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Nana M, Medina V, Maxwell C, McCormick C, Taliani G, Beuers U, Money D, Jacobsson B, Kapur A, Beyuo T, Ruiloba F, Smith G, Bergman L, O'Reilly S, O'Brien P, Hanson M, Rosser M, Sosa C, Adam S, Guinto V, Poon L, McAuliffe F, Williamson C. FIGO guideline on liver disease and pregnancy. Int J Gynaecol Obstet 2025. [PMID: 40299540 DOI: 10.1002/ijgo.70161] [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: 01/31/2025] [Revised: 03/27/2025] [Accepted: 04/02/2025] [Indexed: 04/30/2025]
Abstract
The number of women entering pregnancy with chronic liver disease is rising. Gestational liver disorders affect 3% of the pregnant population. Both can be associated with significant maternal and fetal morbidity and mortality. European guidance has recently been published to inform management. This FIGO (the International Federation of Gynecology & Obstetrics) guideline aims to use the latest evidence to inform practice relevant to a global population. The immediate past and present chairs of FIGO's Committee on the Impact of Long-term Health invited the Chair of the European guideline, alongside two trainees with an interest in liver disorders in pregnancy, to develop a guideline relevant to a global audience, thus serving the real-world population and fulfilling FIGO's ambition to enhance their global voice for women's health. Experts in the field with experience in managing liver disorders in pregnancy from a diverse selection of continents helped to develop a guideline. A guideline has been developed including the most common pre-existing and gestational liver disorders. Evidence-based best practice recommendations are summarized in addition to pragmatic recommendations. Printable tables/figures are included in the guideline for ease of use. These include a table of normal ranges of commonly used blood tests, a table outlining safety of investigations, and a table of delivery considerations relevant to a global audience. Figures designed to summarize each section of the guideline and the multidisciplinary approach to managing liver disorders in pregnancy are also included. This guideline incorporates guidance for a global audience aimed at improving the management of women with pre-existing and new liver disease in pregnancy.
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Affiliation(s)
- Melanie Nana
- Department of Women and Childrens' Health, King's College London, London, UK
| | - Virna Medina
- Department of Obstetrics and Gynecology, Faculty of Health, Universidad del Valle, Clínica Imbanaco Quirón Salud, Universidad Libre, Cali, Colombia
| | - Cynthia Maxwell
- Maternal Fetal Medicine, Sinai Health and Women's College Hospital University of Toronto, Ontario, Canada
| | - Ciara McCormick
- UCD Perinatal Research Centre, School of Medicine, University College Dublin, National Maternity Hospital, Dublin, Ireland
| | - Gloria Taliani
- Department of Infectious and Tropical Diseases, La Sapienza University of Rome, Rome, Italy
| | - Ulrich Beuers
- Department of Gastroenterology & Hepatology, Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Centers, Location AMC, Amsterdam, The Netherlands
| | - Deborah Money
- Department of Obstetrics and Gynecology, The University of British Columbia, Vancouver, Canada
| | - Bo Jacobsson
- Department of Obstetrics and Gynecology, Sahlgrenska University Hospital/Ostra, Gothenburg, Sweden
| | - Anil Kapur
- World Diabetes Foundation, Bagsværd, Denmark
| | - Titus Beyuo
- Department of Obstetrics and Gynaecology, University of Ghana Medical School, Accra, Ghana
| | - Francisco Ruiloba
- Instituto Nacional de Perinatologia, Department of Obstetrics and Gynecology, Mexico City, Mexico
| | - Graeme Smith
- Department of Obstetrics & Gynecology, Kingston Health Sciences Centre, Queen's University, Kingston, Ontario, Canada
| | - Lina Bergman
- Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Sharleen O'Reilly
- UCD Perinatal Research Centre, School of Medicine, University College Dublin, National Maternity Hospital, Dublin, Ireland
| | - Patrick O'Brien
- Institute for Women's Health, University College London, London, UK
| | - Mark Hanson
- Institute of Developmental Sciences, University Hospital Southampton, Southampton, UK
| | - Mary Rosser
- Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, New York, USA
| | - Claudio Sosa
- Department of Obstetrics and Gynecology, Pereira-Rossell Hospital, School of Medicine, University of the Republic, Montevideo, Uruguay
| | - Sumaiya Adam
- Department of Obstetrics and Gynecology, School of Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa
| | - Valerie Guinto
- Maternal-Fetal Medicine, University of the Philippines-Philippine General Hospital, Manila, Philippines
| | - Liona Poon
- Department of Obstetrics and Gynaecology, Prince of Wales Hospital, the Chinese University of Hong Kong, Hong Kong, China
| | - Fionnuala McAuliffe
- UCD Perinatal Research Centre, School of Medicine, University College Dublin, National Maternity Hospital, Dublin, Ireland
| | - Catherine Williamson
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
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Basu S, Običan SG, Bertaggia E, Staab H, Izquierdo MC, Gyamfi-Bannerman C, Haeusler RA. Unresolved alterations in bile acid composition and dyslipidemia in maternal and cord blood after UDCA treatment for intrahepatic cholestasis of pregnancy. Am J Physiol Gastrointest Liver Physiol 2025; 328:G364-G376. [PMID: 39947696 PMCID: PMC12053871 DOI: 10.1152/ajpgi.00266.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 09/25/2024] [Accepted: 02/03/2025] [Indexed: 02/19/2025]
Abstract
Intrahepatic cholestasis of pregnancy (ICP) is characterized by elevated plasma bile acid levels. ICP is linked to adverse metabolic outcomes, including a reported increased risk of gestational diabetes. The standard therapeutic approach for managing ICP is treatment with ursodeoxycholic acid (UDCA) and induction of labor before 40 wk of gestation. To investigate bile acid and metabolic parameters after UDCA treatment, we enrolled 12 ICP patients with singleton pregnancies-half with and half without gestational diabetes-and 7 controls. Our study reveals that after UDCA treatment, notwithstanding a reduction in total bile acid and alanine aminotransferase levels, imbalances persist in the cholic acid (CA) to chenodeoxycholic acid (CDCA) ratio in maternal and cord blood plasma. This indicates a continued dysregulation of bile acid metabolism despite therapeutic intervention. Maternal plasma lipid analysis showed a distinct maternal dyslipidemia pattern among patients with ICP, marked by elevated cholesterol levels on VLDL particles and heightened triglyceride concentrations on LDL particles, persisting even after UDCA treatment. Cord plasma lipid profiles in patients with ICP exhibited elevated triglyceride and free fatty acid levels alongside a tendency toward increased β-hydroxybutyrate. The changes in lipid metabolism in both maternal and cord blood correlated with the high CA/CDCA ratio but not total bile acid levels or gestational diabetes status. Understanding the imbalances in maternal and cord bile acid and lipid profiles that persist after standard UDCA therapy provides insights for improving management strategies and mitigating the long-term consequences of ICP.NEW & NOTEWORTHY This study uncovers that despite ursodeoxycholic acid treatment, intrahepatic cholestasis of pregnancy (ICP) is associated with increases in the ratio of cholic acid to chenodeoxycholic acid in both maternal and cord blood, suggesting ongoing dysregulation of bile acid metabolism. The high cholic to chenodeoxycholic acid ratio is correlated with maternal dyslipidemia and high cord blood lipids. These findings may inform more targeted approaches to managing ICP.
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Affiliation(s)
- Srijani Basu
- Naomi Berrie Diabetes Center, Columbia University, New York, New York, United States
- Columbia University Digestive and Liver Disease Research Center, Columbia University, New York, New York, United States
- Department of Medicine, Columbia University, New York, New York, United States
| | - Sarah G Običan
- Department of Obstetrics and Gynecology, Columbia University, New York, New York, United States
- Department of Obstetrics and Gynecology, University of South Florida, Tampa, Florida, United States
| | - Enrico Bertaggia
- Naomi Berrie Diabetes Center, Columbia University, New York, New York, United States
- Department of Pathology and Cell Biology, Columbia University, New York, New York, United States
| | - Hannah Staab
- Naomi Berrie Diabetes Center, Columbia University, New York, New York, United States
| | - M Concepcion Izquierdo
- Naomi Berrie Diabetes Center, Columbia University, New York, New York, United States
- Department of Pathology and Cell Biology, Columbia University, New York, New York, United States
| | | | - Rebecca A Haeusler
- Naomi Berrie Diabetes Center, Columbia University, New York, New York, United States
- Columbia University Digestive and Liver Disease Research Center, Columbia University, New York, New York, United States
- Department of Medicine, Columbia University, New York, New York, United States
- Department of Pathology and Cell Biology, Columbia University, New York, New York, United States
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Yang J, Gao J, Zhou D, Ye H, Huang G, Lian X, Zhang X. Comparing risk factors and neonatal outcomes in women with intrahepatic cholestasis of pregnancy between assisted reproductive technology and spontaneous conception. Int J Gynaecol Obstet 2025; 168:663-672. [PMID: 39175277 DOI: 10.1002/ijgo.15878] [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: 04/29/2024] [Revised: 08/02/2024] [Accepted: 08/13/2024] [Indexed: 08/24/2024]
Abstract
OBJECTIVE The aim of the present study was to investigate the incidence of intrahepatic cholestasis of pregnancy (ICP) as well as neonatal outcomes between conception via in vitro fertilization (IVF) compared with spontaneous conception (SC) and screen the risk factors of ICP in IVF. METHODS This retrospective cohort study included 4467 puerperae who conceived via IVF, and 28 336 puerperae who conceived spontaneously and linked the information from neonates. The general linear model (GLM), multivariate logistic regression analysis, a forest plot, and nomogram were used to assess impact factors and risk prediction. RESULTS Logistic analysis adjusted for confounders revealed significant differences in the ICP rate of singleton delivery (4.24% vs 3.41%, adjusted OR [aOR] = 1.26; 95% confidence interval [CI] 1.03-1.53, P = 0.025) and in groups with total bile acids (TBA) ≥40 and <100 μmol/L (14.77% vs 10.39%, aOR = 1.31; 95% CI: 1.06-1.63, P = 0.023) between IVF and SC. When we divided newborns into singleton and twins delivery, the GLM revealed a higher rate with Apgar score <7 (13.44% vs 3.87%, aOR = 3.85; 95% CI: 2.07-7.17, P < 0.001) and fetal distress for IVF in comparison with SC (19.32% vs 5.55%, OR = 3.48; 95% CI: 2.39-6.95, P < 0.001) in the singleton group. In multivariate logistic regression analysis, body mass index (BMI) (aOR = 1.29; P = 0.031), number of embryo transfers (ET) (single ET vs double ET, aOR = 2.82; P < 0.001), E2 level on the ET day (aOR = 2.79; P = 0.011), fresh ET which compared with frozen ET (FET) (aOR = 1.45; P = 0.014), embryo stage (cleavage embryo vs blastocyst, aOR = 1.75; P = 0.009) and severe ovarian hyperstimulation syndrome (OHSS) which compared with non-OHSS (aOR = 3.73; P = 0.006) were independent predictors of ICP. These predictive factors in the logistic regression model were integrated into the nomogram (C-index = 0.735; 95% CI: 0.702-0.764); for each patient, higher total points indicated a higher risk of ICP. CONCLUSION We observed that the ICP rate of singleton delivery was higher in IVF than in SC. In ICP patients, there were higher rates of neonatal Apgar score <7 and fetal distress in IVF than SC and found the predictors of ICP in IVF.
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Affiliation(s)
- Jingwei Yang
- Chongqing Key Laboratory of Human Embryo Engineering, Center for Reproductive Medicine, Women and Children's Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Clinical Research Center for Reproductive Medicine, Chongqing Health Center for Women and Children, Chongqing, China
- Department of Epidemiology and Health Statistics, School of Public Health, Chongqing Medical University, Chongqing, China
| | - Jing Gao
- Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Danni Zhou
- Chongqing Key Laboratory of Human Embryo Engineering, Center for Reproductive Medicine, Women and Children's Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Clinical Research Center for Reproductive Medicine, Chongqing Health Center for Women and Children, Chongqing, China
| | - Hong Ye
- Chongqing Key Laboratory of Human Embryo Engineering, Center for Reproductive Medicine, Women and Children's Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Clinical Research Center for Reproductive Medicine, Chongqing Health Center for Women and Children, Chongqing, China
| | - Guoning Huang
- Chongqing Key Laboratory of Human Embryo Engineering, Center for Reproductive Medicine, Women and Children's Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Clinical Research Center for Reproductive Medicine, Chongqing Health Center for Women and Children, Chongqing, China
| | - Xuemei Lian
- Department of Epidemiology and Health Statistics, School of Public Health, Chongqing Medical University, Chongqing, China
| | - Xiaodong Zhang
- Chongqing Key Laboratory of Human Embryo Engineering, Center for Reproductive Medicine, Women and Children's Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Clinical Research Center for Reproductive Medicine, Chongqing Health Center for Women and Children, Chongqing, China
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Gabrielli F, Crepaldi E, Cavicchioli A, Rivi M, Costanzo AC, Cursaro C, Andreone P. Itching for Answers: A Comprehensive Review of Cholestatic Pruritus Treatments. Biomolecules 2024; 14:1227. [PMID: 39456160 PMCID: PMC11505983 DOI: 10.3390/biom14101227] [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] [Received: 07/23/2024] [Revised: 08/21/2024] [Accepted: 08/28/2024] [Indexed: 10/28/2024] Open
Abstract
Cholestasis is a clinical and laboratory syndrome indicating impaired bile production or excretion. One of the hallmark symptoms of cholestasis is pruritus. Itch can be severe and debilitating for patients, impacting their quality of life similarly to pain, and, in some cases, it can be refractory. Current therapies like anion exchange resins and rifampicin, offer partial relief but with side effects. Effective, well-tolerated treatments are urgently needed. This literature review examines existing options (bile acid sequestrants, antihistamines, opioid antagonists, sertraline, and rifampicin) and explores novel therapies (monoclonal antibodies, PPAR agonists, and bile-acid-based therapies). We analyze mechanisms, limitations, and adverse effects to aid clinicians and researchers. Novel approaches include monoclonal antibodies to inhibit bile recirculation and PPAR agonists targeting pruritus signaling. Despite the limited current options, ongoing research promises better treatments for cholestatic pruritus, addressing its distressing impact. In summary, cholestasis-associated pruritus poses a significant challenge with limited treatments. Advancements in understanding its pathophysiology offer hope for more effective therapies in the future.
