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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 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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Li T, Chiang JYL. Bile Acid Signaling in Metabolic and Inflammatory Diseases and Drug Development. Pharmacol Rev 2024; 76:1221-1253. [PMID: 38977324 PMCID: PMC11549937 DOI: 10.1124/pharmrev.124.000978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 06/26/2024] [Accepted: 06/28/2024] [Indexed: 07/10/2024] Open
Abstract
Bile acids are the end products of cholesterol catabolism. Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Biliary secretion of bile acids generates bile flow and facilitates biliary secretion of lipids, endogenous metabolites, and xenobiotics. In intestine, bile acids facilitate the digestion and absorption of dietary lipids and fat-soluble vitamins. Through activation of nuclear receptors and G protein-coupled receptors and interaction with gut microbiome, bile acids critically regulate host metabolism and innate and adaptive immunity and are involved in the pathogenesis of cholestasis, metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, type-2 diabetes, and inflammatory bowel diseases. Bile acids and their derivatives have been developed as potential therapeutic agents for treating chronic metabolic and inflammatory liver diseases and gastrointestinal disorders. SIGNIFICANCE STATEMENT: Bile acids facilitate biliary cholesterol solubilization and dietary lipid absorption, regulate host metabolism and immunity, and modulate gut microbiome. Targeting bile acid metabolism and signaling holds promise for treating metabolic and inflammatory diseases.
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Affiliation(s)
- Tiangang Li
- Department of Biochemistry and Physiology, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (T.L.); and Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio (J.Y.L.C.)
| | - John Y L Chiang
- Department of Biochemistry and Physiology, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (T.L.); and Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio (J.Y.L.C.)
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Zöllner J, Williamson C, Dixon PH. Genetic issues in ICP. Obstet Med 2024; 17:157-161. [PMID: 39262913 PMCID: PMC11384815 DOI: 10.1177/1753495x241263441] [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] [Received: 02/19/2024] [Accepted: 06/05/2024] [Indexed: 09/13/2024] Open
Abstract
Intrahepatic cholestasis of pregnancy (ICP) is the commonest gestational liver disorder with variable global incidence. Genetic susceptibility, combined with hormonal and environmental influences, contributes to ICP aetiology. Adverse pregnancy outcomes linked to elevated serum bile acids highlight the importance of comprehensive risk assessment. ABCB4 and ABCB11 gene variants play a significant role in about 20% of severe ICP cases. Several other genes including ATP8B1, NR1H4, ABCC2, TJP2, SERPINA1, GCKR and HNF4A have also been implicated with ICP. Additionally, ABCB4 variants elevate the risk of drug-induced intrahepatic cholestasis, gallstone disease, gallbladder and bile duct carcinoma, liver cirrhosis and abnormal liver function tests. Genetic variations, both rare and common, intricately contribute to ICP susceptibility. Leveraging genetic insights holds promise for personalised management and intervention strategies. Further research is needed to elucidate variant-specific phenotypic expressions and therapeutic implications, advancing precision medicine in ICP management.
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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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5
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Verkade HJ, Felzen A, Keitel V, Thompson R, Gonzales E, Strnad P, Kamath B, van Mil S. EASL Clinical Practice Guidelines on genetic cholestatic liver diseases. J Hepatol 2024; 81:303-325. [PMID: 38851996 DOI: 10.1016/j.jhep.2024.04.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Accepted: 04/05/2024] [Indexed: 06/10/2024]
Abstract
Genetic cholestatic liver diseases are caused by (often rare) mutations in a multitude of different genes. While these diseases differ in pathobiology, clinical presentation and prognosis, they do have several commonalities due to their cholestatic nature. These Clinical Practice Guidelines (CPGs) offer a general approach to genetic testing and management of cholestatic pruritus, while exploring diagnostic and treatment approaches for a subset of genetic cholestatic liver diseases in depth. An expert panel appointed by the European Association for the Study of the Liver has created recommendations regarding diagnosis and treatment, based on the best evidence currently available in the fields of paediatric and adult hepatology, as well as genetics. The management of these diseases generally takes place in a tertiary referral centre, in order to provide up-to-date approaches and expertise. These CPGs are intended to support hepatologists (for paediatric and adult patients), residents and other healthcare professionals involved in the management of these patients with concrete recommendations based on currently available evidence or, if not available, on expert opinion.
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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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Geladari EV, Vallianou NG, Margellou E, Kounatidis D, Sevastianos V, Alexopoulou A. Benign Recurrent Intrahepatic Cholestasis: Where Are We Now? GASTROENTEROLOGY INSIGHTS 2024; 15:156-167. [DOI: 10.3390/gastroent15010011] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2025] Open
Abstract
Benign recurrent intrahepatic cholestasis (BRIC) stands as a rare genetic contributor to cholestasis, aligning itself within the spectrum of inherited intrahepatic cholestasis syndromes, such as progressive familial intrahepatic cholestasis (PFIC) and intrahepatic cholestasis of pregnancy. Manifesting in infancy or early adulthood, BRIC is marked by recurrent episodes of jaundice accompanied by intense pruritus, enduring from weeks to years across the lifespan. Normal gamma-glutamyl transferase (GGT) levels are a characteristic laboratory finding. Initially considered unlikely to progress to chronic liver disease or cirrhosis, some reports suggest BRIC may evolve into a continuous and progressive form of cholestasis. Moreover, these recurrent cholestatic episodes significantly impact quality of life, and certain mutations elevate the risk of hepatobiliary malignancy. Between episodes, histological findings of centrilobular cholestasis and abnormal laboratory parameters revert to normal, potentially obviating the need for liver biopsy. This review focuses on the genetic aspects of BRIC, its pathophysiology, clinical presentation, and prognosis. Additionally, it outlines triggering factors and available treatment options.
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Affiliation(s)
- Eleni V. Geladari
- 3rd Department of Internal Medicine & Liver Outpatient Clinic, Evangelismos General Hospital, 45-47 Ipsilantou Str., 10676 Athens, Greece
| | - Natalia G. Vallianou
- 1st Department of Internal Medicine, Evangelismos General Hospital, 45-47 Ipsilantou Str., 10676 Athens, Greece
| | - Evangelia Margellou
- 1st Department of Internal Medicine, Evangelismos General Hospital, 45-47 Ipsilantou Str., 10676 Athens, Greece
| | - Dimitris Kounatidis
- 2nd Department of Medicine & Research Laboratory, Medical School, National & Kapodistrian University of Athens, Hippokration Hospital, 114 Vasilissis Sofias Str., 11527 Athens, Greece
| | - Vassilios Sevastianos
- 3rd Department of Internal Medicine & Liver Outpatient Clinic, Evangelismos General Hospital, 45-47 Ipsilantou Str., 10676 Athens, Greece
| | - Alexandra Alexopoulou
- 2nd Department of Medicine & Research Laboratory, Medical School, National & Kapodistrian University of Athens, Hippokration Hospital, 114 Vasilissis Sofias Str., 11527 Athens, Greece
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Tang M, Xiong L, Cai J, Fu J, Liu H, Ye Y, Yang L, Xing S, Yang X. Intrahepatic cholestasis of pregnancy: insights into pathogenesis and advances in omics studies. Hepatol Int 2024; 18:50-62. [PMID: 37957532 DOI: 10.1007/s12072-023-10604-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Accepted: 09/28/2023] [Indexed: 11/15/2023]
Abstract
Intrahepatic cholestasis of pregnancy (ICP) is the most common pregnancy-specific liver disease. It is characterized by pruritus, abnormal liver function and elevated total bile acid (TBA) levels, increasing the risk of maternal and fetal adverse outcomes. Its etiology remains poorly elucidated. Over the years, various omics techniques, including metabolomics, microbiome, genomics, etc., have emerged with the advancement of bioinformatics, providing a new direction for exploring the pathogenesis, diagnosis and treatment of ICP. In this review, we first summarize the role of bile acids and related components in the pathogenesis of ICP and then further illustrate the results of omics studies.
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Affiliation(s)
- Mi Tang
- GCP Institution, School of Medicine, Chengdu Women's and Children's Central Hospital, University of Electronic Science and Technology of China, Chengdu, 611731, China
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Liling Xiong
- Obstetrics Department, School of Medicine, Chengdu Women's and Children's Central Hospital, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Jianghui Cai
- Department of Pharmacy, School of Medicine, Chengdu Women's and Children's Central Hospital, University of Electronic Science and Technology of China, Chengdu, 611731, China
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Jinzhu Fu
- Obstetrics Department, School of Medicine, Chengdu Women's and Children's Central Hospital, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Hong Liu
- Operating Theater, School of Medicine, Chengdu Women's and Children's Central Hospital, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Ying Ye
- Operating Theater, School of Medicine, Chengdu Women's and Children's Central Hospital, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Li Yang
- Obstetrics Department, School of Medicine, Chengdu Women's and Children's Central Hospital, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - ShaSha Xing
- GCP Institution, School of Medicine, Chengdu Women's and Children's Central Hospital, University of Electronic Science and Technology of China, Chengdu, 611731, China.
| | - Xiao Yang
- Obstetrics Department, School of Medicine, Chengdu Women's and Children's Central Hospital, University of Electronic Science and Technology of China, Chengdu, 611731, China.
