioblastoma multiforme (GBM), hemorrhagic hydrocephalus, schizophrenia, multiple sclerosis, Alzheimer's disease, metabolic syndrome-induced brain damage, traumatic brain injury, hepatic encephalopathy-induced cerebral edema, macular edema, major depressive disorder, stress-induced psychiatric disorder, alcohol-induced brain damage, HIV-induced brain injury, pruritus, and peripheral nerve injury. ATX activity is now known to be the primary biological source of this bioactive signaling lipid, and as such, represents a potentially high-value drug target. There is currently one ATX inhibitor entering phase III clinical trials, with several additional preclinical compounds under investigation. This review discusses the physiological and pathological significance of the ATX-LPA-LPA receptor signaling axis and summarizes the evidence for targeting this pathway for the treatment of CNS diseases.
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Manzotti C, Casazza G, Stimac T, Nikolova D, Gluud C. Total serum bile acids or serum bile acid profile, or both, for the diagnosis of intrahepatic cholestasis of pregnancy. Cochrane Database Syst Rev 2019; 7:CD012546. [PMID: 31283001 PMCID: PMC6613619 DOI: 10.1002/14651858.cd012546.pub2] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Intrahepatic cholestasis of pregnancy is a pregnancy-specific liver disorder, possibly associated with an increased risk of severe fetal adverse events. Total serum bile acids (TSBA) concentration, alone or in combination with serum aminotransferases, have been the most often used biomarkers for the diagnosis of intrahepatic cholestasis of pregnancy in clinical practice. Serum bile acid profile, composed of primary or secondary, conjugated or non-conjugated bile acids, may provide more specific disease information. OBJECTIVES To assess and compare, independently or in combination, the diagnostic accuracy of total serum bile acids or serum bile acids profile, or both, for the diagnosis of intrahepatic cholestasis of pregnancy in pregnant women, presenting with pruritus. To define the optimal cut-off values for components of serum bile acid profile; to investigate possible sources of heterogeneity. SEARCH METHODS We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Hepato-Biliary Group Diagnostic Test Accuracy Studies Register, the Cochrane Library, MEDLINE Ovid, Embase Ovid, Science Citation Index Expanded, Conference Proceedings Citation Index - Science, BIOSIS, CINAHL, two Chinese databases (CKNI, VIP), Latin American and Caribbean Health Sciences Literature (LILACS), Scientific Electronic Library Online (SciELO), Evidence Search: Health and Social Care by the National Institute for Health and Care Excellence (NICE), the World Health Organization (WHO) Reproductive Health Library (RHL), and the Turning Research into Practice database (TRIP). The most recent date of search was 6 May 2019. We identified additional references by handsearching the references of articles, meta-analyses, and evidence-based guidelines retrieved from the computerised databases, on-line trial registries, and grey literature through OpenSIGLE, National Technical Information Service (NTIS), ProQuest Dissertations & Thesis Database, and Index to Theses in Great Britain and Ireland. SELECTION CRITERIA Prospective or retrospective diagnostic case-control or cross-sectional studies, irrespective of publication date, format, and language, which evaluated the diagnostic accuracy of total serum bile acids (TSBA) or components of serum bile acid profile for the diagnosis of intrahepatic cholestasis of pregnancy in pregnant women of any age or ethnicity, in any clinical setting, symptomatic for pruritus. DATA COLLECTION AND ANALYSIS We selected studies by reading titles, abstracts, or full texts, and assessing their fulfilment of our inclusion criteria. We emailed primary authors to request missing data or individual participant data. Having extracted data from each included study, we built the two-by-two tables for each primary study and for all the index tests considered. We estimated sensitivity and specificity with their 95% confidence intervals (CI). We presented data in coupled forest plots, showing sensitivities and specificities of each study, and we plotted the studies in the Receiver Operating Characteristic (ROC) space. We performed meta-analyses adopting the hierarchical summary ROC model (HSROC) or the bivariate model to meta-analyse the data. We made indirect comparisons of the considered index tests by adding the index tests as covariates to the bivariate or HSROC models. We performed heterogeneity analysis and sensitivity analysis on studies assessing TSBA accuracy. We used Review Manager 5 (RevMan 5) and SAS statistical software, release 9.4 (SAS Institute Inc., Cary, NC, USA), to perform all statistical analyses. We used QUADAS-2 domains to assess the risk of bias of the included studies. MAIN RESULTS Our search yielded 5073 references, but at the end of our selection process, only 16 studies fulfilled the review inclusion criteria. Nine of these provided individual participant data. We analysed only data concerning TSBA, cholic acid (CA), glycocholic acid (GCA), chenodeoxycholic acid (CDCA), and CA/CDCA because the remaining planned index tests were assessed in few studies. Only one study had low risk of bias in all four QUADAS-2 domains. The most biased domains were the patient sampling and the reference standard domains. When considering all studies with a cut-off of 10 μmol/L, TSBA overall sensitivity ranged from 0.72 to 0.98 and specificity ranged from 0.81 to 0.97. After a sensitivity analysis excluding case-control studies, TSBA sensitivity ranged from 0.48 to 0.66 and specificity from 0.52 to 0.99. After a sensitivity analysis excluding studies in which TSBA was part of the reference standard, TSBA sensitivity ranged from 0.49 to 0.65 and specificity from 0.53 to 0.99. We found the estimates of the overall accuracy for some serum bile acid components (CA, GCA, CDCA, and CA/CDCA) to be imprecise, with the CI for sensitivity and specificity very wide or impossible to calculate. Indirect comparisons between serum bile acid profile components and TSBA were not statistically significant. None of the heterogeneity analysis performed was statistically significant, except for the timing of assessment of TSBA (onset of symptoms, peak value among multiple assessments, delivery) but without clinically relevant results. We could not analyse the diagnostic accuracy of combinations of index tests because none of the included studies carried them out, and because of the small number of included studies. AUTHORS' CONCLUSIONS The overall high risk of bias, the existing concern regarding applicability of the results in clinical practice, and the great heterogeneity of the results in the included studies prevents us from making recommendations and reaching definitive conclusions at the present time. Thus, we do not find any compelling evidence to recommend or refute the routine use of any of these tests in clinical practice. So far, the diagnostic accuracy of TSBA for intrahepatic cholestasis of pregnancy might have been overestimated. There were too few studies to permit a precise estimate of the accuracy of serum bile acid profile components. Further primary clinical research is mandatory. We need both further phase II and phase III diagnostic studies.