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Affiliation(s)
- Filippo Gabrielli
- Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41126 Modena, Italy
- Internal and Metabolic Medicine, AOU of Modena-Baggiovara, 41126 Modena, Italy
| | - Eleonora Crepaldi
- Postgraduate School of Allergology and Clinical Immunology, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Alessia Cavicchioli
- Internal and Metabolic Medicine, AOU of Modena-Baggiovara, 41126 Modena, Italy
| | - Marco Rivi
- Postgraduate School of Allergology and Clinical Immunology, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Arianna Carmen Costanzo
- Department of Hepato-bilio-pancreatic Surgery and Liver Transplantation, Hautepierre Hospital, Avenue Molière, 67200 Strasbourg, France
| | - Carmela Cursaro
- Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Pietro Andreone
- Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41126 Modena, Italy
- Internal and Metabolic Medicine, AOU of Modena-Baggiovara, 41126 Modena, Italy
- Postgraduate School of Allergology and Clinical Immunology, University of Modena and Reggio Emilia, 41126 Modena, Italy
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Basu S, Običan SG, Bertaggia E, Staab H, Izquierdo MC, Gyamfi-Bannerman C, Haeusler RA. Unresolved alterations in bile acid composition and dyslipidemia in maternal and cord blood after ursodeoxycholic acid treatment for intrahepatic cholestasis of pregnancy. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.08.21.24312246. [PMID: 39228704 PMCID: PMC11370516 DOI: 10.1101/2024.08.21.24312246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/05/2024]
Abstract
Intrahepatic cholestasis of pregnancy (ICP) is characterized by elevated plasma bile acid levels. ICP is linked to adverse metabolic outcomes, including a reported increased risk of gestational diabetes. The standard therapeutic approach for managing ICP is treatment with ursodeoxycholic acid (UDCA) and induction of labor prior to 40 weeks of gestation. To investigate bile acid and metabolic parameters after UDCA treatment, we enrolled 12 ICP patients with singleton pregnancies-half with and half without gestational diabetes-and 7 controls. Our study reveals that after UDCA treatment, notwithstanding a reduction in total bile acid and ALT levels, imbalances persist in the cholic acid (CA) to chenodeoxycholic acid (CDCA) ratio in maternal and cord blood plasma. This indicates a continued dysregulation of bile acid metabolism despite therapeutic intervention. Maternal plasma lipid analysis showed a distinct maternal dyslipidemia pattern among ICP patients, marked by elevated cholesterol levels on VLDL particles and heightened triglyceride concentrations on LDL particles, persisting even after UDCA treatment. Cord plasma lipid profiles in ICP patients exhibited elevated triglyceride and free fatty acid levels alongside a tendency toward increased β-hydroxybutyrate. The changes in lipid metabolism in both maternal and cord blood correlated with the high CA/CDCA ratio, but not total bile acid levels or gestational diabetes status. Understanding the imbalances in maternal and cord bile acid and lipid profiles that persist after standard UDCA therapy provides insights for improving management strategies and mitigating the long-term consequences of ICP. News and Noteworthy This study uncovers that despite ursodeoxycholic acid treatment, intrahepatic cholestasis of pregnancy (ICP) is associated with increases in the ratio of cholic acid to chenodeoxycholic acid in both maternal and cord blood, suggesting ongoing dysregulation of bile acid metabolism. The high cholic to chenodeoxycholic acid ratio is correlated with maternal dyslipidemia and high cord blood lipids. These findings may inform more targeted approaches to managing ICP.
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Brenøe JE, van Hoorn EGM, Beck L, Bulthuis M, Bezemer RE, Gordijn SJ, Schoots MH, Prins JR. Altered placental macrophage numbers and subsets in pregnancies complicated with intrahepatic cholestasis of pregnancy (ICP) compared to healthy pregnancies. Placenta 2024; 153:22-30. [PMID: 38810541 DOI: 10.1016/j.placenta.2024.05.129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 04/29/2024] [Accepted: 05/15/2024] [Indexed: 05/31/2024]
Abstract
INTRODUCTION Intrahepatic cholestasis of pregnancy (ICP) can result in adverse outcomes for both mother and fetus. Inflammatory (M1 subset) or anti-inflammatory (M2 subset) macrophage polarisation is associated with various complications of pregnancy. However, the influence of ICP on macrophage numbers and polarisation remains unknown. This study analyses macrophage density and distribution in placentas of patients with ICP compared to controls. Clinical parameters were correlated to macrophage distribution and ursodeoxycholic acid use (UDCA). METHODS This study included routinely collected placental tissue samples of 42 women diagnosed with ICP and of 50 control pregnancies. Immunohistochemical staining was performed on placental tissue using CD68 antibody as a pan-macrophage marker, CD206 antibody as an M2 and HLA-DR antibody as an M1 macrophage marker. Macrophage density (cells/mm2) and distribution (CD206+/CD68+ or CD206+/CD68+HLA-DR+) in both decidua (maternal tissue) and villous parenchyma (fetal tissue) were compared between groups. Macrophage density and distribution were correlated to clinical parameters for ICP patients. RESULTS The density of CD68+ macrophages differed significantly between groups in villous parenchyma. In both decidua and villous parenchyma, CD206+/CD68+ ratio was significantly lower in ICP patients compared to controls (p = 0.003 and p=<0.001, respectively). No difference was found based on UDCA use or in CD68+HLA-DR+ cell density. Significant correlations were found between macrophage density and peak serum bile acids and liver enzymes. DISCUSSION In ICP patients, an immune shift was observed in both decidual and villous tissue, indicated by a lower CD206+/CD68+ ratio. ICP seems to affect placental tissue, however more research is required to understand its consequences.
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Affiliation(s)
- J E Brenøe
- Department of Obstetrics and Gynecology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - E G M van Hoorn
- Department of Obstetrics and Gynecology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - L Beck
- Department of Obstetrics and Gynecology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - M Bulthuis
- Department of Pathology and Medical Biology, Division of Pathology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - R E Bezemer
- Department of Obstetrics and Gynecology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - S J Gordijn
- Department of Obstetrics and Gynecology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - M H Schoots
- Department of Pathology and Medical Biology, Division of Pathology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - J R Prins
- Department of Obstetrics and Gynecology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
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Cai J, Tang M, Deng Y, Xiong L, Luo M, Huang C, Yang L, Yang X. Global research status of intrahepatic cholestasis of pregnancy: A bibliometric analysis of hotspots, bursts, and trends. Heliyon 2024; 10:e33940. [PMID: 39055843 PMCID: PMC11269835 DOI: 10.1016/j.heliyon.2024.e33940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 06/28/2024] [Accepted: 07/01/2024] [Indexed: 07/28/2024] Open
Abstract
Background Research on intrahepatic cholestasis of pregnancy (ICP) has recently gained attention. However, no bibliometric analysis was performed in the ICP research field. Therefore, the present study aimed to use bibliometric analysis to analyze the current research hotspots and identify global research status in ICP to reference for future research directions. Methods We comprehensively searched the Web of Science Core Collection (WoSCC) database from its inception to December 31, 2023. Articles and reviews related to ICP were downloaded as plain text file records. We used the VOSviewer and Citespace to perform the bibliometric analysis and visualization. The main bibliometric features were tabulated and calculated. Results A total of 1092 documents, including 921 original articles and 171 reviews, were identified in WoSCC. These publications were published in 395 journals by 4751 authors from 1250 institutions and 61 countries/regions. The global publication numbers exhibited a gradual upward trend. China, the United States, and the United Kingdom were top contributors to scientific research on ICP. King's College London, London Imperial Coll Sci Technol & Med, and Sichuan University were the most productive institutions. Catherine Williamson had published the most papers and received the most total citations. The most productive journal was Journal of Maternal-Fetal & Neonatal Medicine. The most cited paper was Beuers et al. in the Journal of Hepatology (2009). Citation burst terms showed that "risk factors" and "perinatal outcomes" were hotspots. "Inflammation", "risk factors", "perinatal outcomes", and "bile acid" have gained attention in more recent research. Conclusion The present study comprehensively summarizes the global research status and research trends in ICP. Our study identifies hotspots, collaborative networks, and trends that will provide new insights and guidance for further research in the field.
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Affiliation(s)
- Jianghui Cai
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, 611731, China
- Department of Pharmacy, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Mi Tang
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, 611731, China
- Office of Good Clinical Practice, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Yi Deng
- Department of Pharmacy, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Liling Xiong
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, 611731, China
- Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Mengqiu Luo
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Cheng Huang
- Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Li Yang
- Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Xiao Yang
- Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 611731, China
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Feng F, Li J, Liao J, Qin S, Liu Y, Che X, Zhou Y, Jiang D, Xiao H, Chen A, Shao Y. Associations of clinical subtypes and bile acid levels of intrahepatic cholestasis of pregnancy with pregnancy outcomes. Sci Rep 2024; 14:12185. [PMID: 38806569 PMCID: PMC11133304 DOI: 10.1038/s41598-024-63183-9] [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: 11/05/2023] [Accepted: 05/27/2024] [Indexed: 05/30/2024] Open
Abstract
Intrahepatic cholestasis of pregnancy (ICP) can lead to many adverse pregnancy outcomes, and the influencing factors remain unclear at present. This study retrospectively analyzed clinical data from 1815 pregnant women with ICP and evaluated the relationship between ICP subtypes, gestational age at onset, and pregnancy outcomes. The results of this study show that during pregnancy, the levels of biochemical indicators (TBA, DBIL and ALT) in the serum of pregnant women initially diagnosed with subtypes of ICP were noted to constantly change, and the subtype of ICP and its severity also changed. The incidence of adverse pregnancy outcomes [meconium-stained amniotic fluid (MSAF), NICU transfer, Apgar score ≤ 7 at 1 min, and preterm birth] in patients with ICP1 (icteric type) was significantly higher than for patients with ICP2, ICP3 or ICP4. The preterm birth rate of early-onset ICP was higher than that of late-onset ICP in ICP1 and ICP3 subtypes. In conclusion, the outcome of pregnancy in women with ICP is closely related to the serum TBA level and ICP subtype, which should be recognized in the clinic.