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Ontsouka E, Schroeder M, Albrecht C. Revisited role of the placenta in bile acid homeostasis. Front Physiol 2023; 14:1213757. [PMID: 37546542 PMCID: PMC10402276 DOI: 10.3389/fphys.2023.1213757] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 07/03/2023] [Indexed: 08/08/2023] Open
Abstract
To date, the discussion concerning bile acids (BAs) during gestation is almost exclusively linked to pregnancy complications such as intrahepatic cholestasis of pregnancy (ICP) when maternal serum BA levels reach very high concentrations (>100 μM). Generally, the placenta is believed to serve as a protective barrier avoiding exposure of the growing fetus to excessive amounts of maternal BAs that might cause detrimental effects (e.g., intrauterine growth restriction and/or increased vulnerability to metabolic diseases). However, little is known about the precise role of the placenta in BA biosynthesis, transport, and metabolism in healthy pregnancies when serum BAs are at physiological levels (i.e., low maternal and high fetal BA concentrations). It is well known that primary BAs are synthesized from cholesterol in the liver and are later modified to secondary BA species by colonic bacteria. Besides the liver, BA synthesis in extrahepatic sites such as the brain elicits neuroprotective actions through inhibition of apoptosis as well as oxidative and endoplasmic reticulum stress. Even though historically BAs were thought to be only "detergent molecules" required for intestinal absorption of dietary fats, they are nowadays acknowledged as full signaling molecules. They modulate a myriad of signaling pathways with functional consequences on essential processes such as gluconeogenesis -one of the principal energy sources of the fetus- and cellular proliferation. The current manuscript discusses the potential multipotent roles of physiologically circulating BAs on developmental processes during gestation and provides a novel perspective in terms of the importance of the placenta as a previously unknown source of BAs. Since the principle "not too much, not too little" applicable to other signaling molecules may be also true for BAs, the risks associated with fetal exposure to excessive levels of BAs are discussed.
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Xie S, Wei S, Ma X, Wang R, He T, Zhang Z, Yang J, Wang J, Chang L, Jing M, Li H, Zhou X, Zhao Y. Genetic alterations and molecular mechanisms underlying hereditary intrahepatic cholestasis. Front Pharmacol 2023; 14:1173542. [PMID: 37324459 PMCID: PMC10264785 DOI: 10.3389/fphar.2023.1173542] [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] [Received: 03/03/2023] [Accepted: 05/16/2023] [Indexed: 06/17/2023] Open
Abstract
Hereditary cholestatic liver disease caused by a class of autosomal gene mutations results in jaundice, which involves the abnormality of the synthesis, secretion, and other disorders of bile acids metabolism. Due to the existence of a variety of gene mutations, the clinical manifestations of children are also diverse. There is no unified standard for diagnosis and single detection method, which seriously hinders the development of clinical treatment. Therefore, the mutated genes of hereditary intrahepatic cholestasis were systematically described in this review.
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Affiliation(s)
- Shuying Xie
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Shizhang Wei
- Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing, China
| | - Xiao Ma
- Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Ruilin Wang
- Department of Pharmacy, 5th Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Tingting He
- Department of Pharmacy, 5th Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Zhao Zhang
- Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Ju Yang
- Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jiawei Wang
- Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Lei Chang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Manyi Jing
- Department of Pharmacy, Chinese PLA General Hospital, Beijing, China
| | - Haotian Li
- Department of Pharmacy, Chinese PLA General Hospital, Beijing, China
| | - Xuelin Zhou
- Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Yanling Zhao
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
- Department of Pharmacy, Chinese PLA General Hospital, Beijing, China
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11
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Zöllner J, Finer S, Linton KJ, van Heel DA, Williamson C, Dixon PH. Rare variant contribution to cholestatic liver disease in a South Asian population in the United Kingdom. Sci Rep 2023; 13:8120. [PMID: 37208429 PMCID: PMC10199085 DOI: 10.1038/s41598-023-33391-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 04/12/2023] [Indexed: 05/21/2023] Open
Abstract
This study assessed the contribution of five genes previously known to be involved in cholestatic liver disease in British Bangladeshi and Pakistani people. Five genes (ABCB4, ABCB11, ATP8B1, NR1H4, TJP2) were interrogated by exome sequencing data of 5236 volunteers. Included were non-synonymous or loss of function (LoF) variants with a minor allele frequency < 5%. Variants were filtered, and annotated to perform rare variant burden analysis, protein structure, and modelling analysis in-silico. Out of 314 non-synonymous variants, 180 fulfilled the inclusion criteria and were mostly heterozygous unless specified. 90 were novel and of those variants, 22 were considered likely pathogenic and 9 pathogenic. We identified variants in volunteers with gallstone disease (n = 31), intrahepatic cholestasis of pregnancy (ICP, n = 16), cholangiocarcinoma and cirrhosis (n = 2). Fourteen novel LoF variants were identified: 7 frameshift, 5 introduction of premature stop codon and 2 splice acceptor variants. The rare variant burden was significantly increased in ABCB11. Protein modelling demonstrated variants that appeared to likely cause significant structural alterations. This study highlights the significant genetic burden contributing to cholestatic liver disease. Novel likely pathogenic and pathogenic variants were identified addressing the underrepresentation of diverse ancestry groups in genomic research.
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Affiliation(s)
| | - Sarah Finer
- Institute for Population Health Sciences, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Kenneth J Linton
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - David A van Heel
- Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Catherine Williamson
- Department of Women and Children's Health, School of Life Course Sciences, FOLSM, King's College London, 2.30W Hodgkin Building, Guy's Campus, London, SE1 1UL, UK.
| | - Peter H Dixon
- Department of Women and Children's Health, School of Life Course Sciences, FOLSM, King's College London, 2.30W Hodgkin Building, Guy's Campus, London, SE1 1UL, UK
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12
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Helgadottir H, Folvik G, Vesterhus M. Improvement of cholestatic episodes in patients with benign recurrent intrahepatic cholestasis (BRIC) treated with rifampicin. A long-term follow-up. Scand J Gastroenterol 2022; 58:512-520. [PMID: 36369734 DOI: 10.1080/00365521.2022.2143725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
OBJECTIVE Patients with benign recurrent intrahepatic cholestasis (BRIC) suffer from recurrent episodes of cholestatic jaundice. Treatment options remain limited and are mainly symptomatic. In case reports rifampicin, plasmapheresis, and nasobiliary drainage have been reported to be effective. In this case series, we present long-term experience indicating disease-modifying effects of non-invasive treatment with rifampicin for recurrent cholestasis in BRIC type 1 (BRIC1). MATERIALS AND METHODS We included all adult BRIC1 patients diagnosed and followed up at a single centre in Bergen, Norway. Data regarding clinical and biochemical features during BRIC attacks with and without rifampicin treatment were retrieved from medical journals and a data registry. RESULTS Five males with BRIC1 were included. Median age at diagnosis was 22 years (range 15-41). Together they had suffered from 65 cholestatic attacks (including four documented abortive attacks). Twenty-eight attacks were treated with rifampicin alone over the last 12 years; all cases showed symptomatic relief and reduction in the levels of bilirubin and alkaline phosphatase in blood. The attacks treated with rifampicin seemed to have shorter duration and were less likely to result in complications or hospitalization compared to attacks prior to the introduction of rifampicin. No side effects attributable to rifampicin were noted. CONCLUSIONS Episodic treatment of recurrent BRIC1 attacks with rifampicin seems to ameliorate severity and shorten the duration of attacks. Timely diagnosis and effective treatment are of major importance in BRIC, not only to decrease complications but also improving patients' quality of life.
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Affiliation(s)
- Holmfridur Helgadottir
- Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Norwegian PSC Research Centre, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Department of Medicine, Haraldsplass Deaconess Hospital, Bergen, Norway
| | - Geir Folvik
- National Centre for Ultrasound in Gastroenterology, Haukeland University Hospital, Bergen, Norway.,Department of Medicine, Haukeland University Hospital, Bergen, Norway
| | - Mette Vesterhus
- Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Norwegian PSC Research Centre, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Department of Medicine, Haraldsplass Deaconess Hospital, Bergen, Norway.,Department of Clinical Science, University of Bergen, Bergen, Norway
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13
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Yadav S, Goel A, Lingaiah R, Pradhan M, Katiyar H, Aggarwal R. Serum Bile Acid Levels in Women With Intrahepatic Cholestasis of Pregnancy in India. J Clin Exp Hepatol 2022; 12:379-383. [PMID: 35535067 PMCID: PMC9077159 DOI: 10.1016/j.jceh.2021.07.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 07/13/2021] [Indexed: 12/12/2022] Open
Abstract
Introduction Intrahepatic cholestasis of pregnancy (ICP) manifests as unexplained intense pruritus in the third trimester of pregnancy and is often diagnosed based on elevated serum bile acid measurement. There are no data from India on serum bile acid levels in pregnant women with ICP. Methods Pregnant women with significant pruritus during the third trimester of gestation and with elevated serum alanine aminotransferase and/or aspartate aminotransferase (normal: <40 IU/L) were taken as having ICP. Serum BA levels were measured in them and in nonpregnant women and healthy pregnant women without itching. Results Of the 3735 pregnant women screened, 105 (2.8%) had ICP (age 28 [26-32] years; gestational age 32 [30-36] weeks; primigravida 32.3%, and 95.3% normal fetal growth). Median (interquartile range) serum bile acid levels in nonpregnant women (n = 61; 28 [25-31] years) and pregnant women without ICP (n = 59; 28 [25-31] years) were similar (3.7 [1.6-5.1] μmol/L and 3.7 [2.2-5.8] μmol/L, respectively). By comparison, serum bile acid level in women with ICP (n = 105; 28 [26-32] years) was significantly higher (20.2 [12.7-39.5] μmol/L; P < 0.05 each), being above 10 μmol/L in 88 (83.8%). The optimum cut-off for the diagnosis of ICP in our population was ≥8.6 μmol/L, with sensitivity of 87.6%, specificity of 93.3% and area under the receiver-operator characteristics curve of 0.937 (95% CI: 0.904-0.970). Conclusion Serum BA levels in healthy Indian nonpregnant and pregnant women are similar to those in other populations and can be used to diagnose ICP with an optimal cut-off being 8.6 μmol/L.
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Affiliation(s)
- Sangeeta Yadav
- Department of Maternal & Reproductive Health, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Amit Goel
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Raghavendra Lingaiah
- Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Mandakini Pradhan
- Department of Maternal & Reproductive Health, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Harshita Katiyar
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Rakesh Aggarwal
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India,Address for correspondence. Rakesh Aggarwal, Director, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, 605006, India.