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Affiliation(s)
- Cristina Manzotti
- Fondazione IRCCS Ca' Granda ‐ Ospedale Maggiore Policlinico, Università degli Studi di MilanoObstetrics and Gynecology DepartmentVia Commenda 12 ‐ Clinica Mangiagalli, piano terraMilanMilanItaly20122
- Department 7812, Rigshospitalet, Copenhagen University HospitalCochrane Hepato‐Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention ResearchCopenhagenDenmark
- Fondazione IRCCS Ca' Granda ‐ Ospedale Maggiore Policlinico, Università degli Studi di MilanoGastro‐Intestinal UnitVia Commenda 12 ‐ Clinica Mangiagalli, 1° piano, scala AMilanMilanItaly20122
| | - Giovanni Casazza
- Università degli Studi di MilanoDipartimento di Scienze Biomediche e Cliniche "L. Sacco"via GB Grassi 74MilanItaly20157
| | - Tea Stimac
- Clinical Hospital Centre RijekaObstetrics and GynecologyCambierieva 17RijekaCroatia51000
| | - Dimitrinka Nikolova
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalCochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
| | - Christian Gluud
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalCochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
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Dhillon AK, Kremer AE, Kummen M, Boberg KM, Elferink RPO, Karlsen TH, Beuers U, Vesterhus M, Hov JR. Autotaxin activity predicts transplant-free survival in primary sclerosing cholangitis. Sci Rep 2019; 9:8450. [PMID: 31186435 PMCID: PMC6559994 DOI: 10.1038/s41598-019-44762-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Accepted: 05/14/2019] [Indexed: 02/07/2023] Open
Abstract
Autotaxin has been associated with liver disease severity and transplant-free survival. This study aimed to validate autotaxin as a biomarker in two cohorts of Norwegian large-duct PSC patients, one discovery panel (n = 165) and one validation panel (n = 87). Serum activity of autotaxin was measured in diluted sera by a fluorometric enzymatic assay. Patients reaching an end-point, liver transplantation or death, (discovery panel: n = 118 [71.5%]; validation panel: n = 35 [40.2%]), showed higher autotaxin activity compared with the other patients, P < 0.001 and P = 0.004, respectively. Kaplan-Meier survival analyses showed a strong association between increasing autotaxin activity and shorter liver transplant-free survival (discovery panel: P < 0.001, validation panel: P = 0.001). There was no relationship between autotaxin activity and the presence of inflammatory bowel disease or occurrence of hepatobiliary malignancy. In a multivariable analysis, high autotaxin activity was associated with an increased risk of liver transplantation or death (hazard ratio 2.03 (95% confidence interval 1.21–3.40), P < 0.01), independent from Mayo risk score, an in-house enhanced liver fibrosis score and interleukin-8 in serum. In conclusion, increased serum autotaxin activity is associated with reduced liver transplant-free survival independent from Mayo risk score and markers of inflammation and fibrosis.
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Affiliation(s)
- Amandeep K Dhillon
- Norwegian PSC Research Center, Department of transplantation medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Research Institute of Internal Medicine, Division of Surgery, Inflammatory diseases and Transplantation, Oslo University hospital Rikshospitalet, Oslo, Norway
| | - Andreas E Kremer
- Department of Medicine 1, Friedrich-Alexander-University Erlangen-Nürnberg-Erlangen, Erlangen, Germany
| | - Martin Kummen
- Norwegian PSC Research Center, Department of transplantation medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Research Institute of Internal Medicine, Division of Surgery, Inflammatory diseases and Transplantation, Oslo University hospital Rikshospitalet, Oslo, Norway
| | - Kirsten M Boberg
- Norwegian PSC Research Center, Department of transplantation medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Ronald P Oude Elferink
- Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - Tom H Karlsen
- Norwegian PSC Research Center, Department of transplantation medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Research Institute of Internal Medicine, Division of Surgery, Inflammatory diseases and Transplantation, Oslo University hospital Rikshospitalet, Oslo, Norway.,Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Ulrich Beuers
- Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - Mette Vesterhus
- Norwegian PSC Research Center, Department of transplantation medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Department of Medicine, Haraldsplass Deaconess Hospital, Bergen, Norway.,Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Johannes R Hov
- Norwegian PSC Research Center, Department of transplantation medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway. .,Institute of Clinical Medicine, University of Oslo, Oslo, Norway. .,Research Institute of Internal Medicine, Division of Surgery, Inflammatory diseases and Transplantation, Oslo University hospital Rikshospitalet, Oslo, Norway. .,Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.
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25
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Morton A, Laurie J. The biochemical diagnosis of intrahepatic cholestasis of pregnancy. Obstet Med 2019; 12:76-78. [PMID: 31217811 PMCID: PMC6560846 DOI: 10.1177/1753495x18795979] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Accepted: 07/09/2018] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND Bile acid levels and liver function tests may be normal at presentation in women with intrahepatic cholestasis of pregnancy. The biochemical results of patients presenting with pruritus typical for intrahepatic cholestasis of pregnancy were reviewed. METHODS A retrospective audit of women coded as having intrahepatic cholestasis of pregnancy over a three-year period. RESULTS One hundred and ninety-three women (1.1% of the obstetric population) presented with pruritus typical of intrahepatic cholestasis of pregnancy. Forty (21%) of these women had normal biochemistry at presentation, half subsequently developing abnormal results. Women with a history of allergic reactions were more likely to develop intrahepatic cholestasis of pregnancy. CONCLUSIONS Normal biochemistry should not preclude a trial of ursodeoxycholic acid in women with distressing pruritus typical for intrahepatic cholestasis of pregnancy. Biochemical tests which are more sensitive and specific in the diagnosis of intrahepatic cholestasis of pregnancy would be valuable. Investigation of other populations with intrahepatic cholestasis of pregnancy regarding a possible association with atopy/allergy would be interesting.
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Affiliation(s)
- Adam Morton
- Mater Health and University of QLD, South Brisbane, Australia
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Chao S, Xiaojun L, Haizhen W, Ludi F, Shaozhen L, Zhiwen S, Weiliang H, Chunhong J, Ying W, Fan W, Yunfei G. Lithocholic acid activates mTOR signaling inducing endoplasmic reticulum stress in placenta during intrahepatic cholestasis of pregnancy. Life Sci 2018; 218:300-307. [PMID: 30605648 DOI: 10.1016/j.lfs.2018.12.050] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Revised: 12/12/2018] [Accepted: 12/27/2018] [Indexed: 12/23/2022]
Abstract
AIMS Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific disorder, which increases risks of adverse fetal outcomes. However, the pathophysiology is not fully understood. Here, we explored the roles of mTOR signaling and ER stress in placenta during ICP. MATERIALS AND METHODS Placental tissues were collected from normal and ICP pregnancies. mTOR signaling and endoplasmic reticulum stress were detected by immunohistochemistry in the placenta. The human placenta trophoblast cell line HTR-8/SVneo was used in vitro experiment. KEY FINDINGS ICP placenta displayed histological abnormalities with fewer trophoblasts. Moreover, the expression of Bip and the phosphorylation of pS6(S235/236) or pAkt(S473) were higher comparing with normal placenta. In in vitro studies, the bile acids specifically to lithocholic acid rather than taurocholic acid or ursodeoxycholic acid, drastically increased the phosphorylation of pS6K1(T389), pS6(S235/236), or pAkt(S473), whereas the mTOR inhibitor can prohibit the upregulation. Similarly, the expressions of IRE1α and BiP increased sharply under lithocholic acid (20 μM) administration, while the same inhibitor can also decrease the expression. Additionally, transmission electron microscopy showed enlarged endoplasmic reticulum lumen under the lithocholic acid treatment. Furthermore, the cell viability reduced sharply under treatment with different dose of lithocholic acid. The mTOR inhibitor can reverse the decrease of cell viability to some extent. SIGNIFICANCE Bile acid can activate mTOR signaling which resulted in endoplasmic reticulum stress, leading to trophocyte viability decrease. mTOR pathway activation may be associated with the pathophysiology of ICP.