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Affiliation(s)
- Fan Feng
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Juhong Li
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
- Department of Obstetrics and Gynecology, Yubei District Maternal and Child Health Hospital, Chongqing, China
| | - Junqun Liao
- Department of Experiment, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Shiyi Qin
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Yaling Liu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
- Department of Obstetrics and Gynecology, Yubei District Maternal and Child Health Hospital, Chongqing, China
| | - Xian Che
- Department of Obstetrics and Gynecology, Yubei District Maternal and Child Health Hospital, Chongqing, China
| | - Yanjun Zhou
- Department of Obstetrics and Gynecology, Yubei District Maternal and Child Health Hospital, Chongqing, China
| | - Dan Jiang
- Department of Obstetrics and Gynecology, Yubei District Maternal and Child Health Hospital, Chongqing, China
| | - Huiqin Xiao
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Aixing Chen
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Yong Shao
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
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Sentilhes L, Sénat MV, Bouchghoul H, Delorme P, Gallot D, Garabedian C, Madar H, Sananès N, Perrotin F, Schmitz T. [Intrahepatic cholestasis of pregnancy: French College of Obstetricians and Gynecologists guidelines for clinical practice]. GYNECOLOGIE, OBSTETRIQUE, FERTILITE & SENOLOGIE 2023; 51:493-510. [PMID: 37806861 DOI: 10.1016/j.gofs.2023.09.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/10/2023]
Abstract
OBJECTIVE To identify strategies for reducing neonatal and maternal morbidity associated with intrahepatic cholestasis pregnancy (ICP). MATERIAL AND METHODS The quality of evidence of the literature was assessed following the GRADE methodology with questions formulated in the PICO format (Patients, Intervention, Comparison, Outcome) and outcomes defined a priori and classified according to their importance. An extensive bibliographic search was performed on PubMed, Cochrane, EMBASE and Google Scholar databases. The quality of the evidence was assessed (high, moderate, low, very low) and a (i) strong or (ii) weak recommendations or (iii) no recommendation were formulated. The recommendations were reviewed in two rounds with external reviewers (Delphi survey) to select the consensus recommendations. RESULTS Of the 14 questions (from 12 PICO questions and one definition question outside the PICO format), there was agreement between the working group and the external reviewers on 14 (100%). The level of evidence of the literature was insufficient to provide a recommendation on two questions. ICP is defined by the occurrence of suggestive pruritus (palmoplantar, nocturnal) associated with a total bile acid level>10μmol/L or an alanine transaminase level above 2N after ruling out differential diagnoses. In the absence of suggestive symptoms of a differential diagnosis, it is recommended not to carry out additional biological or ultrasound tests. In women with CIP, ursodeoxycholic acid is recommended to reduce the intensity of maternal pruritus (Strong recommendation. Quality of the evidence moderate) and to decrease the level of total bile acids and alanine transaminases. (Strong recommendation. Quality of the evidence moderate). S-adenosyl-methionine, dexamethasone, guar gum or activated charcoal should not be used to reduce the intensity of maternal pruritus (Strong recommendation. Quality of evidence low), and there is insufficient data to recommend the use of antihistamines (No recommendation. Quality of evidence low). Rifampicin (Weak recommendation. Very low quality of evidence) or plasma exchange (Strong recommendation. Very low quality of evidence) should not be used to reduce maternal pruritus and perinatal morbidity. Serum monitoring of bile acids is recommended to reduce perinatal morbidity and mortality (stillbirth, prematurity) (Low recommendation. Quality of the evidence low). The level of evidence is insufficient to determine whether fetal heart rate or fetal ultrasound monitoring are useful to reduce perinatal morbidity (No recommendation). Birth is recommended when bile acid level is above 99μmol/L from 36 weeks gestation to reduce perinatal morbidity, in particular stillbirth. When bile acid level is above 99μmol/L is below 100μmol/L, women should be informed that induction of labor could be considered 37 and 39 weeks gestation to reduce perinatal morbidity. (Strong recommendation. Quality of evidence low). In postpartum, total bile acids and alanine transaminases level should be checked and normalized before prescribing estrogen-progestin contraception, ideally with a low estrogen dose (risk of recurrence of pruritus and cytolysis) (Low recommendation. Quality of evidence very low). CONCLUSION Although the quality of evidence regarding ICP gestational cholestasis remains low, there is a strong consensus in France, as shown by our Delphi study, on how to manage women with ICP. The reference first-line treatment is ursodeoxycholic acid.
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Affiliation(s)
- L Sentilhes
- Service de gynécologie-obstétrique, centre hospitalier universitaire de Bordeaux, Bordeaux, France.
| | - M-V Sénat
- Service de gynécologie-obstétrique, hôpital Bicêtre, AP-HP, Le Kremlin-Bicêtre, France
| | - H Bouchghoul
- Service de gynécologie-obstétrique, centre hospitalier universitaire de Bordeaux, Bordeaux, France
| | - P Delorme
- Service de gynécologie-obstétrique, hôpital Trousseau, AP-HP, Paris, France
| | - D Gallot
- Service de gynécologie-obstétrique, centre hospitalier universitaire de Clermont-Ferrand, Clermont-Ferrand, France
| | - C Garabedian
- Service de gynécologie-obstétrique, CHU de Lille, université de Lille, ULR 2694-METRICS, 59000 Lille, France
| | - H Madar
- Service de gynécologie-obstétrique, centre hospitalier universitaire de Bordeaux, Bordeaux, France
| | - N Sananès
- Service de gynécologie-obstétrique, hôpitaux universitaires de Strasbourg, Strasbourg, France
| | - F Perrotin
- Service de gynécologie-obstétrique, centre hospitalier universitaire de Tours, Tours, France
| | - T Schmitz
- Service de gynécologie obstétrique, hôpital Robert-Debré, AP-HP, Paris, France
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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: 34] [Impact Index Per Article: 17.0] [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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Distribution of endotoxin in maternal and fetal body with intrahepatic cholestasis of pregnancy and its association with adverse fetal outcome. BMC Pregnancy Childbirth 2022; 22:920. [PMID: 36482374 PMCID: PMC9733156 DOI: 10.1186/s12884-022-05235-4] [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: 03/24/2022] [Accepted: 11/20/2022] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Intrahepatic cholestasis of pregnancy is a pregnancy-specific liver disease. In this study, we sought to explore the distribution of lipopolysaccharide in the maternal body, and its effect on the fetal body in the intrahepatic cholestasis of pregnancy mice. It provides a new sight for the clinical treatment of women with intrahepatic cholestasis of pregnancy. METHODS The serum levels of lipopolysaccharide and lipopolysaccharide binding protein in women with intrahepatic cholestasis of pregnancy were analyzed. To assess the association between lipopolysaccharide levels and adverse fetal outcomes, ursodeoxycholic acid, resveratrol, and phosphatidylinositol-3-kinase inhibitor were employed in intrahepatic cholestasis of pregnancy mice, and we studied the fluorescence intensity and distribution of lipopolysaccharide in mice with intrahepatic cholestasis of pregnancy. RESULTS Our data indicated significantly elevated levels of lipopolysaccharide and lipopolysaccharide binding protein in women with intrahepatic cholestasis of pregnancy. In vivo fluorescence imaging revealed that the intensity of lipopolysaccharide in mice with intrahepatic cholestasis of pregnancy was higher than that in the control group, and decreased after ursodeoxycholic and resveratrol treatment. The fluorescence intensity analysis indicated that lipopolysaccharide levels in maternal liver, placenta, fetal brain and fetal liver were significantly higher in the intrahepatic cholestasis pregnancy mice group than in the control group. CONCLUSIONS This study provided evidence of endotoxin distribution in maternal liver, placenta, fetal liver and fetal brain in mice with intrahepatic cholestasis of pregnancy. Ursodeoxycholic acid and resveratrol treatment effectively reduced lipopolysaccharide levels in pregnant mice with intrahepatic cholestasis of pregnancy.
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Muacevic A, Adler JR, Kumar M, Swati S. Feto-Maternal Effects of Adding Rifampicin to Ursodeoxycholic Acid in the Treatment of Intrahepatic Cholestasis of Pregnancy. Cureus 2022; 14:e32509. [PMID: 36654556 PMCID: PMC9840412 DOI: 10.7759/cureus.32509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/12/2022] [Indexed: 12/15/2022] Open
Abstract
Background Various pharmacological agents are used to manage intrahepatic cholestasis of pregnancy (ICP) for maternal pruritus and to lower serum bile acids in fear of adverse fetal outcomes. Ursodeoxycholic acid (UDCA) is the most widely used drug, but some patients do not respond to it. Neither UDCA nor any other drug being used for ICP is based on a high level of evidence. Methods A total of 108 pregnant women with ICP who were receiving UDCA with or without rifampicin were included in a prospective observational study from December 2018 to November 2020. Seventy-eight patients receiving UDCA only were labeled as group A, and 30 patients receiving UDCA with rifampicin were labeled as group B. Results The study subjects were comparable in both groups with respect to demographic factors. Pruritus, being the major symptom of ICP, has a mean (standard deviation (SD)) onset at 30.02 (2.93) weeks and 26.70 (4.56) weeks of gestation in groups A and B, respectively. Group B patients had earlier onset of symptoms and earlier mean (SD) gestational age at diagnosis at 28.89 (4.29) weeks compared to 32.47 (2.93) weeks in group A. Therefore, the mean (SD) gestational age to start UDCA was early in group B (29.32 (4.24) weeks). Relief in itch from UDCA was seen in 93.59% (73) in group A and 10% (3) in group B (partial relief). The mean (SD) duration for receiving only UDCA was 3.84 (2.07) weeks and 2.86 (1.58) weeks, respectively, for groups A and B. The mean (SD) gestational age at starting rifampicin was 32.11 (3.4) weeks for group B (n = 30). UDCA plus rifampicin was given for a mean (SD) duration of 3.48 (1.42) weeks. The mean (SD) dosage of UDCA given per day was 911.54 (229.05) mg in group A and 880 (260.50) mg in group B (p value = 0.563). The mean (SD) dosage of rifampicin used in group B was 700 (363.89) mg/day. The mean (SD) of baseline bile acids (pretreatment) was 36.94 (13) umol/L and 42.50 (15.23) umol/L in groups A and B, respectively (p value = 0.274). At the two-week follow-up, the mean (SD) value of serum bile acids was 22.92 (10.67) umol/L and 14.88 (10.27) umol/L in groups A and B, respectively (p value = 0.039). Group B having an earlier onset of ICP also had early gestational age at delivery at 35.70 (2.57) weeks versus 37.011 (1.18) weeks in group A. Of the babies in groups A and B, 63% and 50% were born full term, respectively. There was no significant difference in the mode of delivery for both study groups. The mean (SD) birth weight of babies was 2,706.85 (206.19) grams for group A and 2,522.67 (342.20) grams in group B. Adverse neonatal outcomes for both groups were comparable (68.5% in group A and 70% in group B) (p value = 0.881). Of the patients, 9% and 6.7% had antepartum stillbirth in groups A and B, respectively. Of the babies in groups A and B, 10.3% and 6.7% were born with dark-colored meconium or placental membranes and cord stained with meconium, respectively. In groups A and B, 9% and 6.7% of the babies were born with thin/light green meconium-stained liquor, respectively. Conclusion Rifampicin, if added to UDCA for the management of ICP, does not cause any adverse fetal outcome. It is a useful adjunct to UDCA for severe and/or resistant ICP, and it helps improve pruritus and serum bile acids.
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Abdelhafez MMA, Ahmed KAM, Than WW, Baharuddin DMP, Kadir F, Jeffree S, Hayati MF, Daud MNBM, Eldiastey AM, Tay KX. Intrahepatic cholestasis of pregnancy: from an obstetrician point of view. J OBSTET GYNAECOL 2022; 42:2550-2557. [PMID: 35666947 DOI: 10.1080/01443615.2022.2081801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Intrahepatic cholestasis of pregnancy (ICP) is the commonest among the specific dermatoses of pregnancy. The disease is characterised by intense pruritus and specifically by elevated bile acid levels and owing to the rarity of data published in this context, the disease carries a great challenge in both diagnosis and management. The disease is associated with significant maternal as well as perinatal adverse effects, hence, this article aims at improving the knowledge of the women's health carers with the up-to-date and evidence-based, whenever possible, recommendations while managing patients with ICP.
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Affiliation(s)
- Mohsen M A Abdelhafez
- Department of Obstetrics and Gynaecology, Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah, Kota Kinabalu, Malaysia
| | - Karim A M Ahmed
- Department of Dermatology, Helios Saint Johannes Klinikum, Duisburg, Germany
| | - Win Win Than
- Department of Obstetrics and Gynaecology, Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah, Kota Kinabalu, Malaysia
| | - Dg Marshitah Pg Baharuddin
- Department of Obstetrics and Gynaecology, Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah, Kota Kinabalu, Malaysia
| | - Fairrul Kadir
- Department of Emergency Medicine, Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah, Kota Kinabalu, Malaysia
| | - Saffree Jeffree
- Department of Public Health Medicine, Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah, Kota Kinabalu, Malaysia
| | - Mohammad Firdaus Hayati
- Department of Surgery, Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah, Kota Kinabalu, Malaysia
| | - Mohd Nazri Bin Mohd Daud
- Department of Public Health Medicine, Faculty of Medicine and Health Sciences, Family Medicine Unit, Universiti Malaysia Sabah, Kota Kinabalu, Malaysia
| | | | - Kai Xin Tay
- Faculty of Business, Economic, and Accountancy, Universiti Malaysia Sabah, Kota Kinabalu, Malaysia
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14
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Recognizing, Diagnosing, and Managing Pregnancy Dermatoses. Obstet Gynecol 2022; 140:679-695. [PMID: 36075066 DOI: 10.1097/aog.0000000000004938] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Accepted: 05/26/2022] [Indexed: 01/05/2023]
Abstract
Pregnancy dermatoses are inflammatory skin disorders that occur during pregnancy or immediately postpartum. This heterogenous group of disorders includes pemphigoid gestationis, polymorphic eruption of pregnancy, intrahepatic cholestasis of pregnancy, atopic eruption of pregnancy, and pustular psoriasis of pregnancy. In this article, we provide a comprehensive literature review of each condition focusing on nomenclature, epidemiology, pathogenesis, clinical presentation, diagnosis, differential diagnosis, maternal risk, fetal risk, and treatment. We aim to increase awareness and help clinicians recognize, diagnose, and manage these unique conditions.