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14
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Eke AC. An update on the physiologic changes during pregnancy and their impact on drug pharmacokinetics and pharmacogenomics. J Basic Clin Physiol Pharmacol 2021; 33:581-598. [PMID: 34881531 DOI: 10.1515/jbcpp-2021-0312] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Accepted: 11/21/2021] [Indexed: 01/23/2023]
Abstract
For many years, the medical community has relied in clinical practice on historic data about the physiological changes that occur during pregnancy. However, some newer studies have disputed a number of assumptions in these data for not being evidence-based or derived from large prospective cohort-studies. Accurate knowledge of these physiological changes is important for three reasons: Firstly, it facilitates correct diagnosis of diseases during pregnancy; secondly, it enables us to answer questions about the effects of medication during pregnancy and the ways in which pregnancy alters pharmacokinetic and drug-effects; and thirdly, it allows for proper modeling of physiologically-based pharmacokinetic models, which are increasingly used to predict gestation-specific changes and drug-drug interactions, as well as develop new knowledge on the mode-of-action of drugs, the mechanisms underlying their interactions, and any adverse effects following drug exposure. This paper reviews new evidence regarding the physiologic changes during pregnancy in relation to existing knowledge.
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Affiliation(s)
- Ahizechukwu C Eke
- Division of Maternal Fetal Medicine, Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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15
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Chiou FK, Rizvi H, Quinlivan R, Gupte GL. Congenital Myotonic Dystrophy with Combined Heterozygous ATP8B1/ABCB4 Mutation Leading to Progressive Cholestasis and Liver Failure. JPGN REPORTS 2021; 2:e121. [PMID: 37206451 PMCID: PMC10191590 DOI: 10.1097/pg9.0000000000000121] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 04/30/2021] [Indexed: 05/21/2023]
Abstract
Myotonic dystrophy (MyoD) is an inherited genetic disorder caused by the expansion of a CTG trinucleotide repeat in the dystrophia myotonica protein kinase gene. It manifests as a multisystem disease affecting not only skeletal muscles, but also heart, lung, eye, gastrointestinal tract, central nervous system, and endocrine system. However, MyoD is rarely associated with a progressive liver disorder. We report a case of congenital MyoD with combined heterozygous ATP8B1/ABCB4 mutation who developed chronic, progressive low gamma-glutamyltransferase cholestatic liver disease at early infancy, and eventually underwent successful liver transplantation.
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Affiliation(s)
- Fang Kuan Chiou
- From the Liver Unit (including small bowel transplantation), Birmingham Women’s and Children’s Hospital NHS Foundation Trust, Birmingham, UK
- Gastroenterology, Hepatology & Nutrition Service, Paediatric Medicine, KK Women’s and Children’s Hospital, Singapore, Singapore
| | - Hina Rizvi
- From the Liver Unit (including small bowel transplantation), Birmingham Women’s and Children’s Hospital NHS Foundation Trust, Birmingham, UK
| | - Ros Quinlivan
- MRC Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, London, UK
| | - Girish L. Gupte
- From the Liver Unit (including small bowel transplantation), Birmingham Women’s and Children’s Hospital NHS Foundation Trust, Birmingham, UK
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16
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Provenzano A, Farina A, Seidenari A, Azzaroli F, Serra C, Della Gatta A, Zuffardi O, Giglio SR. Prenatal Noninvasive Trio-WES in a Case of Pregnancy-Related Liver Disorder. Diagnostics (Basel) 2021; 11:diagnostics11101904. [PMID: 34679599 PMCID: PMC8534548 DOI: 10.3390/diagnostics11101904] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 10/11/2021] [Accepted: 10/13/2021] [Indexed: 01/16/2023] Open
Abstract
Liver disease in pregnancy may present as an acute condition related to the gestational period, characterized by pruritus, jaundice, and abnormal liver function. The disease may be misdiagnosed with other liver diseases, some of which may have consequences for fetal health. It is therefore advisable to implement rapid diagnostic strategies to provide information for the management of pregnancy in these conditions. We report the case of a healthy woman with a twin pregnancy from homologous in vitro fertilization (IVF), who in the third trimester presented jaundice and malaise. Biochemical investigations and liver hyperechogenicity raised the suspicion of acute fatty liver disease of pregnancy (AFLP). Non-invasive prenatal whole-exome sequencing (WES) in the trio identified the Phe305Ile heterozygous variant in the ATP8B1 gene. Considering the twin pregnancy, the percentage of the variant versus the wild allele was of 31%, suggesting heterozygosity present in the mother alone. This analysis showed that the mother was affected by benign recurrent intrahepatic cholestasis of pregnancy (ICP1: # 147480) and indicated the opportunity to anticipate childbirth to avoid worsening of the mother’s health. WES after the birth of the twins confirmed the molecular data.
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Affiliation(s)
- Aldesia Provenzano
- Medical Genetics Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50139 Florence, Italy
- Correspondence:
| | - Antonio Farina
- Division of Obstetrics and Prenatal Medicine, IRCCS Sant’Orsola-Malpighi Hospital, University of Bologna, 40138 Bologna, Italy; (A.F.); (A.S.); (A.D.G.)
| | - Anna Seidenari
- Division of Obstetrics and Prenatal Medicine, IRCCS Sant’Orsola-Malpighi Hospital, University of Bologna, 40138 Bologna, Italy; (A.F.); (A.S.); (A.D.G.)
| | - Francesco Azzaroli
- Division of Internal Medicine, IRCCS, Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy;
| | - Carla Serra
- Department of Organ Failure and Transplantation, Sant’Orsola-Malpighi Hospital, Via Massarenti 9, 40138 Bologna, Italy;
| | - Anna Della Gatta
- Division of Obstetrics and Prenatal Medicine, IRCCS Sant’Orsola-Malpighi Hospital, University of Bologna, 40138 Bologna, Italy; (A.F.); (A.S.); (A.D.G.)
| | - Orsetta Zuffardi
- Medical Genetics Unit, Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy;
| | - Sabrina Rita Giglio
- Medical Genetics Unit, Department of Medical Sciences and Public Health, University of Cagliari, 09126 Cagliari, Italy;
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17
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Hertel PM, Bull LN, Thompson RJ, Goodrich NP, Ye W, Magee JC, Squires RH, Bass LM, Heubi JE, Kim GE, Ranganathan S, Schwarz KB, Bozic MA, Horslen SP, Clifton MS, Turmelle YP, Suchy FJ, Superina RA, Wang KS, Loomes KM, Kamath BM, Sokol RJ, Shneider BL. Mutation Analysis and Disease Features at Presentation in a Multi-Center Cohort of Children With Monogenic Cholestasis. J Pediatr Gastroenterol Nutr 2021; 73:169-177. [PMID: 34016879 PMCID: PMC8373673 DOI: 10.1097/mpg.0000000000003153] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
OBJECTIVES To advance our understanding of monogenic forms of intrahepatic cholestasis. METHODS Analyses included participants with pathogenic biallelic mutations in adenosine triphosphate (ATP)-binding cassette subfamily B member 11 (ABCB11) (bile salt export pump; BSEP) or adenosine triphosphatase (ATPase) phospholipid transporting 8B1 (ATP8B1) (familial intrahepatic cholestasis; FIC1), or those with monoallelic or biallelic mutations in adenosine triphosphate (ATP)-binding cassette subfamily B member 4 (ABCB4) (multidrug resistance; MDR3), prospectively enrolled in the Longitudinal Study of Genetic Causes of Intrahepatic Cholestasis (LOGIC; NCT00571272) between November 2007 and December 2013. Summary statistics were calculated to describe baseline demographics, history, anthropometrics, laboratory values, and mutation data. RESULTS Ninety-eight participants with FIC1 (n = 26), BSEP (n = 53, including 8 with biallelic truncating mutations [severe] and 10 with p.E297G or p.D482G [mild]), or MDR3 (n = 19, including four monoallelic) deficiency were analyzed. Thirty-five had a surgical interruption of the enterohepatic circulation (sEHC), including 10 who underwent liver transplant (LT) after sEHC. Onset of symptoms occurred by age 2 years in most with FIC1 and BSEP deficiency, but was later and more variable for MDR3. Pruritus was nearly universal in FIC1 and BSEP deficiency. In participants with native liver, failure to thrive was common in FIC1 deficiency, high ALT was common in BSEP deficiency, and thrombocytopenia was common in MDR3 deficiency. sEHC was successful after more than 1 year in 7 of 19 participants with FIC1 and BSEP deficiency. History of LT was most common in BSEP deficiency. Of 102 mutations identified, 43 were not previously reported. CONCLUSIONS In this cohort, BSEP deficiency appears to be correlated with a more severe disease course. Genotype-phenotype correlations in these diseases are not straightforward and will require the study of larger cohorts.