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Affiliation(s)
- Sheng Chao
- Division of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Lin Xiaojun
- Division of Pediatrics, The Third Affiliated Hospital of Guangzhou medical University, Guangzhou 510150, China
| | - Wang Haizhen
- Division of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Fu Ludi
- Laboratory Animal Center, Guangzhou university of Chinese Medicine, Guangzhou 510006, China
| | - Liang Shaozhen
- Division of Pediatrics, The Third Affiliated Hospital of Guangzhou medical University, Guangzhou 510150, China
| | - Su Zhiwen
- Division of Pediatrics, The Third Affiliated Hospital of Guangzhou medical University, Guangzhou 510150, China
| | - Huang Weiliang
- Division of Pediatrics, The Third Affiliated Hospital of Guangzhou medical University, Guangzhou 510150, China
| | - Jia Chunhong
- Division of Pediatrics, The Third Affiliated Hospital of Guangzhou medical University, Guangzhou 510150, China
| | - Wang Ying
- Department of Pharmacy, The Third Affiliated Hospital of Guangzhou medical University, Guangzhou 510150, China
| | - Wu Fan
- Division of Pediatrics, The Third Affiliated Hospital of Guangzhou medical University, Guangzhou 510150, China.
| | - Gao Yunfei
- Division of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
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27
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Ovadia C, Lövgren-Sandblom A, Edwards LA, Langedijk J, Geenes V, Chambers J, Cheng F, Clarke L, Begum S, Noori M, Pusey C, Padmagirison R, Agarwal S, Peerless J, Cheesman K, Heneghan M, Oude Elferink R, Patel VC, Marschall HU, Williamson C. Therapeutic plasma exchange as a novel treatment for severe intrahepatic cholestasis of pregnancy: Case series and mechanism of action. J Clin Apher 2018; 33:638-644. [PMID: 30321466 DOI: 10.1002/jca.21654] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Revised: 07/19/2018] [Accepted: 07/30/2018] [Indexed: 12/27/2022]
Abstract
INTRODUCTION Intrahepatic cholestasis of pregnancy is characterised by pruritus and elevated serum bile acids. The pruritus can be severe, and pharmacological options achieve inconsistent symptomatic improvement. Raised bile acids are linearly associated with adverse fetal outcomes, with existing management of limited benefit. We hypothesised that therapeutic plasma exchange removes pruritogens and lowers total bile acid concentrations, and improves symptoms and biochemical abnormalities in severe cases that have not responded to other treatments. METHODS Four women with severe pruritus and hypercholanemia were managed with therapeutic plasma exchange. Serial blood biochemistry and visual analogue scores of itch severity were obtained. Blood and waste plasma samples were collected before and after exchange; individual bile acids and sulfated progesterone metabolites were measured with HPLC-MS, autotaxin activity and cytokine profiles with enzymatic methods. Results were analysed using segmental linear regression to describe longitudinal trends, and ratio t tests. RESULTS Total bile acids and visual analogue itch scores demonstrated trends to transiently improve following plasma exchange, with temporary symptomatic benefit reported. Individual bile acids (excluding the drug ursodeoxycholic acid), and the sulfated metabolites of progesterone reduced following exchange (P = .03 and P = .04, respectively), whilst analysis of waste plasma demonstrated removal of autotaxin and cytokines. CONCLUSIONS Therapeutic plasma exchange can lower potentially harmful bile acids and improve itch, likely secondary to the demonstrated removal of pruritogens. However, the limited current experience and potential complications, along with minimal sustained symptomatic benefit, restrict its current use to women with the most severe disease for whom other treatment options have been exhausted.
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Affiliation(s)
- Caroline Ovadia
- Department of Women and Children's Health, King's College London, London, United Kingdom
| | - Anita Lövgren-Sandblom
- Department of Clinical Chemistry, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Lindsey A Edwards
- Division of Transplantation, Immunology and Mucosal Biology, King's College London, London, United Kingdom
| | - Jacqueline Langedijk
- Academic Medical Center, Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands
| | - Victoria Geenes
- Department of Women and Children's Health, King's College London, London, United Kingdom
| | - Jenny Chambers
- Department of Women and Children's Health, King's College London, London, United Kingdom.,Women's Health Research Centre, Imperial College London, London, United Kingdom
| | - Floria Cheng
- Women's Health Research Centre, Imperial College London, London, United Kingdom
| | - Louise Clarke
- Department of Women and Children's Health, King's College London, London, United Kingdom
| | - Shahina Begum
- Department of Women and Children's Health, King's College London, London, United Kingdom
| | - Muna Noori
- Department of Obstetrics and Gynaecology, Imperial College Hospitals, London, United Kingdom
| | - Charles Pusey
- Department of Medicine, Imperial College London, London, United Kingdom
| | - Radhika Padmagirison
- Department of Obstetrics and Gynaecology, Lister Hospital, Stevenage, Hertfordshire, United Kingdom
| | - Sangita Agarwal
- Department of Rheumatology, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
| | - James Peerless
- Department of Anaesthetics, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
| | - Kate Cheesman
- Department of Anaesthetics, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
| | - Michael Heneghan
- Division of Transplantation, Immunology and Mucosal Biology, King's College London, London, United Kingdom
| | - Ronald Oude Elferink
- Academic Medical Center, Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands
| | - Vishal C Patel
- Division of Transplantation, Immunology and Mucosal Biology, King's College London, London, United Kingdom
| | - Hanns-Ulrich Marschall
- Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Catherine Williamson
- Department of Women and Children's Health, King's College London, London, United Kingdom
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28
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Yang R, Zhao Q, Hu DD, Xiao XR, Huang JF, Li F. Metabolomic analysis of cholestatic liver damage in mice. Food Chem Toxicol 2018; 120:253-260. [DOI: 10.1016/j.fct.2018.07.022] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Revised: 06/27/2018] [Accepted: 07/11/2018] [Indexed: 02/08/2023]
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Macias RIR, Matilla S, Lozano E, Estiú MC, Oude Elferink RP, Marin JJG. Role of the placenta in serum autotaxin elevation during maternal cholestasis. Am J Physiol Gastrointest Liver Physiol 2018; 315:G399-G407. [PMID: 29927323 DOI: 10.1152/ajpgi.00112.2018] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Intrahepatic cholestasis of pregnancy (ICP) is frequently accompanied by pruritus, whose etiology has been associated with an enhanced production of lysophosphatidic acid (LPA) by the combined action of phospholipase A1/A2 (PLA1/PLA2) and autotaxin (ATX). Here, we have investigated whether the placenta is involved in LPA release to maternal circulation during ICP. Serum levels of ATX and LPA (determined by ELISA) were elevated in women with ICP, and a correlation between both parameters was found. No relationship between serum levels of ATX or LPA and bile acids was found. Expression levels of ATX and PLA2 were determined by RT-qPCR and Western blot. Placenta ATX but not PLA2 was significantly upregulated in ICP, and a tendency to increase was found at the protein level. A correlation between serum ATX and placental ATX mRNA levels was found. In human placenta at term, ATX was clearly detected (by immunofluorescence) in Hofbauer cells, but only faintly in trophoblast cells. In pregnant rats, the expression of Atx and Pla2 in placenta was lower than in liver. When obstructive cholestasis was imposed by bile duct ligation from day 14 of gestation until term, placenta Atx and Pla2 expression was markedly enhanced, and overexpression was confirmed at the protein level for Pla2, whereas Atx protein was not detected. In conclusion, the placenta substantially participates in LPA production during gestation. This contribution is markedly higher during maternal cholestasis and hence, may be involved in ICP-associated pruritus. NEW & NOTEWORTHY Fetal placental macrophages and, to a lesser extent, trophoblast cells express high levels of autotaxin at term. An increased expression of mRNA and protein autotaxin, the key secretory enzyme responsible for the production of lysophosphatidic acid in serum, has been observed in placentas of women with cholestasis of pregnancy, which supports that the placenta can contribute to an increased production of this pruritogenic compound in women suffering from this liver disease.