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Wang P, Yuan P, Lin S, Zhong H, Zhang X, Zhuo Y, Li J, Che L, Feng B, Lin Y, Xu S, Wu D, Burrin DG, Fang Z. Maternal and Fetal Bile Acid Homeostasis Regulated by Sulfated Progesterone Metabolites through FXR Signaling Pathway in a Pregnant Sow Model. Int J Mol Sci 2022; 23:6496. [PMID: 35742938 PMCID: PMC9224516 DOI: 10.3390/ijms23126496] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 06/05/2022] [Accepted: 06/07/2022] [Indexed: 12/24/2022] Open
Abstract
Abnormally elevated circulating bile acids (BA) during pregnancy endanger fetal survival and offspring health; however, the pathology and underlying mechanisms are poorly understood. A total of nineteen pregnant sows were randomly assigned to day 60 of gestation, day 90 of gestation (G60, G90), and the farrowing day (L0), to investigate the intercorrelation of reproductive hormone, including estradiol, progesterone and sulfated progesterone metabolites (PMSs), and BA in the peripheral blood of mother and fetuses during pregnancy. All data were analyzed by Student's t-test or one-way ANOVA of GraphPad Prism and further compared by using the Student-Newman-Keuls test. Correlation analysis was also carried out using the CORR procedure of SAS to study the relationship between PMSs and BA levels in both maternal and fetal serum at G60, G90, and L0. Allopregnanolone sulphate (PM4S) and epiallopregnanolone sulphate (PM5S) were firstly identified in the maternal and fetal peripheral blood of pregnant sows by using newly developed ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) methods. Correlation analysis showed that pregnancy-associated maternal BA homeostasis was correlated with maternal serum PM4S levels, whereas fetal BA homeostasis was correlated with fetal serum PM5S levels. The antagonist activity role of PM5S on farnesoid X receptor (FXR)-mediated BA homeostasis and fibroblast growth factor 19 (FGF19) were confirmed in the PM5S and FXR activator co-treated pig primary hepatocytes model, and the antagonist role of PM4S on FXR-mediated BA homeostasis and FGF19 were also identified in the PM4S-treated pig primary hepatocytes model. Together with the high relative expression of FGF19 in pig hepatocytes, the pregnant sow is a promising animal model to investigate the pathogenesis of cholestasis during pregnancy.
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Affiliation(s)
- Peng Wang
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, China; (P.W.); (P.Y.); (H.Z.); (X.Z.); (Y.Z.); (J.L.); (L.C.); (B.F.); (Y.L.); (S.X.); (D.W.)
- College of Biology Engineering, Henan University of Technology, Zhengzhou 450000, China
| | - Peiqiang Yuan
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, China; (P.W.); (P.Y.); (H.Z.); (X.Z.); (Y.Z.); (J.L.); (L.C.); (B.F.); (Y.L.); (S.X.); (D.W.)
| | - Sen Lin
- Sericultural & Agri-Food Research Institute, Guangdong Academy of Agricultural Sciences, Guangzhou 510000, China;
| | - Heju Zhong
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, China; (P.W.); (P.Y.); (H.Z.); (X.Z.); (Y.Z.); (J.L.); (L.C.); (B.F.); (Y.L.); (S.X.); (D.W.)
| | - Xiaoling Zhang
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, China; (P.W.); (P.Y.); (H.Z.); (X.Z.); (Y.Z.); (J.L.); (L.C.); (B.F.); (Y.L.); (S.X.); (D.W.)
| | - Yong Zhuo
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, China; (P.W.); (P.Y.); (H.Z.); (X.Z.); (Y.Z.); (J.L.); (L.C.); (B.F.); (Y.L.); (S.X.); (D.W.)
| | - Jian Li
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, China; (P.W.); (P.Y.); (H.Z.); (X.Z.); (Y.Z.); (J.L.); (L.C.); (B.F.); (Y.L.); (S.X.); (D.W.)
| | - Lianqiang Che
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, China; (P.W.); (P.Y.); (H.Z.); (X.Z.); (Y.Z.); (J.L.); (L.C.); (B.F.); (Y.L.); (S.X.); (D.W.)
| | - Bin Feng
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, China; (P.W.); (P.Y.); (H.Z.); (X.Z.); (Y.Z.); (J.L.); (L.C.); (B.F.); (Y.L.); (S.X.); (D.W.)
- Key Laboratory for Food Science and Human Health, College of Food Science, Sichuan Agricultural University, Ya’an 625014, China
| | - Yan Lin
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, China; (P.W.); (P.Y.); (H.Z.); (X.Z.); (Y.Z.); (J.L.); (L.C.); (B.F.); (Y.L.); (S.X.); (D.W.)
| | - Shengyu Xu
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, China; (P.W.); (P.Y.); (H.Z.); (X.Z.); (Y.Z.); (J.L.); (L.C.); (B.F.); (Y.L.); (S.X.); (D.W.)
| | - De Wu
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, China; (P.W.); (P.Y.); (H.Z.); (X.Z.); (Y.Z.); (J.L.); (L.C.); (B.F.); (Y.L.); (S.X.); (D.W.)
| | - Douglas G Burrin
- USDA/ARS Children’s Nutrition Research Center, Section of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA;
| | - Zhengfeng Fang
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, China; (P.W.); (P.Y.); (H.Z.); (X.Z.); (Y.Z.); (J.L.); (L.C.); (B.F.); (Y.L.); (S.X.); (D.W.)
- Key Laboratory for Food Science and Human Health, College of Food Science, Sichuan Agricultural University, Ya’an 625014, China
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Sangaraju D, Katavolos P, Liang X, Chou C, Zabka TS, Dean B, Maher J. Establishment of baseline profiles of 50 bile acids in preclinical toxicity species: A comprehensive assessment of translational differences and study design considerations for biomarker development. Toxicol Appl Pharmacol 2022; 443:116008. [DOI: 10.1016/j.taap.2022.116008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 03/27/2022] [Accepted: 03/28/2022] [Indexed: 11/29/2022]
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Sahoo SM, Mahapatra SJ. Intrahepatic cholestasis of pregnancy: are we expecting too much from ursodeoxycholic acid? Lancet Gastroenterol Hepatol 2021; 6:886. [PMID: 34626559 DOI: 10.1016/s2468-1253(21)00306-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 07/29/2021] [Accepted: 08/09/2021] [Indexed: 12/31/2022]
Affiliation(s)
- Sushree Monika Sahoo
- Department of Obstetrics and Gynecology, Vardhman Mahavir Medical College and Safdarjung Hospital, 110029 New Delhi, India.
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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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Ovadia C, Sajous J, Seed PT, Patel K, Williamson NJ, Attilakos G, Azzaroli F, Bacq Y, Batsry L, Broom K, Brun-Furrer R, Bull L, Chambers J, Cui Y, Ding M, Dixon PH, Estiú MC, Gardiner FW, Geenes V, Grymowicz M, Günaydin B, Hague WM, Haslinger C, Hu Y, Indraccolo U, Juusela A, Kane SC, Kebapcilar A, Kebapcilar L, Kohari K, Kondrackienė J, Koster MPH, Lee RH, Liu X, Locatelli A, Macias RIR, Madazli R, Majewska A, Maksym K, Marathe JA, Morton A, Oudijk MA, Öztekin D, Peek MJ, Shennan AH, Tribe RM, Tripodi V, Türk Özterlemez N, Vasavan T, Wong LFA, Yinon Y, Zhang Q, Zloto K, Marschall HU, Thornton J, Chappell LC, Williamson C. Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy: a systematic review and individual participant data meta-analysis. Lancet Gastroenterol Hepatol 2021; 6:547-558. [PMID: 33915090 PMCID: PMC8192305 DOI: 10.1016/s2468-1253(21)00074-1] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 02/19/2021] [Accepted: 02/22/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND Ursodeoxycholic acid is commonly used to treat intrahepatic cholestasis of pregnancy, yet its largest trial detected minimal benefit for a composite outcome (stillbirth, preterm birth, and neonatal unit admission). We aimed to examine whether ursodeoxycholic acid affects specific adverse perinatal outcomes. METHODS In this systematic review and individual participant data meta-analysis, we searched PubMed, Web of Science, Embase, MEDLINE, CINAHL, Global Health, MIDIRS, and Cochrane without language restrictions for relevant articles published between database inception, and Jan 1, 2020, using search terms referencing intrahepatic cholestasis of pregnancy, ursodeoxycholic acid, and perinatal outcomes. Eligible studies had 30 or more study participants and reported on at least one individual with intrahepatic cholestasis of pregnancy and bile acid concentrations of 40 μmol/L or more. We also included two unpublished cohort studies. Individual participant data were collected from the authors of selected studies. The primary outcome was the prevalence of stillbirth, for which we anticipated there would be insufficient data to achieve statistical power. Therefore, we included a composite of stillbirth and preterm birth as a main secondary outcome. A mixed-effects meta-analysis was done using multi-level modelling and adjusting for bile acid concentration, parity, and multifetal pregnancy. Individual participant data analyses were done for all studies and in different subgroups, which were produced by limiting analyses to randomised controlled trials only, singleton pregnancies only, or two-arm studies only. This study is registered with PROSPERO, CRD42019131495. FINDINGS The authors of the 85 studies fulfilling our inclusion criteria were contacted. Individual participant data from 6974 women in 34 studies were included in the meta-analysis, of whom 4726 (67·8%) took ursodeoxycholic acid. Stillbirth occurred in 35 (0·7%) of 5097 fetuses among women with intrahepatic cholestasis of pregnancy treated with ursodeoxycholic acid and in 12 (0·6%) of 2038 fetuses among women with intrahepatic cholestasis of pregnancy not treated with ursodeoxycholic acid (adjusted odds ratio [aOR] 1·04, 95% CI 0·35-3·07; p=0·95). Ursodeoxycholic acid treatment also had no effect on the prevalence of stillbirth when considering only randomised controlled trials (aOR 0·29, 95% CI 0·04-2·42; p=0·25). Ursodeoxycholic acid treatment had no effect on the prevalence of the composite outcome in all studies (aOR 1·28, 95% CI 0·86-1·91; p=0·22), but was associated with a reduced composite outcome when considering only randomised controlled trials (0·60, 0·39-0·91; p=0·016). INTERPRETATION Ursodeoxycholic acid treatment had no significant effect on the prevalence of stillbirth in women with intrahepatic cholestasis of pregnancy, but our analysis was probably limited by the low overall event rate. However, when considering only randomised controlled trials, ursodeoxycholic acid was associated with a reduction in stillbirth in combination with preterm birth, providing evidence for the clinical benefit of antenatal ursodeoxycholic acid treatment. FUNDING Tommy's, the Wellcome Trust, ICP Support, and the National Institute for Health Research.
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Affiliation(s)
- Caroline Ovadia
- Department of Women and Children's Health, King's College London, London, UK
| | - Jenna Sajous
- Department of Women and Children's Health, King's College London, London, UK
| | - Paul T Seed
- Department of Women and Children's Health, King's College London, London, UK
| | - Kajol Patel
- Department of Women and Children's Health, King's College London, London, UK
| | | | - George Attilakos
- Department of Obstetrics and Gynaecology, University College London Hospitals NHS Foundation Trust, London, UK
| | - Francesco Azzaroli
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Yannick Bacq
- Department of Hepatology and Gastroenterology, University Hospital of Tours, Tours, France
| | - Linoy Batsry
- Department of Obstetrics and Gynecology, Sheba Medical Center, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Kelsey Broom
- Bendigo Healthcare Group, Bendigo, VIC, Australia
| | - Romana Brun-Furrer
- Department of Obstetrics, University Hospital Zurich, Zurich, Switzerland
| | - Laura Bull
- Department of Medicine and Institute for Human Genetics, University of California, San Francisco, CA, USA
| | - Jenny Chambers
- Women's Health Research Centre, Imperial College London, London, UK
| | - Yue Cui
- School of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Min Ding
- School of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Peter H Dixon
- Department of Women and Children's Health, King's College London, London, UK
| | - Maria C Estiú
- Ramón Sardá Mother's and Children's Hospital, Buenos Aires, Argentina
| | | | - Victoria Geenes
- Department of Women and Children's Health, King's College London, London, UK
| | - Monika Grymowicz
- Department of Gynecological Endocrinology, Medical University of Warsaw, Warsaw, Poland
| | - Berrin Günaydin
- Department of Anesthesiology and Reanimation, Gazi University School of Medicine, Ankara, Turkey
| | - William M Hague
- Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia
| | | | - Yayi Hu
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Ugo Indraccolo
- Maternal-Infantile Department, Complex Operative Unit of Obstetrics and Gynecology Alto Tevere Hospital of Città di Castello, Città di Castello, Italy
| | | | - Stefan C Kane
- Department of Maternal-Fetal Medicine, Royal Women's Hospital, Parkville, VIC, Australia; Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, VIC, Australia
| | - Ayse Kebapcilar
- Department of Gynecology and Obstetrics, Selcuk University, Konya, Turkey
| | | | - Katherine Kohari
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA
| | - Jūratė Kondrackienė
- Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Maria P H Koster
- Department of Obstetrics and Gynaecology, Erasmus MC, University Medical Center Rotterdam, Netherlands
| | - Richard H Lee
- Department of Obstetrics and Gynecology, Keck School of Medicine University of Southern California, Los Angeles, CA, USA
| | - Xiaohua Liu
- Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China
| | - Anna Locatelli
- Department of Obstetrics and Gynecology, University of Milano-Bicocca, Monza, Italy
| | - Rocio I R Macias
- Department of Physiology and Pharmacology, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Institute of Biomedical Research of Salamanca, University of Salamanca, Salamanca, Spain
| | - Riza Madazli
- Department of Obstetrics and Gynecology, Istanbul University, Cerrahpaşa, Istanbul, Turkey
| | - Agata Majewska
- First Department of Obstetrics and Gynecology, Medical University of Warsaw, Warsaw, Poland
| | - Kasia Maksym
- Department of Obstetrics and Gynaecology, University College London Hospitals NHS Foundation Trust, London, UK
| | - Jessica A Marathe
- Department of Cardiology, Royal Adelaide Hospital, Adelaide, SA, Australia
| | - Adam Morton
- Department of Obstetric Medicine, Mater Health Services Public Hospital, Brisbane, QLD, Australia
| | - Martijn A Oudijk
- Department of Obstetrics, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - Deniz Öztekin
- Department of Obstetrics and Gynecology, İzmir Bakircay University, İzmir, Turkey
| | - Michael J Peek
- ANU Medical School, College of Health and Medicine, The Australian National University, Canberra, ACT, Australia
| | - Andrew H Shennan
- Department of Women and Children's Health, King's College London, London, UK
| | - Rachel M Tribe
- Department of Women and Children's Health, King's College London, London, UK
| | - Valeria Tripodi
- Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Naciye Türk Özterlemez
- Department of Anesthesiology and Reanimation, Gazi University School of Medicine, Ankara, Turkey
| | - Tharni Vasavan
- Department of Women and Children's Health, King's College London, London, UK
| | - L F Audris Wong
- Department of Women's and Newborn, Gold Coast University Hospital, Southport, QLD, Australia
| | - Yoav Yinon
- Department of Obstetrics and Gynecology, Sheba Medical Center, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Qianwen Zhang
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Keren Zloto
- Department of Obstetrics and Gynecology, Sheba Medical Center, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Hanns-Ulrich Marschall
- Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Jim Thornton
- Division of Child Health, Obstetrics and Gynaecology, University of Nottingham, Nottingham, UK
| | - Lucy C Chappell
- Department of Women and Children's Health, King's College London, London, UK
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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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21
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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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22
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Intrahepatic Cholestasis of Pregnancy and Associated Adverse Maternal and Fetal Outcomes: A Retrospective Case-Control Study. Gastroenterol Res Pract 2021; 2021:6641023. [PMID: 33833795 PMCID: PMC8016576 DOI: 10.1155/2021/6641023] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 02/02/2021] [Accepted: 03/10/2021] [Indexed: 12/11/2022] Open
Abstract
Objective Intrahepatic cholestasis of pregnancy (ICP) is a common pregnancy-related liver disease and is associated with an increased risk of adverse neonatal outcomes. Ursodeoxycholic acid (UDCA) is the most effective treatment. This study was aimed at investigating the adverse outcomes of ICP and evaluating the effects of treatment with UDCA in patients with ICP. Methods We included 114 women with ICP and 3725 women without ICP (no-ICP group) who delivered in our hospital between September 2017 and August 2019. The prevalence of ICP in this study was 3.15%. We matched each woman with ICP to five controls. Of all the 114 women with ICP, 73 (64.04%) received UDCA while 41 (35.96%) did not. Logistic multivariate regression analysis was used to compare the adverse outcomes between those with ICP and matched controls as well as between those who received UDCA (UDCA group) and those who did not (non-UDCA group). Results Compared with controls, women with ICP were more likely to have preeclampsia (adjusted odds ratio, aOR = 16.74, 95% CI 5.29-52.98), cesarean section (aOR = 1.76, 95% CI 1.10-2.81), and preterm birth (aOR = 24.35, 95% CI 2.74-216.67). Administration of UDCA reduced the rate of preterm birth (1.37% vs. 14.63%, aOR = 0.10, 95% CI 0.01-0.90). Conclusion ICP increased the risk of preeclampsia, cesarean section, and preterm birth. UDCA could reduce the rate of preterm birth.