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Affiliation(s)
- Paula M. Hertel
- Texas Children’s Hospital, Baylor College of Medicine, Houston TX
| | - Laura N. Bull
- University of California, San Francisco, San Francisco CA
| | | | | | - Wen Ye
- University of Michigan Hospitals and Health Centers, Ann Arbor MI
| | - John C. Magee
- University of Michigan Hospitals and Health Centers, Ann Arbor MI
| | | | - Lee M. Bass
- Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago IL
| | - James E. Heubi
- Cincinnati Children’s Hospital Medical Center, Cincinnati OH
| | - Grace E. Kim
- University of California, San Francisco, San Francisco CA
| | | | | | - Molly A. Bozic
- Indiana University-Riley Hospital for Children, Indianapolis IN
| | | | | | | | - Frederick J. Suchy
- University of Colorado School of Medicine, Children’s Hospital Colorado, Aurora CO
| | | | - Kasper S. Wang
- Children’s Hospital Los Angeles, University of Southern California, Los Angeles CA
| | | | | | - Ronald J. Sokol
- University of Colorado School of Medicine, Children’s Hospital Colorado, Aurora CO
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Aydın GA, Özgen G, Görükmez O. The role of genetic mutations in intrahepatic cholestasis of pregnancy. Taiwan J Obstet Gynecol 2021; 59:706-710. [PMID: 32917322 DOI: 10.1016/j.tjog.2020.07.014] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/15/2020] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVE Intrahepatic cholestasis of pregnancy (ICP) is a liver disorder of pregnancy characterized by pruritus, elevated liver enzymes and fasting serum bile acids. Genetic predisposition has been suggested to play a role in its etiology and mutations in the ATP8B1(OMIM ∗602397) (FIC1), ABCB11(OMIM ∗603201) (BSEP), and ABCB4(OMIM ∗171060) (MDR3) genes have been implicated. In the present study, we aimed to investigate the possible role of ATP8B1, ABCB11, and ABCB4 gene mutations in the patients with ICP. MATERIALS AND METHODS A total of 25 patients who were diagnosed with ICP were included in the study. Genetic test results and mutation status of the patients as assessed by the next-generation sequencing technology were retrospectively retrieved from the hospital database. RESULTS Of all patients, significant alterations in the ATP8B1 (n = 2), ABCB11 (n = 1), and ABCB4 (n = 7) genes were observed in 10 patients using the molecular analysis testing. All these alterations were heterozygous. Of these alterations, four were reported in the literature previously, while six were not. Using the in-silico parameters, there was a pathogenic alteration in the ABCB4 gene in one patient, while there was no clinically relevant alteration in the other gene mutations in the remaining nine patients. CONCLUSION Considering the fact that the alterations were compatible with clinical presentations of the ICP patients and the incidence of these mutations is low in the general population, we believe that our study results are clinically relevant. Further molecular genetic tests in ICP patients and functional studies supporting the results would shed light into the clinical importance of these alterations.
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Affiliation(s)
- Gültekin Adanaş Aydın
- Bursa Yüksek İhtisas Training and Research Hospital, Department of Obstetrics and Gynecology, 16330, Bursa, Turkey.
| | - Gülten Özgen
- Bursa Yüksek İhtisas Training and Research Hospital, Department of Obstetrics and Gynecology, 16330, Bursa, Turkey
| | - Orhan Görükmez
- Bursa Yüksek İhtisas Training and Research Hospital, Department of Medical Genetics, 16330, Bursa, Turkey
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Kroll T, Prescher M, Smits SHJ, Schmitt L. Structure and Function of Hepatobiliary ATP Binding Cassette Transporters. Chem Rev 2020; 121:5240-5288. [PMID: 33201677 DOI: 10.1021/acs.chemrev.0c00659] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The liver is beyond any doubt the most important metabolic organ of the human body. This function requires an intensive crosstalk within liver cellular structures, but also with other organs. Membrane transport proteins are therefore of upmost importance as they represent the sensors and mediators that shuttle signals from outside to the inside of liver cells and/or vice versa. In this review, we summarize the known literature of liver transport proteins with a clear emphasis on functional and structural information on ATP binding cassette (ABC) transporters, which are expressed in the human liver. These primary active membrane transporters form one of the largest families of membrane proteins. In the liver, they play an essential role in for example bile formation or xenobiotic export. Our review provides a state of the art and comprehensive summary of the current knowledge of hepatobiliary ABC transporters. Clearly, our knowledge has improved with a breath-taking speed over the last few years and will expand further. Thus, this review will provide the status quo and will lay the foundation for new and exciting avenues in liver membrane transporter research.
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Affiliation(s)
- Tim Kroll
- Institute of Biochemistry, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
| | - Martin Prescher
- Institute of Biochemistry, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
| | - Sander H J Smits
- Institute of Biochemistry, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany.,Center for Structural Studies, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
| | - Lutz Schmitt
- Institute of Biochemistry, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
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20
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Çebi AH, Altıner Ş. Application of Chromosome Microarray Analysis in the Investigation of Developmental Disabilities and Congenital Anomalies: Single Center Experience and Review of NRXN3 and NEDD4L Deletions. Mol Syndromol 2020; 11:197-206. [PMID: 33224013 PMCID: PMC7675229 DOI: 10.1159/000509645] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Accepted: 05/27/2020] [Indexed: 01/01/2023] Open
Abstract
Chromosomal microarray analysis (CMA) is a first step test used for the diagnosis of patients with developmental delay, intellectual disability, autistic spectrum disorder, and multiple congenital anomalies. Its widespread usage has allowed genome-wide identification of copy number variations (CNVs). In our study, we performed a retrospective study on clinical and microarray data of 237 patients with developmental disabilities and/or multiple congenital anomalies and investigated the clinical utility of CMA. Phenotype-associated CNVs were detected in 15.18% of patients. Besides, we detected submicroscopic losses on 14q24.3q31.1 in a patient with speech delay and on 18q21.31q21.32 in twin patients with seizures. Deletions of NRXN3 and NEDD4L were responsible for the phenotypes, respectively. This study showed that CMA is a powerful diagnostic tool in this patient group and expands the genotype-phenotype correlations on developmental disabilities.
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Affiliation(s)
- Alper Han Çebi
- Department of Medical Genetics, Karadeniz Technical University School of Medicine, Trabzon, Turkey
| | - Şule Altıner
- Department of Medical Genetics, University of Health Sciences, Trabzon Kanuni Training and Research Hospital, Trabzon, Turkey
- Department of Medical Genetics, Ankara University School of Medicine, Ankara, Turkey
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21
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Wang R, Cheng N, Peng R, Yu Z, Nan M, Cao H. Oral herbal medicine for women with intrahepatic cholestasis in pregnancy: a systematic review of randomized controlled trials. BMC Complement Med Ther 2020; 20:303. [PMID: 33028282 PMCID: PMC7542867 DOI: 10.1186/s12906-020-03097-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 09/28/2020] [Indexed: 01/17/2023] Open
Abstract
Background Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy complication whose range has been calculated to be between 0.01 and 15.6% all around the world. We wanted to systematically evaluate the effect and safety of oral herbal medicine on treatment for ICP. Methods Details of the methods could be found in the registered protocol on PROSPERO (CRD42018096013). Trials assessing the effectiveness of herbal medicine for ICP were searched from seven electronic databases from inception to 28th February 2020. RevMan 5.3 software was used to perform all statistical analysis. Meta-analysis, additional analysis, Trial Sequential Analysis (TSA) and Grading of Recommendations Assessment, Development and Evaluation (GRADE) were conducted if data permitted. Results Totally 43 randomized controlled trials with 3556 patients were included. Meta-analysis showed potential good adjunctive effect of herbal medicine on decreasing the pruritus scores (MD -0.58, 95% CI − 0.79 to − 0.36), the serum TBA scores (MD − 3.99 μmol/L, 95% CI − 4.24 to − 3.74) on the basis with Ursodesoxycholic acid. Compared to the medicine alone, significantly lower incidence of fetal distress (RR 0.41, 95% CI 0.32 to 0.51), asphyxia neonatorum (RR 0.35, 95%CI 0.25 to 0.49), cesarean section (RR 0.73, 95% CI 0.63 to 0.85), postpartum hemorrhage (RR 0.45, 95% CI 0.28 to 0.72) were observed in the combination group. But the comparison between herbal medicine and medicine showed inconsistent results among trials. Insufficient information could be used to evaluate the safety of herbal medicine for ICP. Conclusion This review found the current evidence may support the effectiveness of combination of herbal medicine and conventional medicine for decreasing the maternal pruritus scores, the serum TBA, and the number of fetal distress, or asphyxia neonatorum events related to this condition (which was supported by TSA results). Since there were obvious statistical and clinical heterogeneity among trials, and the methodological quality of the included studies was poor, the level of the evidence could only be defined as “very low” according to the GRADE criteria. Further high quality studies are still needed to testify the effectiveness and safety of herbal medicine for ICP.
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Affiliation(s)
- Ruiting Wang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Nuo Cheng
- Beijing University of Chinese Medicine, Beijing, China
| | - Rongyan Peng
- Beijing University of Chinese Medicine, Beijing, China
| | - Zeyu Yu
- Centre for Evidence Based Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Mengdie Nan
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Huijuan Cao
- Centre for Evidence Based Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.
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22
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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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Intrahepatic Cholestasis in Pregnancy: Review of the Literature. J Clin Med 2020; 9:jcm9051361. [PMID: 32384779 PMCID: PMC7290322 DOI: 10.3390/jcm9051361] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 04/27/2020] [Accepted: 05/04/2020] [Indexed: 12/14/2022] Open
Abstract
Intrahepatic cholestasis of pregnancy (ICP) is the most common hepatic disorder related to pregnancy in women. It usually develops within the third trimester of pregnancy and presents with pruritus as well as elevated levels of bile acid and/or alanine aminotransferase. Clinical signs quickly resolve after delivery; however, there is a high risk of the disorder recurring in subsequent pregnancies. ICP is associated with an increased risk of perinatal complications (premature birth, respiratory disorders, even stillbirth). Elevated levels of gestational hormones and genetic predispositions are important factors for the development of ICP; among the latter, mutations in hepatobiliary transport proteins (multidrug resistance protein 3-MDR3, bile salt export pump- BSEP) play a major role. Clinical and biochemical symptoms of ICP include pruritus and increased levels of total bile acids (TBA). Serum levels of TBA should be monitored in ICP patients throughout the pregnancy as concentrations above 40 μmol/L, which define that severe ICP isassociated with an increased risk of fetal complications. Therapeutic management is aimed at reducing the clinical symptoms, normalizing maternal biochemistry and preventing complications to the fetus. Pharmacological treatment of intrahepatic cholestasis of pregnancy consists of the administration of ursodeoxycholic acid to lower the levels of TBA and possibly reduce pruritus. If the treatment fails, premature delivery should be considered.