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Affiliation(s)
- Rocio I R Macias
- Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca , Salamanca , Spain.,Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health , Madrid , Spain
| | - Sonia Matilla
- Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca , Salamanca , Spain
| | - Elisa Lozano
- Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca , Salamanca , Spain.,Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health , Madrid , Spain
| | - Maria C Estiú
- Ramón Sardá Mother's and Children's Hospital , Buenos Aires , Argentina
| | - Ronald P Oude Elferink
- Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam , Amsterdam , The Netherlands
| | - Jose J G Marin
- Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca , Salamanca , Spain.,Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health , Madrid , Spain
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30
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Ando W, Yokomori H, Kaneko F, Kaneko M, Igarashi K, Suzuki H. Serum Autotaxin Concentrations Reflect Changes in Liver Stiffness and Fibrosis After Antiviral Therapy in Patients with Chronic Hepatitis C. Hepatol Commun 2018; 2:1111-1122. [PMID: 30202824 PMCID: PMC6128230 DOI: 10.1002/hep4.1230] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2016] [Accepted: 06/07/2016] [Indexed: 01/14/2023] Open
Abstract
The purpose of this study was to determine whether serum autotaxin concentrations reflect liver stiffness in patients with chronic hepatitis C virus (HCV) treated with direct‐acting antiviral agents. Adult patients with chronic HCV were enrolled from January 2016 to August 2017. Autotaxin concentrations in these patients were compared with those of a control group consisting of healthy individuals. Liver stiffness was determined by transient elastography. The relationship between fibrosis markers and fibrosis scores was evaluated before and after treatment. Data from 155 HCV patients and 56 control subjects were analyzed. Autotaxin concentrations were significantly higher in HCV patients with liver stiffness scores less than or equal to 7.4 kPa versus controls. Autotaxin concentrations at the end of treatment and beyond were significantly lower than those prior to treatment. Pretreatment and posttreatment autotaxin concentrations in male and female patients with liver stiffness scores greater than 14.9 kPa changed significantly (P < 0.01 and P < 0.01, respectively). From the start of treatment to 6 months following treatment, the fibrosis marker/liver stiffness score ratios changed as follows: autotaxin: 0.189 (95% confidence interval [CI]: 0.169‐0.209) to 0.191 (95% CI: 0.166‐0.216; P= 0.88); Wisteria floribundaagglutinin‐positive Mac‐2‐binding protein: 0.294 (95% CI: 0.256‐0.332) to 0.223 (95% CI: 0.191‐0.255; P< 0.001); hyaluronic acid: 19.05 (95% CI: 14.29‐23.81) to 13.92 (95% CI: 11.16‐16.70; P = 0.044); and type IV collagen 7S: 0.560 (95% CI: 0.515‐0.604) to 0.546 (95% CI: 0.497‐0.895; P = 0.052). Conclusion: Autotaxin concentrations reflect liver stiffness before and after antiviral treatment in patients with chronic HCV infection.
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Affiliation(s)
- Wataru Ando
- Department of Clinical Pharmacy, School of Pharmacy Kitasato University Tokyo Japan
| | - Hiroaki Yokomori
- Department of Gastroenterology Kitasato University Medical Center Saitama Japan
| | - Fumihiko Kaneko
- Department of Internal Medicine Saitama Medical Center Saitama Japan
| | - Mana Kaneko
- Department of Clinical Pharmacy, School of Pharmacy Kitasato University Tokyo Japan
| | - Koji Igarashi
- Bioscience Division, Research and Development Management Department Tosoh Corporation Kanagawa Japan
| | - Hidekazu Suzuki
- Fellowship Training Center and Medical Education Center Keio University School of Medicine Keio University Tokyo Japan
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31
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Ninou I, Magkrioti C, Aidinis V. Autotaxin in Pathophysiology and Pulmonary Fibrosis. Front Med (Lausanne) 2018; 5:180. [PMID: 29951481 PMCID: PMC6008954 DOI: 10.3389/fmed.2018.00180] [Citation(s) in RCA: 85] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Accepted: 05/25/2018] [Indexed: 12/17/2022] Open
Abstract
Lysophospholipid signaling is emerging as a druggable regulator of pathophysiological responses, and especially fibrosis, exemplified by the relative ongoing clinical trials in idiopathic pulmonary fibrosis (IPF) patients. In this review, we focus on ectonucleotide pyrophosphatase-phosphodiesterase 2 (ENPP2), or as more widely known Autotaxin (ATX), a secreted lysophospholipase D (lysoPLD) largely responsible for extracellular lysophosphatidic acid (LPA) production. In turn, LPA is a bioactive phospholipid autacoid, forming locally upon increased ATX levels and acting also locally through its receptors, likely guided by ATX's structural conformation and cell surface associations. Increased ATX activity levels have been detected in many inflammatory and fibroproliferative conditions, while genetic and pharmacologic studies have confirmed a pleiotropic participation of ATX/LPA in different processes and disorders. In pulmonary fibrosis, ATX levels rise in the broncheoalveolar fluid (BALF) and stimulate LPA production. LPA engagement of its receptors activate multiple G-protein mediated signal transduction pathways leading to different responses from pulmonary cells including the production of pro-inflammatory signals from stressed epithelial cells, the modulation of endothelial physiology, the activation of TGF signaling and the stimulation of fibroblast accumulation. Genetic or pharmacologic targeting of the ATX/LPA axis attenuated disease development in animal models, thus providing the proof of principle for therapeutic interventions.
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Affiliation(s)
- Ioanna Ninou
- Division of Immunology, Alexander Fleming Biomedical Sciences Research Center, Athens, Greece
| | - Christiana Magkrioti
- Division of Immunology, Alexander Fleming Biomedical Sciences Research Center, Athens, Greece
| | - Vassilis Aidinis
- Division of Immunology, Alexander Fleming Biomedical Sciences Research Center, Athens, Greece
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Abstract
Pruritus in pregnancy can be a source of significant discomfort in the pregnant patient. Some cases are associated with pregnancy-specific dermatoses, although some patients experience a flare of a preexisting dermatosis. Severe pruritus may be a manifestation of a pregnancy-specific dermatosis associated with increased fetal risks and complications. Early accurate diagnosis and appropriate management are important. Examination often reveals important clinical findings, aiding accurate diagnosis. Pemphigoid gestationis often presents with periumbilical involvement, whereas polymorphic eruption of pregnancy spares the umbilicus and presents in the striae distensae. Intrahepatic cholestasis of pregnancy is associated with intense pruritus of the palms.
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Affiliation(s)
- Mark A Bechtel
- Division of Dermatology, Ohio State University College of Medicine, 540 Officenter Place, #240, Gahanna, OH 43230, USA.
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Jurate K, Rimantas Z, Jolanta S, Vladas G, Limas K. Sensitivity and Specificity of Biochemical Tests for Diagnosis of Intrahepatic Cholestasis of Pregnancy. Ann Hepatol 2018; 16:569-573. [PMID: 28611260 DOI: 10.5604/01.3001.0010.0294] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIM Intrahepatic cholestasis of pregnancy (ICP) is linked with increased risk of fetal complications. An accurate diagnostic test is needed to diagnose this disorder on time. We aimed to assess sensitivity and specificity of laboratory tests used for diagnosis of intrahepatic cholestasis of pregnancy and determine more reliable cut-off values of transaminases. MATERIAL AND METHODS Sixty one symptomatic patients with ICP and 29 healthy pregnant women were included in the retrospective analysis. RESULTS ICP patients had higher total bile acids (TBA) levels than healthy women (32 vs. 6; P < 0.0001) due to increase in cholic acid (CA) and chenodeoxycholic acid (CDCA). CA/CDCA ratio was significantly higher in ICP patients compared to healthy pregnant women (1.13 vs. 0.68; P < 0.00002). TBA, CA, CDCA and CA/CDCA ratio demonstrate the following sensitivity (94%, 96%, 89%, 71.9%) and specificity (63%, 63%, 59%, 79.3%, respectively) for ICP diagnosis. Lowering cut-off values for ALT (31 U/L) and AST (30 U/L) resulted only in minimal increase of sensitivity to 92.2% vs. 90.1% for ALT and to 92.2%, vs. 90.6% for AST. CONCLUSION The present study did not reveal any single specific and sensitive marker for reliable diagnosis of ICP. Establishment of lower cut-off values for transaminases activity might only minimally increase the accuracy of diagnosing ICP.