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23
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Sticova E, Jirsa M. ABCB4 disease: Many faces of one gene deficiency. Ann Hepatol 2021; 19:126-133. [PMID: 31759867 DOI: 10.1016/j.aohep.2019.09.010] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2019] [Revised: 09/04/2019] [Accepted: 09/06/2019] [Indexed: 02/07/2023]
Abstract
ATP-binding cassette (ABC) subfamily B member 4 (ABCB4), also known as multidrug resistance protein 3 (MDR3), encoded by ABCB4, is involved in biliary phospholipid secretion, protecting hepatobiliary system from deleterious detergent and lithogenic properties of the bile. ABCB4 mutations altering canalicular ABCB4 protein function and expression may have variable clinical presentation and predispose to several human liver diseases. Well-established phenotypes of ABCB4 deficit are: progressive familial intrahepatic cholestasis type 3, gallbladder disease 1 (syn. low phospholipid associated cholelithiasis syndrome), high ɣ-glutamyl transferase intrahepatic cholestasis of pregnancy, chronic cholangiopathy, and adult biliary fibrosis/cirrhosis. Moreover, ABCB4 aberrations may be involved in some cases of drug induced cholestasis, transient neonatal cholestasis, and parenteral nutrition-associated liver disease. Recently, genome-wide association studies have documented occurrence of malignant tumours, predominantly hepatobiliary malignancies, in patients with ABCB4/MDR3 deficit. The patient's age at the time of the first presentation of cholestatic disease, as well as the severity of liver disorder and response to treatment are related to the ABCB4 allelic status. Mutational analysis of ABCB4 in patients and their families should be considered in all individuals with cholestasis of unknown aetiology, regardless of age and/or time of onset of the first symptoms.
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Affiliation(s)
- Eva Sticova
- Institute for Clinical and Experimental Medicine, Videnska, Prague, Czech Republic; Pathology Department, Third Faculty of Medicine, Charles University and University Hospital Kralovske Vinohrady, Srobarova, Prague, Czech Republic.
| | - Milan Jirsa
- Institute for Clinical and Experimental Medicine, Videnska, Prague, Czech Republic; Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and Faculty General Hospital, U Nemocnice, Prague, Czech Republic
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Abstract
OBJECTIVES To provide an investigation protocol to help health care providers determine the cause of a fetal death. OPTIONS Consideration has been given to protocols for the investigation of fetal death that are currently available in Canada and in other countries. OUTCOMES Identification of possible causes of stillbirth and their relationship to future pregnancies. EVIDENCE Articles related to the etiology of fetal death were identified in a search of PubMed (June 2006 to September 2018), the Cochrane Library, and investigation protocols from the American College of Obstetricians and Gynecologists, the International Stillbirth Alliance Collaborative for Improving Classification of Perinatal Deaths, the Royal College of Obstetricians and Gynaecologists, the Queensland clinical guidelines, and the Reproductive Care Program of Nova Scotia. BENEFITS To provide better advice for women regarding possible causes of fetal death and implications for future pregnancies. VALIDATION The evidence obtained was reviewed and evaluated by the Maternal-Fetal Medicine Committee and the Clinical Practice Obstetrics Committee of the Society of Obstetricians and Gynaecologists of Canada. The level of evidence and quality of the recommendation made was described using the Evaluation of Evidence criteria of the Canadian Task Force on Preventive Health Care. RECOMMENDATIONS
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25
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Fleminger J, Seed PT, Smith A, Juszczak E, Dixon PH, Chambers J, Dorling J, Williamson C, Thornton JG, Chappell LC. Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy: a secondary analysis of the PITCHES trial. BJOG 2020; 128:1066-1075. [PMID: 33063439 PMCID: PMC8246759 DOI: 10.1111/1471-0528.16567] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/08/2020] [Indexed: 12/13/2022]
Abstract
OBJECTIVE To evaluate whether a particular group of women with intrahepatic cholestasis of pregnancy (ICP), based on their presenting characteristics, would benefit from treatment with ursodeoxycholic acid (UDCA). DESIGN Secondary analysis of the PITCHES trial (ISRCTN91918806). SETTING United Kingdom. POPULATION OR SAMPLE 527 women with ICP. METHODS Subgroup analyses were performed to determine whether baseline bile acid concentrations or baseline itch scores moderated a woman's response to treatment with UDCA. MAIN OUTCOME MEASURES Bile acid concentration and itch score. RESULTS In women with baseline bile acid concentrations less than 40 μmol/l, treatment with UDCA resulted in increased post-randomisation bile acid concentrations (geometric mean ratio 1.19, 95% CI 1.00-1.41, P = 0.048). A test of interaction showed no significance (P = 0.647). A small, clinically insignificant difference was seen in itch response in women with a high baseline itch score (-6.0 mm, 95% CI -11.80 to -0.21, P = 0.042), with a test of interaction not showing significance (P = 0.640). Further subgroup analyses showed no significance. Across all women there was a weak relationship between bile acid concentrations and itch severity. CONCLUSIONS There was no subgroup of women with ICP in whom a beneficial effect of treatment with UDCA on bile acid concentration or itch score could be identified. This confirms that its routine use in women with this condition for improvement of bile acid concentration or itch score should be reconsidered. TWEETABLE ABSTRACT PITCHES: No group of women with ICP has been found in whom UDCA reduces bile acid concentrations or pruritus.
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Affiliation(s)
- J Fleminger
- Department of Women and Children's Health, School of Life Course Sciences, King's College London, London, UK
| | - P T Seed
- Department of Women and Children's Health, School of Life Course Sciences, King's College London, London, UK
| | - A Smith
- National Perinatal Epidemiology Unit Clinical Trials Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - E Juszczak
- National Perinatal Epidemiology Unit Clinical Trials Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - P H Dixon
- Department of Women and Children's Health, School of Life Course Sciences, King's College London, London, UK
| | | | - J Dorling
- Division of Neonatal-Perinatal Medicine, IWK Health Centre, Halifax, NS, Canada
| | - C Williamson
- Department of Women and Children's Health, School of Life Course Sciences, King's College London, London, UK
| | - J G Thornton
- Division of Child Health, Obstetrics and Gynaecology, University of Nottingham, Nottingham, UK
| | - L C Chappell
- Department of Women and Children's Health, School of Life Course Sciences, King's College London, London, UK
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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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Spann RA, Grayson BE. Curbing Obesity from One Generation to Another: the Effects of Bariatric Surgery on the In Utero Environment and Beyond. Reprod Sci 2020; 27:1821-1833. [PMID: 32578163 PMCID: PMC7483648 DOI: 10.1007/s43032-020-00221-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 05/25/2020] [Indexed: 02/06/2023]
Abstract
Approximately 250,000 individuals seek bariatric surgery each year in the USA for the long-term resolution of obesity-related comorbidities. Greater than 80% of these individuals are women and approximately half are of child-bearing age. Although there are many positive metabolic benefits that are realized through surgical weight loss for both men and women, the various long-term hormonal, molecular, nutrient, and epigenetic changes following bariatric surgery have not been evaluated for the surgical recipient or in the context of pregnancy and the offspring. Pregnancy may be a vulnerable period of time for the bariatric surgery recipient, and thoughtful consideration of pregnancy management should be taken by health care providers and recipients alike. The purpose of this review is to explore potential etiologies of some of the gestation-specific outcomes for the mother and offspring.
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Affiliation(s)
- Redin A Spann
- Department of Neurobiology and Anatomical Sciences, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS, 39216, USA
| | - Bernadette E Grayson
- Department of Neurobiology and Anatomical Sciences, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS, 39216, USA.
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Donet A, Girault A, Pinton A, Lepercq J. Intrahepatic cholestasis of pregnancy: Is a screening for differential diagnoses necessary? J Gynecol Obstet Hum Reprod 2020; 49:101907. [PMID: 32931957 DOI: 10.1016/j.jogoh.2020.101907] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 09/04/2020] [Accepted: 09/06/2020] [Indexed: 12/21/2022]
Abstract
OBJECTIVE To evaluate the benefit of performing a screening for differential diagnoses by hepatobiliary ultrasound and viral serologies, in case of suspected intrahepatic cholestasis of pregnancy (ICP). METHODS Retrospective single-center study in a tertiary maternity unit, including all women with a suspected ICP between January 2012 and September 2018. The primary outcome was the differential diagnosis rate obtained through initial screening. We described women characteristics, symptoms, and blood results that led to ICP suspicion. We evaluated the rate of differential diagnosis established by the initial screening. We described the population of women presenting with an ICP differential diagnosis. RESULTS The study included 254 women. Prevalence of differential diagnosis was 2 %. ICP was suspected in more than 50 % of cases in third trimester of pregnancy (79.5 %). Women presented with pruritus in 90.9 % of cases. Bile acid levels were between 20 and 40 μmol/L in 56.3 % of cases and above 40 μmol/L in 12.2 % of cases. The screening to rule out differential diagnosis of ICP was performed in half of the cases. When performed, the screening did not lead to the diagnosis of any differential disease. CONCLUSION In this cohort, among the 254 women, one (0.4 %) would have been wrongly diagnosed with ICP if the initial screening for differential diagnosis had not been performed. Screening for differential diagnosis does not seem to provide any benefit regarding the management of suspected ICP and could therefore only be performed in case of atypical clinical presentation of ICP, resistance to treatment or persisting abnormal liver function tests in the postpartum period.