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24
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Adult onset of genetic disorders in bile acid transport in the liver. Hum Pathol 2020; 96:2-7. [DOI: 10.1016/j.humpath.2019.10.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Accepted: 10/09/2019] [Indexed: 12/27/2022]
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Zhang J, Liu LL, Gong JY, Hao CZ, Qiu YL, Lu Y, Feng JY, Li JQ, Li ZD, Wang MX, Xing QH, Knisely AS, Wang JS. TJP2 hepatobiliary disorders: Novel variants and clinical diversity. Hum Mutat 2019; 41:502-511. [PMID: 31696999 DOI: 10.1002/humu.23947] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2019] [Revised: 10/27/2019] [Accepted: 11/03/2019] [Indexed: 12/12/2022]
Abstract
To assess the spectrum of pediatric clinical phenotypes in TJP2 disease, we reviewed records of our seven patients in whom intrahepatic cholestasis was associated with biallelic TJP2 variants (13; 12 novel) and correlated clinical manifestations with mutation type. The effect of a splicing variant was analyzed with a minigene assay. The effects of three missense variants were analyzed with protein expression in vitro. Our patients had both remitting and persistent cholestasis. Three exhibited growth retardation. Six responded to treatment with cholestyramine, ursodeoxycholic acid, or both. Two had cholecystolithiasis. None required liver transplantation or developed hepatocellular or cholangiocellular malignancy. None manifested extrahepatic disease not attributable to effects of cholestasis. The variant c.2180-5T>G resulted in exon 15 skipping with in-frame deletion of 32 amino acid residues in TJP2. The three missense variants decreased but did not abolish TJP2 expression. Patients with truncating or canonical splice-site variants had clinically more severe disease. TJP2 disease in children includes a full clinical spectrum of severity, with mild or intermittent forms as well as the severe and minimal forms hitherto described. Biallelic TJP2 variants must be considered in children with clinically intermittent or resolved intrahepatic cholestasis.
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Affiliation(s)
- Jing Zhang
- The Department of Pediatrics, Jinshan Hospital of Fudan University, Shanghai, China.,The Center for Liver Diseases, Children's Hospital of Fudan University, Shanghai, China
| | - Lang-Li Liu
- The Department of Pediatrics, Jinshan Hospital of Fudan University, Shanghai, China.,The Center for Liver Diseases, Children's Hospital of Fudan University, Shanghai, China
| | - Jing-Yu Gong
- The Department of Pediatrics, Jinshan Hospital of Fudan University, Shanghai, China
| | - Chen-Zhi Hao
- The Center for Liver Diseases, Children's Hospital of Fudan University, Shanghai, China
| | - Yi-Ling Qiu
- The Department of Pediatrics, Jinshan Hospital of Fudan University, Shanghai, China.,The Center for Liver Diseases, Children's Hospital of Fudan University, Shanghai, China
| | - Yi Lu
- The Center for Liver Diseases, Children's Hospital of Fudan University, Shanghai, China
| | - Jia-Yan Feng
- The Department of Pathology, Children's Hospital of Fudan University, Shanghai, China
| | - Jia-Qi Li
- The Department of Pediatrics, Jinshan Hospital of Fudan University, Shanghai, China
| | - Zhong-Die Li
- The Center for Liver Diseases, Children's Hospital of Fudan University, Shanghai, China
| | - Meng-Xuan Wang
- The Department of Pediatrics, Jinshan Hospital of Fudan University, Shanghai, China.,The Center for Liver Diseases, Children's Hospital of Fudan University, Shanghai, China
| | - Qing-He Xing
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - A S Knisely
- Institut für Pathologie, Medizinische Universität Graz, Graz, Austria
| | - Jian-She Wang
- The Center for Liver Diseases, Children's Hospital of Fudan University, Shanghai, China
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Deferm N, De Vocht T, Qi B, Van Brantegem P, Gijbels E, Vinken M, de Witte P, Bouillon T, Annaert P. Current insights in the complexities underlying drug-induced cholestasis. Crit Rev Toxicol 2019; 49:520-548. [PMID: 31589080 DOI: 10.1080/10408444.2019.1635081] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Drug-induced cholestasis (DIC) poses a major challenge to the pharmaceutical industry and regulatory agencies. It causes both drug attrition and post-approval withdrawal of drugs. DIC represents itself as an impaired secretion and flow of bile, leading to the pathological hepatic and/or systemic accumulation of bile acids (BAs) and their conjugate bile salts. Due to the high number of mechanisms underlying DIC, predicting a compound's cholestatic potential during early stages of drug development remains elusive. A profound understanding of the different molecular mechanisms of DIC is, therefore, of utmost importance. Although many knowledge gaps and caveats still exist, it is generally accepted that alterations of certain hepatobiliary membrane transporters and changes in hepatocellular morphology may cause DIC. Consequently, liver models, which represent most of these mechanisms, are valuable tools to predict human DIC. Some of these models, such as membrane-based in vitro models, are exceptionally well-suited to investigate specific mechanisms (i.e. transporter inhibition) of DIC, while others, such as liver slices, encompass all relevant biological processes and, therefore, offer a better representation of the in vivo situation. In the current review, we highlight the principal molecular mechanisms associated with DIC and offer an overview and critical appraisal of the different liver models that are currently being used to predict the cholestatic potential of drugs.
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Affiliation(s)
- Neel Deferm
- Department of Pharmaceutical and Pharmacological Sciences, Drug Delivery and Disposition, KU Leuven, Leuven, Belgium
| | - Tom De Vocht
- Department of Pharmaceutical and Pharmacological Sciences, Drug Delivery and Disposition, KU Leuven, Leuven, Belgium
| | - Bing Qi
- Department of Pharmaceutical and Pharmacological Sciences, Drug Delivery and Disposition, KU Leuven, Leuven, Belgium
| | - Pieter Van Brantegem
- Department of Pharmaceutical and Pharmacological Sciences, Drug Delivery and Disposition, KU Leuven, Leuven, Belgium
| | - Eva Gijbels
- Entity of In Vitro Toxicology and Dermato-Cosmetology, Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Brussels, Belgium
| | - Mathieu Vinken
- Entity of In Vitro Toxicology and Dermato-Cosmetology, Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Brussels, Belgium
| | - Peter de Witte
- Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
| | - Thomas Bouillon
- Department of Pharmaceutical and Pharmacological Sciences, Drug Delivery and Disposition, KU Leuven, Leuven, Belgium
| | - Pieter Annaert
- Department of Pharmaceutical and Pharmacological Sciences, Drug Delivery and Disposition, KU Leuven, Leuven, Belgium
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Abstract
The farnesoid X receptor (FXR, NR1H4) is a bile acid (BA)-activated transcription factor, which is essential for BA homeostasis. FXR and its hepatic and intestinal target genes, small heterodimer partner (SHP, NR0B2) and fibroblast growth factor 15/19 (Fgf15 in mice, FGF19 in humans), transcriptionally regulate BA synthesis, detoxification, secretion, and absorption in the enterohepatic circulation. Furthermore, FXR modulates a large variety of physiological processes, such as lipid and glucose homeostasis as well as the inflammatory response. Targeted deletion of FXR renders mice highly susceptible to cholic acid feeding resulting in cholestatic liver injury, weight loss, and increased mortality. Combined deletion of FXR and SHP spontaneously triggers early-onset intrahepatic cholestasis in mice resembling human progressive familial intrahepatic cholestasis (PFIC). Reduced expression levels and activity of FXR have been reported in human cholestatic conditions, such as PFIC type 1 and intrahepatic cholestasis of pregnancy. Recently, two pairs of siblings with homozygous FXR truncation or deletion variants were identified. All four children suffered from severe, early-onset PFIC and liver failure leading to death or need for liver transplantation before the age of 2. These findings underscore the central role of FXR as regulator of systemic and hepatic BA levels. Therefore, targeting FXR has been exploited in different animal models of both intrahepatic and obstructive cholestasis, and the first FXR agonist obeticholic acid (OCA) has been approved for the treatment of primary biliary cholangitis (PBC). Further FXR agonists as well as a FGF19 analogue are currently tested in clinical trials for different cholestatic liver diseases. This chapter will summarize the current knowledge on the role of FXR in cholestasis both in rodent models and in human diseases.
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Rhee ES, Kim YB, Lee S, Oh SH, Lee BH, Kim KM, Yoo HW. Novel ATP8B1 Gene Mutations in a Child with Progressive Familial Intrahepatic Cholestasis Type 1. Pediatr Gastroenterol Hepatol Nutr 2019; 22:479-486. [PMID: 31555573 PMCID: PMC6751104 DOI: 10.5223/pghn.2019.22.5.479] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Accepted: 08/31/2018] [Indexed: 01/26/2023] Open
Abstract
Progressive familial intrahepatic cholestasis (PFIC) is a group of severe genetic disorders, inherited in an autosomal recessive manner, causing cholestasis of hepatocellular origin, later progressing to biliary cirrhosis and liver failure. This is the first report of PFIC type 1 with novel compound heterozygous mutations in Korea. The patient was presented with intrahepatic cholestasis, a normal level of serum γ-glutamyl transferase, steatorrhea, and growth failure. Genetic testing of this patient revealed novel compound heterozygous mutations (p.Glu585Ter and p.Leu749Pro) in the ATP8B1 gene. After a liver transplantation at age 19 months, the patient developed severe post-transplant steatohepatitis.