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Affiliation(s)
- Kondrackiene Jurate
- Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | | | - Sumskiene Jolanta
- Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Gintautas Vladas
- Department of Obstetrics and Gynecology, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Kupcinskas Limas
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
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YATOMI Y, KURANO M, IKEDA H, IGARASHI K, KANO K, AOKI J. Lysophospholipids in laboratory medicine. PROCEEDINGS OF THE JAPAN ACADEMY. SERIES B, PHYSICAL AND BIOLOGICAL SCIENCES 2018; 94:373-389. [PMID: 30541965 PMCID: PMC6374142 DOI: 10.2183/pjab.94.025] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/05/2023]
Abstract
Lysophospholipids (LPLs), such as lysophosphatidic acid (LPA), sphingosine 1-phosphate (S1P), and lysophosphatidylserine (LysoPS), are attracting attention as second-generation lipid mediators. In our laboratory, the functional roles of these lipid mediators and the mechanisms by which the levels of these mediators are regulated in vivo have been studied. Based on these studies, the clinical introduction of assays for LPLs and related proteins has been pursued and will be described in this review. Although assays of these lipids themselves are possible, autotaxin (ATX), apolipoprotein M (ApoM), and phosphatidylserine-specific phospholipase A1 (PS-PLA1) are more promising as alternate biomarkers for LPA, S1P, and LysoPS, respectively. Presently, ATX, which produces LPA through its lysophospholipase D activity, has been shown to be a useful laboratory test for the diagnosis and staging of liver fibrosis, whereas PS-PLA1 and ApoM are considered to be promising clinical markers reflecting the in vivo actions induced by LysoPS and S1P.
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Affiliation(s)
- Yutaka YATOMI
- Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Correspondence should be addressed: Y. Yatomi, Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan (e-mail: )
| | - Makoto KURANO
- Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hitoshi IKEDA
- Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Koji IGARASHI
- Bioscience Division, TOSOH Corporation, Kanagawa, Japan
| | - Kuniyuki KANO
- Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Miyagi, Japan
| | - Junken AOKI
- Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Miyagi, Japan
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Prevalence and Relevance of Pruritus in Pregnancy. BIOMED RESEARCH INTERNATIONAL 2017; 2017:4238139. [PMID: 29147651 PMCID: PMC5632889 DOI: 10.1155/2017/4238139] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Revised: 08/13/2017] [Accepted: 08/23/2017] [Indexed: 11/17/2022]
Abstract
Pregnant women are at greater risk to suffer from chronic pruritus, but data on this symptom in this group is very limited. The aim of this study was to investigate the prevalence, clinical characteristics, and the importance of pruritus in pregnant women. A total of 292 consecutive pregnant women at the 33.0 ± 6.1 weeks of gestation (WoG) were recruited into this prospective, cross-sectional study. All patients underwent thorough anamnesis and detailed physical examination with the special emphasis on pruritus. Pruritus was assessed according to Visual Analogue Scale (VAS). Quality of life was measured with the Dermatology Life Quality Index (DLQI). The point prevalence of pruritus was 20.2% (n = 59), while pruritus prevalence during the entire pregnancy was 38.0% (n = 111). Pruritus started on average at the 27.2 ± 7.6 WoG; it was significantly more common among women in third trimester. The mean VAS was 4.8 (±2.4) points. The DLQI scoring significantly correlated with VAS (r = 0.52, p < 0.001). Based on the results of our study about one-third of women suffer from pruritus during pregnancy. Many of them find it a very distressing and disturbing symptom.
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Pataia V, Dixon PH, Williamson C. Pregnancy and bile acid disorders. Am J Physiol Gastrointest Liver Physiol 2017; 313:G1-G6. [PMID: 28450276 DOI: 10.1152/ajpgi.00028.2017] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Revised: 04/20/2017] [Accepted: 04/20/2017] [Indexed: 01/31/2023]
Abstract
During pregnancy, extensive adaptations in maternal metabolic and immunological physiology occur. Consequently, preexisting disease may be exacerbated or attenuated, and new disease susceptibility may be unmasked. Cholestatic diseases, characterized by a supraphysiological raise in bile acid levels, require careful monitoring during pregnancy. This review describes the latest advances in the knowledge of intrahepatic cholestasis of pregnancy (ICP), the most common bile acid disorder specific to pregnancy, with a focus on the disease etiology and potential mechanisms of ICP-associated adverse pregnancy outcomes, including fetal demise. The course of preexisting cholestatic conditions in pregnancy is considered, including primary sclerosing cholangitis, primary biliary cholangitis, biliary atresia, and Alagille syndrome. The currently accepted treatments for cholestasis in pregnancy and promising new therapeutics for the condition are described.
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Affiliation(s)
- Vanessa Pataia
- Division of Women's Health, King's College London, London, United Kingdom
| | - Peter H Dixon
- Division of Women's Health, King's College London, London, United Kingdom
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Tajiri K, Shimizu Y. Recent advances in the management of pruritus in chronic liver diseases. World J Gastroenterol 2017; 23:3418-3426. [PMID: 28596678 PMCID: PMC5442078 DOI: 10.3748/wjg.v23.i19.3418] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Revised: 03/13/2017] [Accepted: 05/04/2017] [Indexed: 02/06/2023] Open
Abstract
Pruritus is a symptom found in patients with chronic liver diseases, especially cholestatic liver diseases such as primary biliary cholangitis. This symptom impairs patient quality of life by disturbing sleep and may lead to consideration of liver transplantation. Mechanisms implicated in pruritus have been associated with the peripheral and central nervous systems, leading to the development of various therapeutic options. Little evidence for the efficacy of most of these treatments is currently available, indicating a need for further investigations.