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Affiliation(s)
- Agathe Donet
- Port-Royal Maternity Unit, Department of Obstetrics, Cochin Broca Hôtel-Dieu Hospital, Assistance Publique-Hôpitaux de Paris, France
| | - Aude Girault
- Port-Royal Maternity Unit, Department of Obstetrics, Cochin Broca Hôtel-Dieu Hospital, Assistance Publique-Hôpitaux de Paris, France; INSERM UMR 1153, Obstetrical, Perinatal and Paediatric Epidemiology Research Team (Epopé), Centre for Epidemiology and Statistics Sorbonne Paris Cité (CRESS), DHU Risks in Pregnancy, Paris Descartes University, Paris, France
| | - Anne Pinton
- Port-Royal Maternity Unit, Department of Obstetrics, Cochin Broca Hôtel-Dieu Hospital, Assistance Publique-Hôpitaux de Paris, France
| | - Jacques Lepercq
- Port-Royal Maternity Unit, Department of Obstetrics, Cochin Broca Hôtel-Dieu Hospital, Assistance Publique-Hôpitaux de Paris, France
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Jiao T, Yao X, Zhao Y, Zhou Y, Gao Y, Fan S, Chen P, Li X, Jiang Y, Yang X, Gonzalez FJ, Huang M, Bi H. Dexamethasone-Induced Liver Enlargement Is Related to PXR/YAP Activation and Lipid Accumulation but Not Hepatocyte Proliferation. Drug Metab Dispos 2020; 48:830-839. [PMID: 32561593 PMCID: PMC7497622 DOI: 10.1124/dmd.120.000061] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Accepted: 05/29/2020] [Indexed: 12/11/2022] Open
Abstract
Dexamethasone (Dex), a widely prescribed anti-inflammatory drug, was reported to induce liver enlargement (hepatomegaly) in clinical practice and in animal models. However, the underlying mechanisms are not elucidated. Dex is a known activator of pregnane X receptor (PXR). Yes-associated protein (YAP) has been implicated in chemically induced liver enlargement. Here, the roles of PXR and YAP pathways were investigated in Dex-induced hepatomegaly. Upregulation of PXR downstream proteins, including cytochrome P450 (CYP) 3A11, 2B10, and organic anion transporter polypeptide 2 (OATP2), indicated PXR signaling was activated after high dose of Dex (50 mg/kg, i.p.), and Dex at 100 μM activated PXR in the dual-luciferase reporter gene assay. Dex also increased the expression of total YAP, nuclear YAP, and YAP downstream proteins, including connective tissue growth factor and cysteine-rich angiogenic inducer 61, indicating activation of the YAP pathway. Furthermore, nuclear translocation of YAP was promoted by activation of PXR. However, hepatocyte proliferation was inhibited with significant decrease in the expression of proliferation-related proteins cyclin D1 and proliferating cell nuclear antigen as well as other regulatory factors, such as forkhead box protein M1, c-MYC, and epidermal growth factor receptor. The inhibitory effect of Dex on hepatocyte proliferation was likely due to its anti-inflammation effect of suppression of inflammation factors. β-catenin staining revealed enlarged hepatocytes, which were mostly attributable to the accumulation of lipids, such as triglycerides. In summary, high-dose Dex increased liver size accompanied by enlarged hepatocytes, and this was due to the activation of PXR/YAP and their effects on lipid accumulation but not hepatocyte proliferation. These findings provide new insights for understanding the mechanism of Dex-induced hepatomegaly. SIGNIFICANCE STATEMENT: This study identified the roles of pregnane X receptor (PXR) and yes-associated protein (YAP) pathways in dexamethasone (Dex)-induced hepatomegaly. Dex induced PXR/YAP activation, enlarged hepatocytes, and promoted liver enlargement with lipid accumulation, such as triglycerides. However, hepatocyte proliferation was inhibited by the anti-inflammatory effect of Dex. These findings provide new insights for understanding the mechanism of Dex-induced hepatomegaly.
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Affiliation(s)
- Tingying Jiao
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (T.J., X.P.Y., Yi.Z., Ya.Z., Y.G., S.F., P.C., X.L., Y.J., X.Y., M.H., H.B.) and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland (F.J.G.)
| | - Xinpeng Yao
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (T.J., X.P.Y., Yi.Z., Ya.Z., Y.G., S.F., P.C., X.L., Y.J., X.Y., M.H., H.B.) and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland (F.J.G.)
| | - Yingyuan Zhao
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (T.J., X.P.Y., Yi.Z., Ya.Z., Y.G., S.F., P.C., X.L., Y.J., X.Y., M.H., H.B.) and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland (F.J.G.)
| | - Yanying Zhou
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (T.J., X.P.Y., Yi.Z., Ya.Z., Y.G., S.F., P.C., X.L., Y.J., X.Y., M.H., H.B.) and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland (F.J.G.)
| | - Yue Gao
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (T.J., X.P.Y., Yi.Z., Ya.Z., Y.G., S.F., P.C., X.L., Y.J., X.Y., M.H., H.B.) and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland (F.J.G.)
| | - Shicheng Fan
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (T.J., X.P.Y., Yi.Z., Ya.Z., Y.G., S.F., P.C., X.L., Y.J., X.Y., M.H., H.B.) and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland (F.J.G.)
| | - Panpan Chen
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (T.J., X.P.Y., Yi.Z., Ya.Z., Y.G., S.F., P.C., X.L., Y.J., X.Y., M.H., H.B.) and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland (F.J.G.)
| | - Xuan Li
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (T.J., X.P.Y., Yi.Z., Ya.Z., Y.G., S.F., P.C., X.L., Y.J., X.Y., M.H., H.B.) and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland (F.J.G.)
| | - Yiming Jiang
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (T.J., X.P.Y., Yi.Z., Ya.Z., Y.G., S.F., P.C., X.L., Y.J., X.Y., M.H., H.B.) and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland (F.J.G.)
| | - Xiao Yang
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (T.J., X.P.Y., Yi.Z., Ya.Z., Y.G., S.F., P.C., X.L., Y.J., X.Y., M.H., H.B.) and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland (F.J.G.)
| | - Frank J Gonzalez
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (T.J., X.P.Y., Yi.Z., Ya.Z., Y.G., S.F., P.C., X.L., Y.J., X.Y., M.H., H.B.) and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland (F.J.G.)
| | - Min Huang
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (T.J., X.P.Y., Yi.Z., Ya.Z., Y.G., S.F., P.C., X.L., Y.J., X.Y., M.H., H.B.) and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland (F.J.G.)
| | - Huichang Bi
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (T.J., X.P.Y., Yi.Z., Ya.Z., Y.G., S.F., P.C., X.L., Y.J., X.Y., M.H., H.B.) and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland (F.J.G.)
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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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Afra TP, Razmi T M, Thoyyib M, Gangadhar P, Shihabudheen P, Shahul Hameed DK, Anver PC. Autoimmune progesterone dermatitis as a clue to refractory jaundice in a young woman. Clin Exp Dermatol 2020; 46:163-164. [PMID: 32510632 DOI: 10.1111/ced.14332] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 05/25/2020] [Accepted: 06/03/2020] [Indexed: 11/28/2022]
Affiliation(s)
- T P Afra
- Departments of, Department of, Dermatology, IQRAA International Hospital and Research Centre, Calicut, India
| | - M Razmi T
- Departments of, Department of, Dermatology, IQRAA International Hospital and Research Centre, Calicut, India
| | - M Thoyyib
- Department of, Internal Medicine, IQRAA International Hospital and Research Centre, Calicut, India
| | - P Gangadhar
- Department of, Endocrinology, IQRAA International Hospital and Research Centre, Calicut, India
| | - P Shihabudheen
- Department of, Critical Care, IQRAA International Hospital and Research Centre, Calicut, India
| | - D K Shahul Hameed
- Department of, Radiology, IQRAA International Hospital and Research Centre, Calicut, India
| | - P C Anver
- Department of, Internal Medicine, IQRAA International Hospital and Research Centre, Calicut, India
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Dąbrowski K, Kierach R, Grabarek BO, Boroń D, Kukla M. Effect of ursodeoxycholic acid therapy due to pregnant intrahepatic cholestasis on chemerin and irisin levels. Dermatol Ther 2020; 33:e13272. [PMID: 32061000 DOI: 10.1111/dth.13272] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 02/08/2020] [Accepted: 02/11/2020] [Indexed: 12/15/2022]
Abstract
The purpose of the work was to assess changes in chemerin and irisin levels in women with diagnosed intrahepatic cholestasis of pregnant women treated with ursodeoxycholic acid. The study group consisted of 50 patients with diagnosed and confirmed intrahepatic cholestasis of pregnant women at 24-25 weeks of pregnancy treatment by ursodeoxycholic acid (UDCA). The study also included a group of 40 pregnant women, without concomitant intrahepatic cholestasis of pregnancy (ICP). In the pregnant ICP group, whole blood was collected 4 times: before the first dose of drug, 4 and 8 weeks after the first dose, and day after delivery. It was observed that statistically significant differences in the concentration of irisine occur between the time before starting treatment and the 8-week therapy and 1 day after delivery. The Pearson correlation analysis (r's) showed two statistically significant relationships (p < .05). The first of these can be found between the concentration of irisine and chemerin in the group of nonpregnant women and the second in the group of patients with intrahepatic pregnant cholestasis before the first dose of UDCA. A significant relationship between irisin and chemerin concentrations was confirmed in the group of pregnant ICP patients during UDCA acid therapy and among healthy pregnant women.
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Affiliation(s)
| | - Rafał Kierach
- Gynecology and Obstetrics Ward District Railway Hospital, Katowice, Poland
| | - Beniamin O Grabarek
- Maria Sklodowska-Curie National Research Institute of Oncology, Krakow Branch, Kraków, Poland.,Department of Histology, Cytophysiology and Embryology in Zabrze, University of Technology, Faculty of Medicine, Katowice, Poland
| | - Dariusz Boroń
- Department of Histology, Cytophysiology and Embryology in Zabrze, University of Technology, Faculty of Medicine, Katowice, Poland.,Faculty of Health Science, Public Higher Medical Professional School, Opole, Poland.,Department of Gynecology and Obstetrics with Gynecologic Oncology, Ludwik Rydygier Memorial Specialized Hospital, Kraków, Poland
| | - Michał Kukla
- Department of Endoscopy, University Hospital, Kraków, Poland
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Directive clinique No 394 - Investigation sur la mortinaissance. JOURNAL OF OBSTETRICS AND GYNAECOLOGY CANADA 2020; 42:100-108. [DOI: 10.1016/j.jogc.2019.09.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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Chappell LC, Bell JL, Smith A, Linsell L, Juszczak E, Dixon PH, Chambers J, Hunter R, Dorling J, Williamson C, Thornton JG. Ursodeoxycholic acid versus placebo in women with intrahepatic cholestasis of pregnancy (PITCHES): a randomised controlled trial. Lancet 2019; 394:849-860. [PMID: 31378395 PMCID: PMC6739598 DOI: 10.1016/s0140-6736(19)31270-x] [Citation(s) in RCA: 178] [Impact Index Per Article: 29.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Revised: 05/10/2019] [Accepted: 05/21/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Intrahepatic cholestasis of pregnancy, characterised by maternal pruritus and increased serum bile acid concentrations, is associated with increased rates of stillbirth, preterm birth, and neonatal unit admission. Ursodeoxycholic acid is widely used as a treatment without an adequate evidence base. We aimed to evaluate whether ursodeoxycholic acid reduces adverse perinatal outcomes in women with intrahepatic cholestasis of pregnancy. METHODS We did a double-blind, multicentre, randomised placebo-controlled trial at 33 hospital maternity units in England and Wales. We recruited women with intrahepatic cholestasis of pregnancy, who were aged 18 years or older and with a gestational age between 20 weeks and 40 weeks and 6 days, with a singleton or twin pregnancy and no known lethal fetal anomaly. Participants were randomly assigned 1:1 to ursodeoxycholic acid or placebo, given as two oral tablets a day at an equivalent dose of 500 mg twice a day. The dose could be increased or decreased at the clinician's discretion, to a maximum of four tablets and a minimum of one tablet a day. We recommended that treatment should be continued from enrolment until the infant's birth. The primary outcome was a composite of perinatal death (in-utero fetal death after randomisation or known neonatal death up to 7 days after birth), preterm delivery (<37 weeks' gestation), or neonatal unit admission for at least 4 h (from birth until hospital discharge). Each infant was counted once within this composite. All analyses were done according to the intention-to-treat principle. The trial was prospectively registered with the ISRCTN registry, number 91918806. FINDINGS Between Dec 23, 2015, and Aug 7, 2018, 605 women were enrolled and randomly allocated to receive ursodeoxycholic acid (n=305) or placebo (n=300). The primary outcome analysis included 304 women and 322 infants in the ursodeoxycholic acid group, and 300 women and 318 infants in the placebo group (consent to use data was withdrawn for 1 woman and 2 infants). The primary composite outcome occurred in 74 (23%) of 322 infants in the ursodeoxycholic acid group and 85 (27%) of 318 infants in the placebo group (adjusted risk ratio 0·85 [95% CI 0·62-1·15]). Two serious adverse events were reported in the ursodeoxycholic acid group and six serious adverse events were reported in the placebo group; no serious adverse events were regarded as being related to treatment. INTERPRETATION Treatment with ursodeoxycholic acid does not reduce adverse perinatal outcomes in women with intrahepatic cholestasis of pregnancy. Therefore, its routine use for this condition should be reconsidered. FUNDING National Institute for Health Research Efficacy and Mechanism Evaluation Programme.