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Affiliation(s)
- Eun Sang Rhee
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Yu Bin Kim
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Sunghee Lee
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Seak Hee Oh
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Beom Hee Lee
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Kyung Mo Kim
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Han-Wook Yoo
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
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Familial intrahepatic cholestasis: New and wide perspectives. Dig Liver Dis 2019; 51:922-933. [PMID: 31105019 DOI: 10.1016/j.dld.2019.04.013] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Revised: 04/01/2019] [Accepted: 04/12/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND Progressive familial intrahepatic cholestasis (PFIC) includes autosomal recessive cholestatic rare diseases of childhood. AIMS To update the panel of single genes mutations involved in familial cholestasis. METHODS PubMed search for "familial intrahepatic cholestasis" alone as well as in combination with other key words was performed considering primarily original studies and meta-analyses. RESULTS PFIC1 involves ATP8B1 gene encoding for aminophospholipid flippase FIC1. PFIC2 includes ABCB11 gene, encoding for protein functioning as bile salt export pump. PFIC3 is due to mutations of ABCB4 gene responsible for the synthesis of class III multidrug resistance P-glycoprotein flippase. PFIC4 and PFIC5 involve tight junction protein-2 gene and NR1H4 gene encoding for farnesoid X receptor. Benign Intrahepatic Cholestasis, Intrahepatic Cholestasis of Pregnancy and Low-phospholipid-associated cholelithiasis involve the same genes and are characterized by intermittent attacks of cholestasis, no progression to cirrhosis, reversible pregnancy-specific cholestasis and cholelithiasis in young people. Blood and liver tissue levels of bile-excreted drugs can be influenced by the presence of mutations in PFIC genes, causing drug-induced cholestasis. Mutations in PFIC genes might increase the risk of liver cancer. CONCLUSION There is a high proportion of unexplained cholestasis potentially caused by specific genetic pathophysiologic pathways. The use of next generation sequencing and whole-exome sequencing could improve the diagnostic process in this setting.
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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: 42] [Impact Index Per Article: 7.0] [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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31
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Abstract
Bile acids facilitate nutrient absorption and are endogenous ligands for nuclear receptors that regulate lipid and energy metabolism. The brain-gut-liver axis plays an essential role in maintaining overall glucose, bile acid, and immune homeostasis. Fasting and feeding transitions alter nutrient content in the gut, which influences bile acid composition and pool size. In turn, bile acid signaling controls lipid and glucose use and protection against inflammation. Altered bile acid metabolism resulting from gene mutations, high-fat diets, alcohol, or circadian disruption can contribute to cholestatic and inflammatory diseases, diabetes, and obesity. Bile acids and their derivatives are valuable therapeutic agents for treating these inflammatory metabolic diseases.
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Affiliation(s)
- John Y L Chiang
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio 44272;
| | - Jessica M Ferrell
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio 44272;
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32
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Chen HL, Wu SH, Hsu SH, Liou BY, Chen HL, Chang MH. Jaundice revisited: recent advances in the diagnosis and treatment of inherited cholestatic liver diseases. J Biomed Sci 2018; 25:75. [PMID: 30367658 PMCID: PMC6203212 DOI: 10.1186/s12929-018-0475-8] [Citation(s) in RCA: 85] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Accepted: 10/03/2018] [Indexed: 12/17/2022] Open
Abstract
Background Jaundice is a common symptom of inherited or acquired liver diseases or a manifestation of diseases involving red blood cell metabolism. Recent progress has elucidated the molecular mechanisms of bile metabolism, hepatocellular transport, bile ductular development, intestinal bile salt reabsorption, and the regulation of bile acids homeostasis. Main body The major genetic diseases causing jaundice involve disturbances of bile flow. The insufficiency of bile salts in the intestines leads to fat malabsorption and fat-soluble vitamin deficiencies. Accumulation of excessive bile acids and aberrant metabolites results in hepatocellular injury and biliary cirrhosis. Progressive familial intrahepatic cholestasis (PFIC) is the prototype of genetic liver diseases manifesting jaundice in early childhood, progressive liver fibrosis/cirrhosis, and failure to thrive. The first three types of PFICs identified (PFIC1, PFIC2, and PFIC3) represent defects in FIC1 (ATP8B1), BSEP (ABCB11), or MDR3 (ABCB4). In the last 5 years, new genetic disorders, such as TJP2, FXR, and MYO5B defects, have been demonstrated to cause a similar PFIC phenotype. Inborn errors of bile acid metabolism also cause progressive cholestatic liver injuries. Prompt differential diagnosis is important because oral primary bile acid replacement may effectively reverse liver failure and restore liver functions. DCDC2 is a newly identified genetic disorder causing neonatal sclerosing cholangitis. Other cholestatic genetic disorders may have extra-hepatic manifestations, such as developmental disorders causing ductal plate malformation (Alagille syndrome, polycystic liver/kidney diseases), mitochondrial hepatopathy, and endocrine or chromosomal disorders. The diagnosis of genetic liver diseases has evolved from direct sequencing of a single gene to panel-based next generation sequencing. Whole exome sequencing and whole genome sequencing have been actively investigated in research and clinical studies. Current treatment modalities include medical treatment (ursodeoxycholic acid, cholic acid or chenodeoxycholic acid), surgery (partial biliary diversion and liver transplantation), symptomatic treatment for pruritus, and nutritional therapy. New drug development based on gene-specific treatments, such as apical sodium-dependent bile acid transporter (ASBT) inhibitor, for BSEP defects are underway. Short conclusion Understanding the complex pathways of jaundice and cholestasis not only enhance insights into liver pathophysiology but also elucidate many causes of genetic liver diseases and promote the development of novel treatments.
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Affiliation(s)
- Huey-Ling Chen
- Departments of Pediatrics, National Taiwan University College of Medicine and Children's Hospital, 17F, No. 8, Chung Shan S. Rd, Taipei, 100, Taiwan. .,Department of Medical Education and Bioethics, National Taiwan University College of Medicine, No. 1, Jen Ai Rd Section 1, Taipei, 100, Taiwan. .,Hepatitis Research Center, National Taiwan University Hospital, Changde St. No.1, Zhongzhen Dist., Taipei 100, Taiwan.
| | - Shang-Hsin Wu
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, No. 7 Chung Shan S. Rd, Taipei 100, Taiwan
| | - Shu-Hao Hsu
- Graduate Institute of Anatomy and Cell Biology, Nationatl Taiwan University College of Medicine, No. 1 Jen Ai Rd Section 1, Taipei 100, Taiwan
| | - Bang-Yu Liou
- Departments of Pediatrics, National Taiwan University College of Medicine and Children's Hospital, 17F, No. 8, Chung Shan S. Rd, Taipei, 100, Taiwan
| | - Hui-Ling Chen
- Hepatitis Research Center, National Taiwan University Hospital, Changde St. No.1, Zhongzhen Dist., Taipei 100, Taiwan
| | - Mei-Hwei Chang
- Departments of Pediatrics, National Taiwan University College of Medicine and Children's Hospital, 17F, No. 8, Chung Shan S. Rd, Taipei, 100, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, Changde St. No.1, Zhongzhen Dist., Taipei 100, Taiwan
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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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Reduced Hepatocellular Expression of Canalicular Transport Proteins in Infants with Neonatal Cholestasis and Congenital Hypopituitarism. J Pediatr 2018; 200:181-187. [PMID: 29935878 DOI: 10.1016/j.jpeds.2018.05.009] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2017] [Revised: 04/12/2018] [Accepted: 05/05/2018] [Indexed: 01/30/2023]
Abstract
OBJECTIVE To assess whether prolonged neonatal cholestasis, described in congenital hypopituitarism and septo-optic dysplasia (SOD), is associated with altered expression of selected canalicular ectoenzymes and canalicular transport proteins. STUDY DESIGN Children with congenital hypopituitarism (n = 21), SOD (n = 18), and cholestasis seen in our center over 26 years were reviewed. Histopathologic findings in archival liver biopsy specimens were assessed (n = 10) and in those with low/normal levels of serum γ-glutamyltransferase (GGT) activity despite conjugated hyperbilirubinemia, expression of canalicular ectoenzymes and canalicular transport proteins was evaluated immunohistochemically. RESULTS Patients presented at a median age of 8 weeks (range 3-20 weeks) with median total bilirubin 116 µmol/L (45-287 µmol/L), GGT 95 IU/L (25-707 UI/L), and serum cortisol 51 nmol/L (17-240 nmol/L). All but 3 had low free thyroxin (median 9.6 pmol/L [6.8-26.9]) with increased thyroid-stimulating hormone levels (median 5.95 mU/L [<0.1-9.24]). Liver histologic features included moderate-to-severe intralobular cholestasis with nonspecific hepatitis, giant-cell transformation of hepatocytes, and fibrosis. In all, immunohistochemical staining for canalicular ectoenzymes and canalicular transport proteins revealed a degree of reduced expression, associated with normal serum GGT values in 6 of the 10 patients, and another 6 nonbiopsied infants with cholestasis also had low/normal serum GGT activity. Sequencing of ABCB11 and ATP8B1 performed in 6 of the biopsied patients did not identify pathogenic mutations. Following replacement therapy, biochemical evidence of hepatobiliary injury resolved in all children within a median period of 6 months. CONCLUSION Hepatobiliary involvement in congenital hypopituitarism associated with SOD has a good prognosis, but its etiology remains uncertain. Immunohistochemical expression of canalicular transport proteins was reduced in available liver samples.