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Manzotti C, Casazza G, Stimac T, Nikolova D, Gluud C. Total serum bile acids or serum bile acid profile, or both, for the diagnosis of intrahepatic cholestasis of pregnancy. THE COCHRANE DATABASE OF SYSTEMATIC REVIEWS 2017. [DOI: 10.1002/14651858.cd012546] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Cristina Manzotti
- Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Università degli Studi di Milano; Obstetrics and Gynecology Department; Via Commenda 12 - Clinica Mangiagalli, piano terra Milan Milan Italy 20122
- Department 7812, Rigshospitalet, Copenhagen University Hospital; The Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research; Copenhagen Denmark
- Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Università degli Studi di Milano; Gastro-Intestinal Unit; Via Commenda 12 - Clinica Mangiagalli, 1° piano, scala A Milan Milan Italy 20122
| | - Giovanni Casazza
- Università degli Studi di Milano; Dipartimento di Scienze Biomediche e Cliniche "L. Sacco"; via GB Grassi 74 Milan Italy 20157
| | - Tea Stimac
- Clinical Hospital Centre Rijeka; Obstetrics and Gynecology; Cambierieva 17 Rijeka Croatia 51000
| | - Dimitrinka Nikolova
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital; The Cochrane Hepato-Biliary Group; Blegdamsvej 9 Copenhagen Denmark DK-2100
| | - Christian Gluud
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital; The Cochrane Hepato-Biliary Group; Blegdamsvej 9 Copenhagen Denmark DK-2100
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Downregulation of peroxiredoxin-3 by hydrophobic bile acid induces mitochondrial dysfunction and cellular senescence in human trophoblasts. Sci Rep 2016; 6:38946. [PMID: 27958341 PMCID: PMC5154184 DOI: 10.1038/srep38946] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Accepted: 11/16/2016] [Indexed: 12/19/2022] Open
Abstract
Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific disorder characterised by raised bile acids in foetal-maternal circulation, which threatens perinatal health. During the progression of ICP, the effect of oxidative stress is underscored. Peroxiredoxin-3 (PRDX3) is a mitochondrial antioxidant enzyme that is crucial to balance intracellular oxidative stress. However, the role of PRDX3 in placental trophoblast cells under ICP is not fully understood. We demonstrated that the level of PRDX3 was downregulated in ICP placentas as well as bile acids–treated trophoblast cells and villous explant in vitro. Toxic levels of bile acids and PRDX3 knockdown induced oxidative stress and mitochondrial dysfunction in trophoblast cells. Moreover, silencing of PRDX3 in trophoblast cell line HTR8/SVneo induced growth arrest and cellular senescence via activation of p38-mitogen-activated protein kinase (MAPK) and induction of p21WAF1/CIP and p16INK4A. Additionally, enhanced cellular senescence, determined by senescence-associated beta-galactosidase staining, was obviously attenuated by p38-MAPK inhibitor SB203580. Our data determined that exposure to bile acid decreased PRDX3 level in human trophoblasts. PRDX3 protected trophoblast cells against mitochondrial dysfunction and cellular senescence induced by oxidative stress. Our results suggest that decreased PRDX3 by excessive bile acids in trophoblasts plays a critical role in the pathogenesis and progression of ICP.
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Wunsch E, Krawczyk M, Milkiewicz M, Trottier J, Barbier O, Neurath MF, Lammert F, Kremer AE, Milkiewicz P. Serum Autotaxin is a Marker of the Severity of Liver Injury and Overall Survival in Patients with Cholestatic Liver Diseases. Sci Rep 2016; 6:30847. [PMID: 27506882 PMCID: PMC4978954 DOI: 10.1038/srep30847] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Accepted: 07/08/2016] [Indexed: 02/07/2023] Open
Abstract
Autotaxin (ATX) is involved in the synthesis of lysophosphatidic acid. Both have recently been linked to cholestatic pruritus and liver injury. We aimed to investigate whether ATX is an indicator of cholestatic liver injury, health-related quality of life (HRQoL) and prognosis based on a group of 233 patients, 118 with primary biliary cholangitis (PBC) and 115 with primary sclerosing cholangitis (PSC). Patients were followed for 1–60 months, cumulative survival rates were calculated. ATX activity was significantly higher in both groups than in the 103 controls, particularly in patients with cirrhosis and in patients with longer disease duration. Ursodeoxycholic acid (UDCA) non-responders with PBC exhibited increased ATX activity. ATX activity was correlated with liver biochemistry, MELD, Mayo Risk scores and was associated with worse disease-specific HRQoL aspects. In both groups, Cox model analysis indicated that ATX was a negative predictor of survival. Increased ATX levels were associated with a 4-fold higher risk of death/liver transplantation in patients with PBC and a 2.6-fold higher risk in patients with PSC. We conclude that in patients with cholestatic conditions, ATX is not only associated with pruritus but also indicates impairment of other HRQoL aspects, liver dysfunction, and can serve as a predictor of survival.
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Affiliation(s)
- Ewa Wunsch
- Department of Clinical and Molecular Biochemistry, Pomeranian Medical University in Szczecin, 70-111 Szczecin, Poland
| | - Marcin Krawczyk
- Department of Medicine II, Saarland University Medical Center, Saarland University, 66421 Homburg, Germany.,Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Malgorzata Milkiewicz
- Department of Medical Biology, Pomeranian Medical University in Szczecin, 70-111 Szczecin, Poland
| | - Jocelyn Trottier
- Laboratory of Molecular Pharmacology, CHU-de-Québec &Faculty of Pharmacy, Laval University, 2705 Québec, QC, Canada
| | - Olivier Barbier
- Laboratory of Molecular Pharmacology, CHU-de-Québec &Faculty of Pharmacy, Laval University, 2705 Québec, QC, Canada
| | - Markus F Neurath
- Department of Medicine I, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Saarland University, 66421 Homburg, Germany
| | - Andreas E Kremer
- Department of Medicine I, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Piotr Milkiewicz
- Department of Clinical and Molecular Biochemistry, Pomeranian Medical University in Szczecin, 70-111 Szczecin, Poland.,Liver and Internal Medicine Unit, Department of General, Transplant and Liver Surgery of the Medical University of Warsaw, 02-097 Warsaw, Poland
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Pařízek A, Hill M, Dušková M, Vítek L, Velíková M, Kancheva R, Šimják P, Koucký M, Kokrdová Z, Adamcová K, Černý A, Hájek Z, Stárka L. A Comprehensive Evaluation of Steroid Metabolism in Women with Intrahepatic Cholestasis of Pregnancy. PLoS One 2016; 11:e0159203. [PMID: 27494119 PMCID: PMC4975406 DOI: 10.1371/journal.pone.0159203] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Accepted: 06/28/2016] [Indexed: 12/27/2022] Open
Abstract
Intrahepatic cholestasis of pregnancy (ICP) is a common liver disorder, mostly occurring in the third trimester. ICP is defined as an elevation of serum bile acids, typically accompanied by pruritus and elevated activities of liver aminotransferases. ICP is caused by impaired biliary lipid secretion, in which endogenous steroids may play a key role. Although ICP is benign for the pregnant woman, it may be harmful for the fetus. We evaluated the differences between maternal circulating steroids measured by RIA (17-hydroxypregnenolone and its sulfate, 17-hydroxyprogesterone, and cortisol) and GC-MS (additional steroids), hepatic aminotransferases and bilirubin in women with ICP (n = 15, total bile acids (TBA) >8 μM) and corresponding controls (n = 17). An age-adjusted linear model, receiver-operating characteristics (ROC), and multivariate regression (a method of orthogonal projections to latent structure, OPLS) were used for data evaluation. While aminotransferases, conjugates of pregnanediols, 17-hydroxypregnenolone and 5β-androstane-3α,17β-diol were higher in ICP patients, 20α-dihydropregnenolone, 16α-hydroxy-steroids, sulfated 17-oxo-C19-steroids, and 5β-reduced steroids were lower. The OPLS model including steroids measured by GC-MS and RIA showed 93.3% sensitivity and 100% specificity, while the model including steroids measured by GC-MS in a single sample aliquot showed 93.3% sensitivity and 94.1% specificity. A composite index including ratios of sulfated 3α/β-hydroxy-5α/β-androstane-17-ones to conjugated 5α/β-pregnane-3α/β, 20α-diols discriminated with 93.3% specificity and 81.3% sensitivity (ROC analysis). These new data demonstrating altered steroidogenesis in ICP patients offer more detailed pathophysiological insights into the role of steroids in the development of ICP.