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Affiliation(s)
- Lucy C Chappell
- Department of Women and Children's Health, School of Life Course Sciences, King's College London, London, UK.
| | - Jennifer L Bell
- National Perinatal Epidemiology Unit Clinical Trials Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Anne Smith
- National Perinatal Epidemiology Unit Clinical Trials Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Louise Linsell
- National Perinatal Epidemiology Unit Clinical Trials Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Edmund Juszczak
- National Perinatal Epidemiology Unit Clinical Trials Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Peter H Dixon
- Department of Women and Children's Health, School of Life Course Sciences, King's College London, London, UK
| | | | - Rachael Hunter
- Research Department of Primary Care and Population Health, University College London, London, UK
| | - Jon Dorling
- Division of Neonatal-Perinatal Medicine, IWK Health Centre, Halifax, NS, Canada
| | - Catherine Williamson
- Department of Women and Children's Health, School of Life Course Sciences, King's College London, London, UK
| | - Jim G Thornton
- Division of Child Health, Obstetrics and Gynaecology, University of Nottingham, Nottingham, UK
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Intrahepatic Cholestasis of Pregnancy: A Case Study of the Rare Onset in the First Trimester. ACTA ACUST UNITED AC 2019; 55:medicina55080454. [PMID: 31404990 PMCID: PMC6723234 DOI: 10.3390/medicina55080454] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 08/06/2019] [Accepted: 08/07/2019] [Indexed: 12/27/2022]
Abstract
Intrahepatic cholestasis of pregnancy (ICP) is a gestation-specific liver disorder, defined most often as the onset of pruritus, usually from the third trimester of pregnancy, associated with abnormal liver test results and/or increased total serum bile acids and spontaneous relief after delivery. The 21-year-old patient was admitted to our ward in the 11th week of pregnancy due to raised liver enzymes. The first onset of pruritus and jaundice appeared a month before hospitalization. Immunology tests and Toxoplasma gondii were negative. We excluded viral etiology, while alpha-1-antitrypsin, serum and urine copper levels, and thyroid hormones were within the reference values. The patient denied she had taken any medicines and herbal preparations before and during pregnancy. Total bile acids in the serum were significantly elevated (242 μmol/L). The abdominal ultrasound revealed a regular finding. Liver biopsy suggested a cholestatic liver disorder. After a presentation of all risks, the patient decided to stop the pregnancy. After a month, the hepatogram was within the reference values. Very rarely an ICP can occur in early pregnancy (first trimester), which calls for close monitoring. The risk of serious adverse fetal outcomes and spontaneous preterm delivery is proportional with increased levels of maternal serum bile acid.
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Henkel SAF, Squires JH, Ayers M, Ganoza A, Mckiernan P, Squires JE. Expanding etiology of progressive familial intrahepatic cholestasis. World J Hepatol 2019; 11:450-463. [PMID: 31183005 PMCID: PMC6547292 DOI: 10.4254/wjh.v11.i5.450] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Revised: 04/19/2019] [Accepted: 04/27/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Progressive familial intrahepatic cholestasis (PFIC) refers to a disparate group of autosomal recessive disorders that are linked by the inability to appropriately form and excrete bile from hepatocytes, resulting in a hepatocellular form of cholestasis. While the diagnosis of such disorders had historically been based on pattern recognition of unremitting cholestasis without other identified molecular or anatomic cause, recent scientific advancements have uncovered multiple specific responsible proteins. The variety of identified defects has resulted in an ever-broadening phenotypic spectrum, ranging from traditional benign recurrent jaundice to progressive cholestasis and end-stage liver disease.
AIM To review current data on defects in bile acid homeostasis, explore the expanding knowledge base of genetic based diseases in this field, and report disease characteristics and management.
METHODS We conducted a systemic review according to PRISMA guidelines. We performed a Medline/PubMed search in February-March 2019 for relevant articles relating to the understanding, diagnosis, and management of bile acid homeostasis with a focus on the family of diseases collectively known as PFIC. English only articles were accessed in full. The manual search included references of retrieved articles. We extracted data on disease characteristics, associations with other diseases, and treatment. Data was summarized and presented in text, figure, and table format.
RESULTS Genetic-based liver disease resulting in the inability to properly form and secrete bile constitute an important cause of morbidity and mortality in children and increasingly in adults. A growing number of PFIC have been described based on an expanded understanding of biliary transport mechanism defects and the development of a common phenotype.
CONCLUSION We present a summary of current advances made in a number of areas relevant to both the classically described FIC1 (ATP8B1), BSEP (ABCB11), and MDR3 (ABCB4) transporter deficiencies, as well as more recently described gene mutations -- TJP2 (TJP2), FXR (NR1H4), MYO5B (MYO5B), and others which expand the etiology and understanding of PFIC-related cholestatic diseases and bile transport.
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Affiliation(s)
- Sarah AF Henkel
- Division of Gastroenterology, Hepatology, and Nutrition, Emory School of Medicine, Atlanta, GA 30322, United States
| | - Judy H Squires
- Department of Radiology, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, United States
| | - Mary Ayers
- Division of Gastroenterology, Hepatology, and Nutrition, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, United States
| | - Armando Ganoza
- Division of Pediatric Transplantation, Department of Surgery, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, United States
| | - Patrick Mckiernan
- Division of Gastroenterology, Hepatology, and Nutrition, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, United States
| | - James E Squires
- Division of Gastroenterology, Hepatology, and Nutrition, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, United States
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Abstract
Liver diseases during pregnancy pose a unique clinical challenge because they can affect the lives of both the mother and unborn child. Although severe liver disease is rare, pregnancy-related liver disease affects approximately 3% of pregnancies and can be fatal. Timely recognition and diagnosis are essential in order to institute appropriate management strategies. This article provides an overview of liver diseases during pregnancy and is divided into 2 sections: (1) liver diseases specific to pregnancy, and (2) preexisting or coincident liver diseases during pregnancy.
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Affiliation(s)
- Karen Ma
- Section of Gastroenterology, Division of Digestive Diseases, Department of Internal Medicine, Rush University Medical Center, 1725 West Harrison Street, Suite 207, Chicago, IL 60612, USA
| | - Daniel Berger
- Section of Gastroenterology, Division of Digestive Diseases, Department of Internal Medicine, Rush University Medical Center, 1725 West Harrison Street, Suite 207, Chicago, IL 60612, USA
| | - Nancy Reau
- Section of Hepatology, Division of Digestive Diseases, Department of Internal Medicine, Rush University Medical Center, 1725 West Harrison Street, Suite 319, Chicago, IL 60612, USA.
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Shen Y, Zhou J, Zhang S, Wang XL, Jia YL, He S, Wang YY, Li WC, Shao JG, Zhuang X, Liu YL, Qin G. Is It Necessary to Perform the Pharmacological Interventions for Intrahepatic Cholestasis of Pregnancy? A Bayesian Network Meta-Analysis. Clin Drug Investig 2019; 39:15-26. [PMID: 30357607 DOI: 10.1007/s40261-018-0717-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND OBJECTIVE Although many meta-analyses have evaluated the pharmacotherapy of intrahepatic cholestasis of pregnancy (ICP) and recommended ursodeoxycholic acid (UDCA) as an effective treatment, the defect of the pair-wise analyses and the mixture of the control group made the outcome uncertain and unclear. We aimed to employ Bayesian network meta-analysis (NMA) to compare the maternal and fetal outcomes after UDCA, S-adenosylmethionine (SAMe) mono-therapy or the combination treatment of these two drugs for ICP patients. METHODS Multiple electronic database searches were conducted for articles published up to 1 September 2018. The relevant information was extracted from the published reports with a predefined data extraction sheet, and the risk of bias was assessed with the Cochrane risk-of-bias tool. Poisson Bayesian network meta-analysis was employed to identify the synthesized evidence from the relevant trials, with reporting hazard risks (HRs) and 95% credible intervals (CrIs). RESULTS The pooled outcomes of the 13 randomized controlled trials (RCTs) with 625 participants indicated that none of the three regimens can significantly improve maternal and fetal outcomes. CONCLUSION This NMA of the RCTs clarified that the current intervention has no favorable effect on pruritus and other symptoms in ICP patients.
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Affiliation(s)
- Yi Shen
- Department of Epidemiology and Medical Statistics, School of Public Health, Nantong University, Nantong, China
| | - Jie Zhou
- Department of Epidemiology and Medical Statistics, School of Public Health, Nantong University, Nantong, China
| | - Sheng Zhang
- Department of Epidemiology and Medical Statistics, School of Public Health, Nantong University, Nantong, China
| | - Xu-Lin Wang
- Department of Epidemiology and Medical Statistics, School of Public Health, Nantong University, Nantong, China
| | - Yu-Long Jia
- Department of Epidemiology and Medical Statistics, School of Public Health, Nantong University, Nantong, China
| | - Shu He
- Department of Epidemiology and Medical Statistics, School of Public Health, Nantong University, Nantong, China
| | - Yuan-Yuan Wang
- Department of Epidemiology and Medical Statistics, School of Public Health, Nantong University, Nantong, China
| | - Wen-Chao Li
- Department of Epidemiology and Medical Statistics, School of Public Health, Nantong University, Nantong, China
| | - Jian-Guo Shao
- Center for Liver Diseases, Nantong Third People's Hospital, Nantong University, 60 Mid-Youth Road, Nantong, 226006, Jiangsu, China
| | - Xun Zhuang
- Department of Epidemiology and Medical Statistics, School of Public Health, Nantong University, Nantong, China
| | - Yuan-Lin Liu
- Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Nantong, China
| | - Gang Qin
- Center for Liver Diseases, Nantong Third People's Hospital, Nantong University, 60 Mid-Youth Road, Nantong, 226006, Jiangsu, China.
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Yeap SP, Harley H, Thompson R, Williamson KD, Bate J, Sethna F, Farrell G, Hague WB. Biliary transporter gene mutations in severe intrahepatic cholestasis of pregnancy: Diagnostic and management implications. J Gastroenterol Hepatol 2019; 34:425-435. [PMID: 29992621 DOI: 10.1111/jgh.14376] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Revised: 06/19/2018] [Accepted: 06/20/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Clinical syndromes associated with biallelic mutations of bile acid (BA) transporters usually present in childhood. Subtle mutations may underlie intrahepatic cholestasis of pregnancy (ICP) and oral contraceptive steroid (OCS) induced cholestasis. In five women with identified genetic mutations of such transporters, with eight observed pregnancies complicated by ICP, we examined relationships between transporter mutations, clinical phenotypes, and treatment outcomes. METHODS Gene mutation analysis for BA transporter deficiencies was performed using Next Generation/Sanger sequencing, with analysis for gene deletions/duplications. RESULTS Intrahepatic cholestasis of pregnancy was early-onset (9-32 weeks gestation) and severe (peak BA 74-370 μmol/L), with premature delivery (28+1 -370 weeks gestation) in 7/8 pregnancies, in utero passage of meconium in 4/8, but overall good perinatal outcomes, with no stillbirths. There was generally no response to ursodeoxycholic acid and variable responses to rifampicin and chelation therapies; naso-biliary drainage appeared effective in 2/2 episodes persisting post-partum in each of the two sisters. Episodic jaundice occurring spontaneously or provoked by non-specific infections, and OCS-induced cholestasis, had previously occurred in 3/5 women. Two cases showed biallelic heterozygosity for several ABCB11 mutations, one was homozygous for an ABCB4 mutation and a fourth case was heterozygous for another ABCB4 mutation. CONCLUSIONS Early-onset or recurrent ICP, especially with previous spontaneous or OCS-induced episodes of cholestasis and/or familial cholestasis, may be attributable to transporter mutations, including biallelic mutations of one or more transporters. Response to standard therapies for ICP is often incomplete; BA sequestering therapy or naso-biliary drainage may be effective. Optimized management can produce good outcomes despite premature birth and evidence of fetal compromise.
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Affiliation(s)
- Sze Pheh Yeap
- Liver Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia
| | - Hugh Harley
- Liver Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia.,Department of Medicine, University of Adelaide, Adelaide, South Australia, Australia
| | | | | | - John Bate
- Liver Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia
| | - Farah Sethna
- Department of Obstetrics and Gynaecology, Canberra Hospital, Canberra, Australian Capital Territory, Australia
| | - Geoffrey Farrell
- Liver Research Unit, Canberra Hospital, Canberra, Australian Capital Territory, Australia.,The Australian National University Medical School, Canberra, Australian Capital Territory, Australia
| | - William Bill Hague
- Obstetric Medicine, Women's and Children's Hospital, North Adelaide, South Australia, Australia.,Robinson Research Institute, University of Adelaide, North Adelaide, South Australia, Australia
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40
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Bicocca MJ, Sperling JD, Chauhan SP. Intrahepatic cholestasis of pregnancy: Review of six national and regional guidelines. Eur J Obstet Gynecol Reprod Biol 2018; 231:180-187. [DOI: 10.1016/j.ejogrb.2018.10.041] [Citation(s) in RCA: 95] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Revised: 10/11/2018] [Accepted: 10/22/2018] [Indexed: 12/27/2022]
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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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Abstract
Importance Intrahepatic cholestasis of pregnancy (ICP) complicates approximately 0.2% to 2% of pregnancies and can lead to increased fetal risks in pregnancy. Objective This review aims to increase the knowledge of women's health care providers regarding the diagnosis, management, and fetal risks associated with ICP. Results The diagnosis of ICP is based on symptoms of pruritus that typically include the palms and soles, as well as elevated bile acid levels. Other liver function tests such as alanine aminotransferase and aspartate aminotransferase are also frequently elevated, and other causes of liver dysfunction should be ruled out. Fetal risks of ICP include increased risk of preterm birth, meconium-stained amniotic fluid, respiratory distress syndrome, or stillbirth. There is evidence that as bile acid levels increase, so does the risk of adverse neonatal outcomes. Ursodeoxycholic acid treatment has been shown to improve maternal pruritus symptoms, as well as biochemical tests, but no treatment has been shown to definitively improve fetal outcomes. Conclusions and Relevance Providers should be aware of the signs and symptoms of ICP and provide accurate diagnosis and management of affected women. Women with a diagnosis of ICP should be treated with ursodeoxycholic acid to improve maternal symptoms. Given the increased risk of stillbirth in the setting of ICP, delivery may be considered at 37 weeks' gestation.