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36
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Dröge C, Bonus M, Baumann U, Klindt C, Lainka E, Kathemann S, Brinkert F, Grabhorn E, Pfister ED, Wenning D, Fichtner A, Gotthardt DN, Weiss KH, McKiernan P, Puri RD, Verma IC, Kluge S, Gohlke H, Schmitt L, Kubitz R, Häussinger D, Keitel V. Sequencing of FIC1, BSEP and MDR3 in a large cohort of patients with cholestasis revealed a high number of different genetic variants. J Hepatol 2017; 67:1253-1264. [PMID: 28733223 DOI: 10.1016/j.jhep.2017.07.004] [Citation(s) in RCA: 85] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Revised: 06/16/2017] [Accepted: 07/07/2017] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS The bile salt export pump (BSEP, ABCB11), multidrug resistance protein 3 (MDR3, ABCB4) and the ATPase familial intrahepatic cholestasis 1 (FIC1, ATP8B1) mediate bile formation. This study aimed to determine the contribution of mutations and common variants in the FIC1, BSEP and MDR3 genes to cholestatic disorders of differing disease onset and severity. METHODS Coding exons with flanking intron regions of ATP8B1, ABCB11, and ABCB4 were sequenced in cholestatic patients with assumed genetic cause. The effects of new variants were evaluated by bioinformatic tools and 3D protein modeling. RESULTS In 427 patients with suspected inherited cholestasis, 149 patients carried at least one disease-causing mutation in FIC1, BSEP or MDR3, respectively. Overall, 154 different mutations were identified, of which 25 were novel. All 13 novel missense mutations were disease-causing according to bioinformatics analyses and homology modeling. Eighty-two percent of patients with at least one disease-causing mutation in either of the three genes were children. One or more common polymorphism(s) were found in FIC1 in 35.3%, BSEP in 64.3% and MDR3 in 72.6% of patients without disease-causing mutations in the respective gene. Minor allele frequencies of common polymorphisms in BSEP and MDR3 varied in our cohort compared to the general population, as described by gnomAD. However, differences in ethnic background may contribute to this effect. CONCLUSIONS In a large cohort of patients, 154 different variants were detected in FIC1, BSEP, and MDR3, 25 of which were novel. In our cohort, frequencies for risk alleles of BSEP (p.V444A) and MDR3 (p.I237I) polymorphisms were significantly overrepresented in patients without disease-causing mutation in the respective gene, indicating that these common variants can contribute to a cholestatic phenotype. LAY SUMMARY FIC1, BSEP, and MDR3 represent hepatobiliary transport proteins essential for bile formation. Genetic variants in these transporters underlie a broad spectrum of cholestatic liver diseases. To confirm a genetic contribution to the patients' phenotypes, gene sequencing of these three major cholestasis-related genes was performed in 427 patients and revealed 154 different variants of which 25 have not been previously reported in a database. In patients without a disease-causing mutation, common genetic variants were detected in a high number of cases, indicating that these common variants may contribute to cholestasis development.
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Affiliation(s)
- Carola Dröge
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany
| | - Michele Bonus
- Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Germany
| | - Ulrich Baumann
- Pediatric Gastroenterology and Hepatology, Department for Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Germany
| | - Caroline Klindt
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany
| | - Elke Lainka
- Department for Pediatric Nephrology, Gastroenterology, Endocrinology and Transplant Medicine, Clinic for Pediatrics II, University Children's Hospital Essen, University Duisburg-Essen, Germany
| | - Simone Kathemann
- Department for Pediatric Nephrology, Gastroenterology, Endocrinology and Transplant Medicine, Clinic for Pediatrics II, University Children's Hospital Essen, University Duisburg-Essen, Germany
| | - Florian Brinkert
- Pediatric Gastroenterology and Hepatology, University Children's Hospital, University Medical Center Hamburg-Eppendorf, Germany
| | - Enke Grabhorn
- Pediatric Gastroenterology and Hepatology, University Children's Hospital, University Medical Center Hamburg-Eppendorf, Germany
| | - Eva-Doreen Pfister
- Pediatric Gastroenterology and Hepatology, Department for Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Germany
| | - Daniel Wenning
- Department of General Pediatrics, Heidelberg University Hospital, Germany
| | - Alexander Fichtner
- Department of General Pediatrics, Heidelberg University Hospital, Germany
| | - Daniel N Gotthardt
- Department of Internal Medicine IV, University Hospital Heidelberg, Germany
| | - Karl Heinz Weiss
- Department of Internal Medicine IV, University Hospital Heidelberg, Germany
| | - Patrick McKiernan
- Pittsburgh Liver Research Center, University of Pittsburgh and Children's Hospital of Pittsburgh of UPMC, Pittsburgh, USA
| | - Ratna Dua Puri
- Institute of Medical Genetics & Genomics, Sir Ganga Ram Hospital, New Delhi, India
| | - I C Verma
- Institute of Medical Genetics & Genomics, Sir Ganga Ram Hospital, New Delhi, India
| | - Stefanie Kluge
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany
| | - Holger Gohlke
- Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Germany
| | - Lutz Schmitt
- Institute of Biochemistry, Heinrich Heine University Düsseldorf, Germany
| | - Ralf Kubitz
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany
| | - Dieter Häussinger
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany.
| | - Verena Keitel
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany.
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Sharanek A, Burban A, Humbert L, Guguen-Guillouzo C, Rainteau D, Guillouzo A. Progressive and Preferential Cellular Accumulation of Hydrophobic Bile Acids Induced by Cholestatic Drugs Is Associated with Inhibition of Their Amidation and Sulfation. Drug Metab Dispos 2017; 45:1292-1303. [PMID: 28928138 DOI: 10.1124/dmd.117.077420] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Accepted: 09/12/2017] [Indexed: 02/13/2025] Open
Abstract
Drug-induced intrahepatic cholestasis is characterized by cellular accumulation of bile acids (BAs), whose mechanisms remain poorly understood. The present study aimed to analyze early and progressive alterations of BA profiles induced by cyclosporine A, chlorpromazine, troglitazone, tolcapone, trovafloxacin, and tacrolimus after 4-hour, 24-hour, and 6-day treatments of differentiated HepaRG cells. In BA-free medium, the potent cholestatic drugs cyclosporine A, chlorpromazine, and troglitazone reduced endogenous BA synthesis after 24 hours, whereas the rarely cholestatic drugs tolcapone, trovafloxacin, and tacrolimus reduced BA synthesis only after 6 days. In the presence of physiologic serum BA concentrations, cyclosporine A, chlorpromazine, and troglitazone induced early and preferential cellular accumulation of unconjugated lithocholic, deoxycholic, and chenodeoxycholic acids that increased 8- to 12-fold and 47- to 50-fold after 24 hours and 6 days, respectively. Accumulation of these hydrophobic BAs resulted from strong inhibition of amidation, and in addition, for lithocholic acid reduction of its sulfoconjugation, and was associated with variable alterations of uptake and efflux transporters. Trovafloxacin also caused BA accumulation, especially after 6 days, whereas tolcapone and tacrolimus were still without effect. However, when exogenous BAs were added to the medium at cholestatic serum concentrations, a 6-day treatment with all drugs resulted in cellular BA accumulation with higher folds of chenodeoxycholic and lithocholic acids. At the tested concentration, tolcapone had the lowest effect. These results bring the first demonstration that major cholestatic drugs can cause preferential and progressive in vitro cellular accumulation of unconjugated toxic hydrophobic BAs and bring new insights into mechanisms involved in drug-induced cellular accumulation of toxic BAs.
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Affiliation(s)
- Ahmad Sharanek
- INSERM UMR991/1241, Liver Metabolism and Cancer/Numecan, Rennes, France (A.S., A.B., C.G.-G., A.G.); Université de Rennes 1, Rennes, France (A.S., A.B., C.G.-G., A.G.); and ERL INSERM U1157/UMR7203, Faculté de Médecine Pierre et Marie Curie, Site Saint Antoine, Paris, France (L.H., D.R.)
| | - Audrey Burban
- INSERM UMR991/1241, Liver Metabolism and Cancer/Numecan, Rennes, France (A.S., A.B., C.G.-G., A.G.); Université de Rennes 1, Rennes, France (A.S., A.B., C.G.-G., A.G.); and ERL INSERM U1157/UMR7203, Faculté de Médecine Pierre et Marie Curie, Site Saint Antoine, Paris, France (L.H., D.R.)
| | - Lydie Humbert
- INSERM UMR991/1241, Liver Metabolism and Cancer/Numecan, Rennes, France (A.S., A.B., C.G.-G., A.G.); Université de Rennes 1, Rennes, France (A.S., A.B., C.G.-G., A.G.); and ERL INSERM U1157/UMR7203, Faculté de Médecine Pierre et Marie Curie, Site Saint Antoine, Paris, France (L.H., D.R.)
| | - Christiane Guguen-Guillouzo
- INSERM UMR991/1241, Liver Metabolism and Cancer/Numecan, Rennes, France (A.S., A.B., C.G.-G., A.G.); Université de Rennes 1, Rennes, France (A.S., A.B., C.G.-G., A.G.); and ERL INSERM U1157/UMR7203, Faculté de Médecine Pierre et Marie Curie, Site Saint Antoine, Paris, France (L.H., D.R.)
| | - Dominique Rainteau
- INSERM UMR991/1241, Liver Metabolism and Cancer/Numecan, Rennes, France (A.S., A.B., C.G.-G., A.G.); Université de Rennes 1, Rennes, France (A.S., A.B., C.G.-G., A.G.); and ERL INSERM U1157/UMR7203, Faculté de Médecine Pierre et Marie Curie, Site Saint Antoine, Paris, France (L.H., D.R.)
| | - André Guillouzo
- INSERM UMR991/1241, Liver Metabolism and Cancer/Numecan, Rennes, France (A.S., A.B., C.G.-G., A.G.); Université de Rennes 1, Rennes, France (A.S., A.B., C.G.-G., A.G.); and ERL INSERM U1157/UMR7203, Faculté de Médecine Pierre et Marie Curie, Site Saint Antoine, Paris, France (L.H., D.R.)