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Affiliation(s)
- Antonín Pařízek
- Department of Obstetrics and Gynecology, General University Hospital and 1st Faculty of Medicine, Charles University in Prague, Prague, Czech Republic
| | - Martin Hill
- Institute of Endocrinology, Prague, Czech Republic
- * E-mail:
| | | | - Libor Vítek
- Institute of Medical Biochemistry and Laboratory Diagnostics and 4th Department of Internal Medicine, General University Hospital and 1st Faculty of Medicine of Charles University in Prague, Prague, Czech Republic
| | | | | | - Patrik Šimják
- Department of Obstetrics and Gynecology, General University Hospital and 1st Faculty of Medicine, Charles University in Prague, Prague, Czech Republic
| | - Michal Koucký
- Department of Obstetrics and Gynecology, General University Hospital and 1st Faculty of Medicine, Charles University in Prague, Prague, Czech Republic
| | - Zuzana Kokrdová
- Department of Obstetrics and Gynecology, General University Hospital and 1st Faculty of Medicine, Charles University in Prague, Prague, Czech Republic
| | - Karolína Adamcová
- Department of Obstetrics and Gynecology, General University Hospital and 1st Faculty of Medicine, Charles University in Prague, Prague, Czech Republic
| | - Andrej Černý
- Department of Obstetrics and Gynecology, General University Hospital and 1st Faculty of Medicine, Charles University in Prague, Prague, Czech Republic
| | - Zdeněk Hájek
- Department of Obstetrics and Gynecology, General University Hospital and 1st Faculty of Medicine, Charles University in Prague, Prague, Czech Republic
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Hegade VS, Bolier R, Oude Elferink RPJ, Beuers U, Kendrick S, Jones DEJ. A systematic approach to the management of cholestatic pruritus in primary biliary cirrhosis. Frontline Gastroenterol 2016; 7:158-166. [PMID: 28839853 PMCID: PMC5369477 DOI: 10.1136/flgastro-2015-100618] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2015] [Revised: 07/24/2015] [Accepted: 08/04/2015] [Indexed: 02/04/2023] Open
Abstract
Pruritus (itch) is an important symptom of primary biliary cirrhosis (PBC), an archetypal cholestatic liver disease. Cholestatic pruritus can be a debilitating symptom causing significant deterioration in patients' quality of life. Effective management of pruritus in PBC involves awareness among clinicians to adequately assess its severity, and treatment with specific drug therapies in line with current practice guidelines. In PBC, antipruritic drugs are not universally effective and/or have significant side effects, and despite best efforts with various combinations of drugs, some patients remain significantly symptomatic, eventually opting for invasive or experimental treatments. Therefore, there is a clear unmet need for better alternative treatments for patients with refractory or intractable cholestatic pruritus. Recent advances in the understanding of pathogenesis of cholestatic pruritus and bile acid physiology have raised hopes for novel therapies, some of which are currently under trial. In this review, we aim to provide a practical guide to the management of this important and complex problem, discussing current knowledge and recent advances in the pathogenesis, summarise the evidence base for available therapeutic approaches and update potential novel future therapies for the management of pruritus in PBC.
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Affiliation(s)
- Vinod S Hegade
- Faculty of Medical Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
| | - Ruth Bolier
- Tytgat Institute for Liver and Intestinal Research, Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Ronald PJ Oude Elferink
- Tytgat Institute for Liver and Intestinal Research, Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Ulrich Beuers
- Tytgat Institute for Liver and Intestinal Research, Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Stuart Kendrick
- GlaxoSmithKline Research and Development, Medicines Research Centre, Stevenage, Hertfordshire, UK
| | - David EJ Jones
- Faculty of Medical Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
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Abstract
Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disease during pregnancy, characterized by otherwise unexplained pruritus in late second and third trimester of pregnancy and elevated bile acids and/or transaminases. ICP is associated with an increased risk of adverse perinatal outcomes for the fetus and the later development of hepatobiliary disease for the mother. Bile acids should be monitored throughout pregnancy since fetal risk is increased at serum bile acids >40 µmol/l. Management of ICP consists of treatment with ursodeoxycholic acid, which reduces pruritus. Early elective delivery is common practice but should be performed on an individualized basis as long as strong evidence supporting this practice is lacking. Mothers should be followed-up for normalization of liver function tests 6-12 weeks after delivery. Future research in large-scale studies is needed to address the impact of ursodeoxycholic acid and early elective delivery on fetal outcome.
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Affiliation(s)
- Hanns-Ulrich Marschall
- a Department of Molecular and Clinical Medicine, University of Gothenburg, Sahlgrenska Academy, Institute of Medicine, S-41345 Gothenburg, Sweden
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46
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Immunology of hepatic diseases during pregnancy. Semin Immunopathol 2016; 38:669-685. [PMID: 27324237 DOI: 10.1007/s00281-016-0573-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2016] [Accepted: 05/18/2016] [Indexed: 02/06/2023]
Abstract
The mother's immune system has to adapt to pregnancy accepting the semi-allograft fetus and preventing harmful effects to the developing child. Aberrations in feto-maternal immune adaptation may result in disease of the mother, such as liver injury. Five pregnancy-associated liver disorders have been described so far, however, little is known concerning immune alterations promoting the respective disease. These liver disorders are pre-eclampsia, hemolysis, elevated liver enzymes, low platelet count (HELLP), acute fatty liver, hyperemesis gravidarum, and intrahepatic cholestasis of pregnancy. On the other hand, pre-existing autoimmune liver injury of the mother can be affected by pregnancy. This review intends to summarize current knowledge linking feto-maternal immunology and liver inflammation with a special emphasis on novel potential biomarkers.
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Steroid binding to Autotaxin links bile salts and lysophosphatidic acid signalling. Nat Commun 2016; 7:11248. [PMID: 27075612 PMCID: PMC4834639 DOI: 10.1038/ncomms11248] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2015] [Accepted: 03/04/2016] [Indexed: 12/12/2022] Open
Abstract
Autotaxin (ATX) generates the lipid mediator lysophosphatidic acid (LPA). ATX-LPA signalling is involved in multiple biological and pathophysiological processes, including vasculogenesis, fibrosis, cholestatic pruritus and tumour progression. ATX has a tripartite active site, combining a hydrophilic groove, a hydrophobic lipid-binding pocket and a tunnel of unclear function. We present crystal structures of rat ATX bound to 7α-hydroxycholesterol and the bile salt tauroursodeoxycholate (TUDCA), showing how the tunnel selectively binds steroids. A structure of ATX simultaneously harbouring TUDCA in the tunnel and LPA in the pocket, together with kinetic analysis, reveals that bile salts act as partial non-competitive inhibitors of ATX, thereby attenuating LPA receptor activation. This unexpected interplay between ATX-LPA signalling and select steroids, notably natural bile salts, provides a molecular basis for the emerging association of ATX with disorders associated with increased circulating levels of bile salts. Furthermore, our findings suggest potential clinical implications in the use of steroid drugs. Autotaxin generates the bioactive lipid lysophosphatidic acid to regulate diverse biological processes. Here, the authors identify a role for bile salts as direct allosteric inhibitors of autotaxin activity, suggesting that steroids may function as regulators of lysophosphatidic acid signalling.