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Wang X, Wang F, Lu Z, Jin X, Zhang Y. Semi-quantitative profiling of bile acids in serum and liver reveals the dosage-related effects of dexamethasone on bile acid metabolism in mice. J Chromatogr B Analyt Technol Biomed Life Sci 2018; 1095:65-74. [DOI: 10.1016/j.jchromb.2018.07.021] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Revised: 07/06/2018] [Accepted: 07/15/2018] [Indexed: 12/11/2022]
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Xia Y, Dong Y, Zhao X, Di L, Li J. Transport mechanism of ursodeoxycholic acid in human placental BeWo cells. Biopharm Drug Dispos 2018; 39:335-343. [PMID: 29978488 DOI: 10.1002/bdd.2150] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2018] [Revised: 06/09/2018] [Accepted: 06/18/2018] [Indexed: 12/27/2022]
Abstract
Ursodeoxycholic acid (UDCA) is a first-line drug to treat intrahepatic cholestasis of pregnancy (ICP). However, its effects on the fetus are not clearly known. To better guide its clinical use, we aimed to study the mechanism underlying the placental transport of UDCA. The uptake and efflux of UDCA across placental apical membranes were studied using BeWo cells; effects of different exposure durations, UDCA concentrations, temperatures, and inhibitors of transporters were studied. A transwell assay was performed, and UDCA concentration in both fetal and maternal sides was measured using LC-MS/MS. Higher unidirectional transport of UDCA was observed in the basolateral-to-apical direction than in the apical-to-basolateral direction. Ko143 and verapamil, which are typical inhibitors of efflux transporters, significantly increased UDCA transport from different directions. UDCA uptake from the apical membrane of BeWo cells was time-dependent, but sodium-independent. It was inhibited by inhibitors of energy metabolism and of organic anion transporters, indicating an active transport mechanism. UDCA uptake from the apical membranes of BeWo cells could be mediated by organic anion-transporting polypeptides, whereas its efflux could be mediated by breast cancer resistance protein and multidrug resistant protein 3. The results of the present study may provide a basis for UDCA use in pregnancy.
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Affiliation(s)
- Yanming Xia
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Ying Dong
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xiaoli Zhao
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Provincial TCM Engineering Technology Research Center of High Efficient Drug Delivery System (DDS), Nanjing, China
| | - Liuqing Di
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Provincial TCM Engineering Technology Research Center of High Efficient Drug Delivery System (DDS), Nanjing, China
| | - Junsong Li
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Provincial TCM Engineering Technology Research Center of High Efficient Drug Delivery System (DDS), Nanjing, China
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New Insights in Genetic Cholestasis: From Molecular Mechanisms to Clinical Implications. Can J Gastroenterol Hepatol 2018; 2018:2313675. [PMID: 30148122 PMCID: PMC6083523 DOI: 10.1155/2018/2313675] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Revised: 07/10/2018] [Accepted: 07/17/2018] [Indexed: 02/06/2023] Open
Abstract
Cholestasis is characterised by impaired bile secretion and accumulation of bile salts in the organism. Hereditary cholestasis is a heterogeneous group of rare autosomal recessive liver disorders, which are characterised by intrahepatic cholestasis, pruritus, and jaundice and caused by defects in genes related to the secretion and transport of bile salts and lipids. Phenotypic manifestation is highly variable, ranging from progressive familial intrahepatic cholestasis (PFIC)-with onset in early infancy and progression to end-stage liver disease-to a milder intermittent mostly nonprogressive form known as benign recurrent intrahepatic cholestasis (BRIC). Cases have been reported of initially benign episodic cholestasis that subsequently transitions to a persistent progressive form of the disease. Therefore, BRIC and PFIC seem to represent two extremes of a continuous spectrum of phenotypes that comprise one disease. Thus far, five representatives of PFIC (named PFIC1-5) caused by pathogenic mutations present in both alleles of ATP8B1, ABCB11, ABCB4, TJP2, and NR1H4 have been described. In addition to familial intrahepatic cholestasis, partial defects in ATP8B1, ABCB11, and ABCB4 predispose patients to drug-induced cholestasis and intrahepatic cholestasis in pregnancy. This review summarises the current knowledge of the clinical manifestations, genetics, and molecular mechanisms of these diseases and briefly outlines the therapeutic options, both conservative and invasive, with an outlook for future personalised therapeutic strategies.
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Gomes CF, Sousa M, Lourenço I, Martins D, Torres J. Gastrointestinal diseases during pregnancy: what does the gastroenterologist need to know? Ann Gastroenterol 2018; 31:385-394. [PMID: 29991883 PMCID: PMC6033757 DOI: 10.20524/aog.2018.0264] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Accepted: 02/26/2018] [Indexed: 12/15/2022] Open
Abstract
Pregnancy is characterized by numerous physiological changes that may lead to a diversity of symptoms and frequently to gastrointestinal complaints, such as heartburn, nausea and vomiting, or constipation. Chronic gastrointestinal diseases require treatment maintenance during this period, raising the challenging question whether outcomes beneficial to the mother may be harmful for the fetus. In addition, certain diseases, such as acute fatty liver of pregnancy, only develop during pregnancy and may require urgent procedures, such as fetus delivery. Even though they are not present in our day-to-day practice, knowledge of pregnancy-related diseases is fundamental and collaboration between gastroenterologists and obstetricians is often necessary. Herein, we review pregnancy-related diseases and systematize the most appropriate treatment choices according to the recent literature and guidelines, so that the article can serve as a guide to the gastroenterologist regarding the medical approach to pregnancy-related gastrointestinal and liver diseases and their therapeutic management.
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Affiliation(s)
- Catarina Frias Gomes
- Surgical Department, Gastroenterology Division (Catarina Frias Gomes, Joana Torres), Hospital Beatriz Ângelo, Loures, Portugal
| | - Mónica Sousa
- Medicine Department, Internal Medicina Division (Mónica Sousa);), Hospital Beatriz Ângelo, Loures, Portugal
| | - Inês Lourenço
- Surgical Department, Gynaecology and Obstetrics Division (Inês Lourenço, Diana Martins), Hospital Beatriz Ângelo, Loures, Portugal
| | - Diana Martins
- Surgical Department, Gynaecology and Obstetrics Division (Inês Lourenço, Diana Martins), Hospital Beatriz Ângelo, Loures, Portugal
| | - Joana Torres
- Surgical Department, Gastroenterology Division (Catarina Frias Gomes, Joana Torres), Hospital Beatriz Ângelo, Loures, Portugal
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Mikolasevic I, Filipec-Kanizaj T, Jakopcic I, Majurec I, Brncic-Fischer A, Sobocan N, Hrstic I, Stimac T, Stimac D, Milic S. Liver Disease During Pregnancy: A Challenging Clinical Issue. Med Sci Monit 2018; 24:4080-4090. [PMID: 29905165 PMCID: PMC6034557 DOI: 10.12659/msm.907723] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Accepted: 12/14/2017] [Indexed: 12/15/2022] Open
Abstract
One of the least studied topics in the field of obstetrics is liver disease during pregnancy, which creates a challenge for both gynecologists and hepatologists. Approximately 3% of pregnant women are affected by some form of liver disease during pregnancy. Some of these conditions can be fatal for both the mother and child. In addition, 3 types of liver disease need to be differentiated during pregnancy. One type is liver disease directly related to pregnancy, which can occur at a specific time during pregnancy. Another type is liver disease not related to pregnancy, which can occur at any time, such as viral- or drug-induced hepatitis. Furthermore, pregnancy can occur in women with pre-existing liver disease. It is essential that the clinicians are familiar with this disorder so they can respond promptly and appropriately in all of these situations, especially when emergency delivery is needed and must not be postponed.
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Affiliation(s)
- Ivana Mikolasevic
- Department of Gastroenterology, University Hospital Center (UHC) Rijeka, School of Medicine, University of Rijeka, Rijeka, Croatia
| | - Tajana Filipec-Kanizaj
- Department of Gastroenterology, University Hospital Merkur, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Ivan Jakopcic
- Department of Gastroenterology, University Hospital Center (UHC) Rijeka, School of Medicine, University of Rijeka, Rijeka, Croatia
| | - Iva Majurec
- Department of Anesthesiology and Intensive Care Unit, University Hospital Merkur, Zagreb, Croatia
| | - Alemka Brncic-Fischer
- Department of Obstetrics and Gynecology, University Hospital Center (UHC) Rijeka, Rijeka, Croatia
| | - Nikola Sobocan
- Department of Gastroenterology, University Hospital Merkur, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Irena Hrstic
- Department of Internal Medicine, General Hospital Pula, Pula, Croatia
| | - Tea Stimac
- Department of Obstetrics and Gynecology, University Hospital Center (UHC) Rijeka, Rijeka, Croatia
| | - Davor Stimac
- Department of Gastroenterology, University Hospital Center (UHC) Rijeka, School of Medicine, University of Rijeka, Rijeka, Croatia
| | - Sandra Milic
- Department of Gastroenterology, University Hospital Center (UHC) Rijeka, School of Medicine, University of Rijeka, Rijeka, Croatia
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Bile acids and their respective conjugates elicit different responses in neonatal cardiomyocytes: role of Gi protein, muscarinic receptors and TGR5. Sci Rep 2018; 8:7110. [PMID: 29740092 PMCID: PMC5940781 DOI: 10.1038/s41598-018-25569-4] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Accepted: 04/18/2018] [Indexed: 12/27/2022] Open
Abstract
Bile acids are recognised as bioactive signalling molecules. While they are known to influence arrhythmia susceptibility in cholestasis, there is limited knowledge about the underlying mechanisms. To delineate mechanisms underlying fetal heart rhythm disturbances in cholestatic pregnancy, we used FRET microscopy to monitor cAMP release and contraction measurements in isolated rodent neonatal cardiomyocytes. The unconjugated bile acids CDCA, DCA and UDCA and, to a lesser extent, CA were found to be relatively potent agonists for the GPBAR1 (TGR5) receptor and elicit cAMP release, whereas all glyco- and tauro- conjugated bile acids are weak agonists. The bile acid-induced cAMP production does not lead to an increase in contraction rate, and seems to be mediated by the RI isoform of adenylate cyclase, unlike adrenaline-dependent release which is mediated by the RII isoform. In contrast, bile acids elicited slowing of neonatal cardiomyocyte contraction indicating that other signalling pathways are involved. The conjugated bile acids were found to be partial agonists of the muscarinic M2, but not sphingosin-1-phosphate-2, receptors, and act partially through the Gi pathway. Furthermore, the contraction slowing effect of unconjugated bile acids may also relate to cytotoxicity at higher concentrations.
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Cholestases intrahepatiques gravidiques (CIG) précoces et tardives : étude des complications materno-fœtales. ACTA ACUST UNITED AC 2018; 46:388-394. [DOI: 10.1016/j.gofs.2018.01.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2017] [Indexed: 12/27/2022]
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Feng C, Li WJ, He RH, Sun XW, Wang G, Wang LQ. Impacts of different methods of conception on the perinatal outcome of intrahepatic cholestasis of pregnancy in twin pregnancies. Sci Rep 2018; 8:3985. [PMID: 29507303 PMCID: PMC5838236 DOI: 10.1038/s41598-018-22387-6] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Accepted: 02/22/2018] [Indexed: 12/15/2022] Open
Abstract
Twin pregnancies have a higher prevalence of intrahepatic cholestasis of pregnancy (ICP) than single pregnancies. It is unknown whether in vitro fertilization-embryo transfer (IVF-ET) influences the fetal outcomes in twin pregnancies complicated by ICP. This study aimed to explore the impact of IVF-ET on the perinatal outcomes of ICP in twin pregnancy. Clinical data from 142 twin pregnant women complicated with ICP were retrospectively analyzed, including 51 patients who conceived through IVF-ET (IVF group) and 91 patients with spontaneous conception (SC group). Several biochemical indicators and perinatal outcomes were analyzed. Compared to the SC group, the IVF group had a higher incidence of early-onset ICP (P = 0.015) and more frequent clinical symptoms (P = 0.020), including skin pruritus, skin scratch, and jaundice. Furthermore, the IVF group had higher rates of neonatal asphyxia (IVF vs. SC, 9.80% vs. 1.10%, P = 0.023) and premature delivery (IVF vs. SC, 96.08% vs. 83.52%, P = 0.027) compared to the SC group. The IVF-conceived twin pregnancy group had a higher risk of early-onset ICP and suffered from clinical symptoms and poor perinatal outcomes.
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Affiliation(s)
- Chun Feng
- The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, China.,The Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310006, China
| | - Wen-Juan Li
- The Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310006, China
| | - Rong-Huan He
- The Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310006, China
| | - Xi-Wen Sun
- The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, China
| | - Guirong Wang
- Department of Surgery, SUNY Upstate Medical University, Syracuse, New York, 13210, USA
| | - Li-Quan Wang
- The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, China. .,The Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310006, China.
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