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Abu‐Hayyeh S, Ovadia C, Lieu T, Jensen DD, Chambers J, Dixon PH, Lövgren‐Sandblom A, Bolier R, Tolenaars D, Kremer AE, Syngelaki A, Noori M, Williams D, Marin JJ, Monte MJ, Nicolaides KH, Beuers U, Oude‐Elferink R, Seed PT, Chappell L, Marschall H, Bunnett NW, Williamson C. Prognostic and mechanistic potential of progesterone sulfates in intrahepatic cholestasis of pregnancy and pruritus gravidarum. Hepatology 2016; 63:1287-98. [PMID: 26426865 PMCID: PMC4869673 DOI: 10.1002/hep.28265] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Accepted: 09/28/2015] [Indexed: 12/17/2022]
Abstract
UNLABELLED A challenge in obstetrics is to distinguish pathological symptoms from those associated with normal changes of pregnancy, typified by the need to differentiate whether gestational pruritus of the skin is an early symptom of intrahepatic cholestasis of pregnancy (ICP) or due to benign pruritus gravidarum. ICP is characterized by raised serum bile acids and complicated by spontaneous preterm labor and stillbirth. A biomarker for ICP would be invaluable for early diagnosis and treatment and to enable its differentiation from other maternal diseases. Three progesterone sulfate compounds, whose concentrations have not previously been studied, were newly synthesized and assayed in the serum of three groups of ICP patients and found to be significantly higher in ICP at 9-15 weeks of gestation and prior to symptom onset (group 1 cases/samples: ICP n = 35/80, uncomplicated pregnancy = 29/100), demonstrating that all three progesterone sulfates are prognostic for ICP. Concentrations of progesterone sulfates were associated with itch severity and, in combination with autotaxin, distinguished pregnant women with itch that would subsequently develop ICP from pruritus gravidarum (group 2: ICP n = 41, pruritus gravidarum n = 14). In a third group of first-trimester samples all progesterone sulfates were significantly elevated in serum from low-risk asymptomatic women who subsequently developed ICP (ICP/uncomplicated pregnancy n = 54/51). Finally, we show mechanistically that progesterone sulfates mediate itch by evoking a Tgr5-dependent scratch response in mice. CONCLUSION Our discovery that sulfated progesterone metabolites are a prognostic indicator for ICP will help predict onset of ICP and distinguish it from benign pruritus gravidarum, enabling targeted obstetric care to a high-risk population. Delineation of a progesterone sulfate-TGR5 pruritus axis identifies a therapeutic target for itch management in ICP.
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Affiliation(s)
- Shadi Abu‐Hayyeh
- Women's Health Academic CentreKing's College LondonLondonUnited Kingdom
| | - Caroline Ovadia
- Women's Health Academic CentreKing's College LondonLondonUnited Kingdom
| | - TinaMarie Lieu
- Monash Institute of Pharmaceutical Sciences and Australian Research Council Centre of Excellence in Convergent Bio‐Nano Science and TechnologyMonash UniversityParkvilleVictoriaAustralia
| | - Dane D. Jensen
- Monash Institute of Pharmaceutical Sciences and Australian Research Council Centre of Excellence in Convergent Bio‐Nano Science and TechnologyMonash UniversityParkvilleVictoriaAustralia
| | - Jenny Chambers
- Women's Health Academic CentreKing's College LondonLondonUnited Kingdom
- Institute of Reproductive and Developmental BiologyImperial College LondonLondonUnited Kingdom
| | - Peter H. Dixon
- Women's Health Academic CentreKing's College LondonLondonUnited Kingdom
- Institute of Reproductive and Developmental BiologyImperial College LondonLondonUnited Kingdom
| | | | - Ruth Bolier
- Tytgat Institute for Liver and Intestinal ResearchAcademic Medical CentreAmsterdamThe Netherlands
| | - Dagmar Tolenaars
- Tytgat Institute for Liver and Intestinal ResearchAcademic Medical CentreAmsterdamThe Netherlands
| | - Andreas E. Kremer
- Tytgat Institute for Liver and Intestinal ResearchAcademic Medical CentreAmsterdamThe Netherlands
- Department of Medicine 1Friedrich‐Alexander‐University of Erlangen‐NurembergErlangenGermany
| | - Argyro Syngelaki
- Harris Birthright Research Centre for Fetal MedicineKing's College HospitalLondonUnited Kingdom
| | - Muna Noori
- Institute of Reproductive and Developmental BiologyImperial College LondonLondonUnited Kingdom
| | - David Williams
- Institute for Women's HealthUniversity College London HospitalsLondonUnited Kingdom
| | - Jose J.G. Marin
- Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), Biomedical Research Institute of Salamanca (IBSAL)University of Salamanca, National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd)SalamancaSpain
| | - Maria J. Monte
- Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), Biomedical Research Institute of Salamanca (IBSAL)University of Salamanca, National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd)SalamancaSpain
| | - Kypros H. Nicolaides
- Harris Birthright Research Centre for Fetal MedicineKing's College HospitalLondonUnited Kingdom
| | - Ulrich Beuers
- Tytgat Institute for Liver and Intestinal ResearchAcademic Medical CentreAmsterdamThe Netherlands
| | - Ronald Oude‐Elferink
- Tytgat Institute for Liver and Intestinal ResearchAcademic Medical CentreAmsterdamThe Netherlands
| | - Paul T. Seed
- Women's Health Academic CentreKing's College LondonLondonUnited Kingdom
| | - Lucy Chappell
- Women's Health Academic CentreKing's College LondonLondonUnited Kingdom
| | - Hanns‐Ulrich Marschall
- Institute of Medicine, Department of Molecular and Clinical MedicineUniversity of GothenburgGothenburgSweden
| | - Nigel W. Bunnett
- Monash Institute of Pharmaceutical Sciences and Australian Research Council Centre of Excellence in Convergent Bio‐Nano Science and TechnologyMonash UniversityParkvilleVictoriaAustralia
- Department of PharmacologyUniversity of MelbourneParkvilleVictoriaAustralia
| | - Catherine Williamson
- Women's Health Academic CentreKing's College LondonLondonUnited Kingdom
- Institute of Reproductive and Developmental BiologyImperial College LondonLondonUnited Kingdom
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Bolier R, Tolenaars D, Kremer AE, Saris J, Parés A, Verheij J, Bosma PJ, Beuers U, Oude Elferink RP. Enteroendocrine cells are a potential source of serum autotaxin in men. Biochim Biophys Acta Mol Basis Dis 2016; 1862:696-704. [DOI: 10.1016/j.bbadis.2016.01.012] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Revised: 12/22/2015] [Accepted: 01/12/2016] [Indexed: 12/26/2022]
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Abstract
OBJECTIVE Pruritus is a common symptom of cholestatic liver disorders. The present study aimed at evaluating autotaxin (ATX), a lysophospholipase recently identified as potential cause for cholestatic pruritus, in pediatric cholestatic diseases presenting with or without itching. METHODS A cohort of 45 children consisting of 14 patients experiencing itching (Alagille syndrome [n = 10], complete extrahepatic biliary atresia [n = 2], neonatal sclerosing cholangitis (n = 1), progressive familial intrahepatic cholestasis type 2 [n = 1]), 9 patients with bile acid synthesis defects (3β-hydroxy-C27-steroid-oxidoreductase [n = 7] and Δ-3-oxosteroid-5β-reductase deficiency [n = 2]), and 22 healthy children were studied. Serum ATX activity and total serum bile salt were determined enzymatically, ATX protein content was semiquantified by Western blotting. Using real-time polymerase chain reaction, ATX mRNA expression was studied in HepG2 cells treated with farnesoid-X-receptor agonists or vehicle. RESULTS Serum ATX activity was increased in pruritic children with Alagille and other cholestatic syndromes (mean ± standard deviation: 16.1 ± 4.3 nmol · mL · min) compared with children with nonpruritic cholestatic diseases with bile acid synthesis defects (10.4 ± 4.7 nmol · mL · min; P < 0.01) and healthy controls (7.6 ± 2.3 nmol · mL · min; P < 0.001). ATX protein levels closely correlated with serum ATX activity. Serum ATX activity and total serum bile salt showed a linear correlation with itch intensity (r = 0.66, P < 0.001 and r = 0.80, P < 0.001, respectively). No correlation was observed between ATX activity and bilirubin. ATX mRNA expression in HepG2 cells was not induced by farnesoid-X-receptor ligands. CONCLUSIONS Serum ATX activity correlated with itch intensity in children with cholestatic diseases. Bile salts did not increase ATX expression in vitro. ATX inhibitors may be useful antipruritic agents in pediatric cholestatic disorders.
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