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Cariello M, Piccinin E, Garcia-Irigoyen O, Sabbà C, Moschetta A. Nuclear receptor FXR, bile acids and liver damage: Introducing the progressive familial intrahepatic cholestasis with FXR mutations. Biochim Biophys Acta Mol Basis Dis 2017; 1864:1308-1318. [PMID: 28965883 DOI: 10.1016/j.bbadis.2017.09.019] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Revised: 09/15/2017] [Accepted: 09/17/2017] [Indexed: 02/07/2023]
Abstract
The nuclear receptor farnesoid X receptor (FXR) is the master regulator of bile acids (BAs) homeostasis since it transcriptionally drives modulation of BA synthesis, influx, efflux, and detoxification along the enterohepatic axis. Due to its crucial role, FXR alterations are involved in the progression of a plethora of BAs associated inflammatory disorders in the liver and in the gut. The involvement of the FXR pathway in cholestasis development and management has been elucidated so far with a direct role of FXR activating therapy in this condition. However, the recent identification of a new type of genetic progressive familial intrahepatic cholestasis (PFIC) linked to FXR mutations has strengthen also the bona fide beneficial effects of target therapies that by-pass FXR activation, directly promoting the action of its target, namely the enterokine FGF19, in the repression of hepatic BAs synthesis with reduction of total BA levels in the liver and serum, accomplishing one of the major goals in cholestasis. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni and Peter Jansen.
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Affiliation(s)
- Marica Cariello
- Department of Interdisciplinary Medicine, "Aldo Moro" University of Bari, 70124 Bari, Italy
| | - Elena Piccinin
- INBB, National Institute for Biostructures and Biosystems, 00136 Rome, Italy
| | - Oihane Garcia-Irigoyen
- Department of Interdisciplinary Medicine, "Aldo Moro" University of Bari, 70124 Bari, Italy
| | - Carlo Sabbà
- Department of Interdisciplinary Medicine, "Aldo Moro" University of Bari, 70124 Bari, Italy
| | - Antonio Moschetta
- Department of Interdisciplinary Medicine, "Aldo Moro" University of Bari, 70124 Bari, Italy; National Cancer Center, IRCCS Istituto Oncologico "Giovanni Paolo II", 70124 Bari, Italy.
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39
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An expanded role for heterozygous mutations of ABCB4, ABCB11, ATP8B1, ABCC2 and TJP2 in intrahepatic cholestasis of pregnancy. Sci Rep 2017; 7:11823. [PMID: 28924228 PMCID: PMC5603585 DOI: 10.1038/s41598-017-11626-x] [Citation(s) in RCA: 86] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Accepted: 08/24/2017] [Indexed: 12/12/2022] Open
Abstract
Intrahepatic cholestasis of pregnancy (ICP) affects 1/140 UK pregnancies; with pruritus, hepatic impairment and elevated serum bile acids. Severe disease is complicated by spontaneous preterm delivery and stillbirth. Previous studies have reported mutations in hepatocellular transporters (ABCB4, ABCB11). High throughput sequencing in 147 patients was performed in the transporters ABCB4, ABCB11, ATP8B1, ABCC2 and tight junction protein 2 (TJP2). Twenty-six potentially damaging variants were identified with the following predicted protein changes: Twelve ABCB4 mutations - Arg47Gln, Met113Val, Glu161Gly, Thr175Ala, Glu528Glyfs*6, Arg590Gln, Ala601Ser, Glu884Ter, Gly722Ala, Tyr775Met (x2), Trp854Ter. Four potential ABCB11 mutations - Glu297Gly (x3) and a donor splice site mutation (intron 19). Five potential ATP8B1 mutations - Asn45Thr (x3), and two others, Glu114Gln and Lys203Glu. Two ABCC2 mutations - Glu1352Ala and a duplication (exons 24 and 25). Three potential mutations were identified in TJP2; Thr62Met (x2) and Thr626Ser. No patient harboured more than one mutation. All were heterozygous. An additional 545 cases were screened for the potential recurrent mutations of ATP8B1 (Asn45Thr) and TJP2 (Thr62Met) identifying three further occurrences of Asn45Thr. This study has expanded known mutations in ABCB4 and ABCB11 and identified roles in ICP for mutations in ATP8B1 and ABCC2. Possible novel mutations in TJP2 were also discovered.
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40
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Mutlu MF, Aslan K, Guler I, Mutlu I, Erdem M, Bozkurt N, Erdem A. Two cases of first onset intrahepatic cholestasis of pregnancy associated with moderate ovarian hyperstimulation syndrome after IVF treatment and review of the literature. J OBSTET GYNAECOL 2017; 37:547-549. [PMID: 28319428 DOI: 10.1080/01443615.2017.1286302] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Intrahepatic cholestasis of pregnancy (ICP) is an uncommon disorder, which generally occurs in the second and third trimester of pregnancy with symptoms of pruritus. The cause of ICP is unknown but genetic, hormonal and environmental factors contribute to its pathogenesis. The aetiology of ICP is unclear but elevation in oestrogen levels thought to cause ICP is typically seen in the third trimester of pregnancy, and for this reason it is not usually considered in the differential diagnosis of pruritus and liver function disorders in the first trimester of the pregnancy. We present two cases of pregnancy after IVF treatment diagnosed with ICP following the development of OHSS, deteriorating liver function tests and severe pruritus.
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Affiliation(s)
- Mehmet Firat Mutlu
- a Department of Obstetrics & Gynecology , Yuksek Ihtisas University Faculty of Medicine , Ankara , Turkey
| | - Koray Aslan
- b Department of Obstetrics & Gynecology , Gazi University Faculty of Medicine , Ankara , Turkey
| | - Ismail Guler
- b Department of Obstetrics & Gynecology , Gazi University Faculty of Medicine , Ankara , Turkey
| | | | - Mehmet Erdem
- b Department of Obstetrics & Gynecology , Gazi University Faculty of Medicine , Ankara , Turkey
| | - Nuray Bozkurt
- b Department of Obstetrics & Gynecology , Gazi University Faculty of Medicine , Ankara , Turkey
| | - Ahmet Erdem
- b Department of Obstetrics & Gynecology , Gazi University Faculty of Medicine , Ankara , Turkey
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41
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Shagrani M, Burkholder J, Broering D, Abouelhoda M, Faquih T, El-Kalioby M, Subhani SN, Goljan E, Albar R, Monies D, Mazhar N, AlAbdulaziz BS, Abdelrahman KA, Altassan N, Alkuraya FS. Genetic profiling of children with advanced cholestatic liver disease. Clin Genet 2017; 92:52-61. [PMID: 28039895 DOI: 10.1111/cge.12959] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2016] [Accepted: 12/27/2016] [Indexed: 12/12/2022]
Abstract
Advanced cholestatic liver disease is a leading referral to pediatric liver transplant centers. Recent advances in the genetic classification of this group of disorders promise a highly personalized management although the genetic heterogeneity also poses a diagnostic challenge. Using a next-generation sequencing-based multi-gene panel, we performed retrospective analysis of 98 pediatric patients who presented with advanced cholestatic liver disease. A likely causal mutation was identified in the majority (61%), spanning many genes including ones that have only rarely been reported to cause cholestatic liver disease, e.g. TJP2 and VIPAS39. We find no evidence to support mono-allelic phenotypic expression in the carrier parents despite the severe nature of the respective mutations, and no evidence of oligogenicity. The high-carrier frequency of the founder mutations identified in our cohort (1 in 87) suggests a minimum incidence of 1:7246, an alarmingly high disease burden that calls for the primary prevention through carrier screening.
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Affiliation(s)
- M Shagrani
- Organ Transplant Centre, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.,Department of Medicine, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - J Burkholder
- Organ Transplant Centre, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - D Broering
- Organ Transplant Centre, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - M Abouelhoda
- Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.,Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - T Faquih
- Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.,Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - M El-Kalioby
- Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.,Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - S N Subhani
- Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.,Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - E Goljan
- Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.,Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - R Albar
- Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia
| | - D Monies
- Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.,Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - N Mazhar
- Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia
| | - B S AlAbdulaziz
- Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia
| | - K A Abdelrahman
- Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia
| | - N Altassan
- Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.,Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - F S Alkuraya
- Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.,Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.,Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
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42
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43
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Hämäläinen ST, Turunen K, Kosunen E, Mattila KJ, Sumanen M. Men’s Health Is Not Affected by Their Mothers’ Intrahepatic Cholestasis of Pregnancy. Am J Mens Health 2016; 10:NP71-NP77. [DOI: 10.1177/1557988315584795] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Little is known about the effects of mother’s intrahepatic cholestasis of pregnancy (ICP) on the health of sons born to these mothers. The purpose of the present study was to explore the health of sons born to mothers with ICP. The study design was a retrospective study of ICP mothers’ sons. In the region of Tampere University Hospital in Finland, 365 sons of mothers with ICP during 1969 to 1988 and 617 sons of mothers without ICP were sent a questionnaire in 2010. The response rates were 37.8% ( n = 138) and 36.6% ( n = 226), respectively. Only minor differences were reported between the two groups. Self-evaluated health was similar. There were no significant differences between the groups regarding symptoms and complaints, diagnosed diseases, mental health, and use of medicines. Cough was 10.8 percentage points less common among ICP mothers’ sons than among controls ( p = .034). Urticaria was more common among ICP mothers’ sons, the difference in percentage points being 2.2 ( p = .026). In general, a mother’s ICP does not affect her son’s health.
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Affiliation(s)
| | | | - Elise Kosunen
- University of Tampere, Tampere, Finland
- Pirkanmaa Hospital District, Tampere, Finland
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44
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Abstract
Pregnancy associated liver diseases affect up to 3% of pregnant women and are the most frequent cause of liver dysfunction in pregnancy. When severe, they are associated with significant morbidity and mortality for both mother and infant. A rapid evaluation to distinguish them from non-pregnancy related liver dysfunction is essential, in order to facilitate appropriate management. Liver disease unrelated to pregnancy can present de novo in pregnancy, or pregnancy can occur in women with preexisting liver pathology (Table 1). Research and subsequent advances in medical care have resulted in improved but still not satisfactory maternal and fetal outcomes. In this review we provide an overview of the liver diseases specific to the pregnant state and an update on their pathogenesis, treatment and outcomes. The risks of pregnancy in women with pre-existent liver pathology is detailed and recent advances in our understanding of specific risks and outcomes are discussed.
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45
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Dixon PH, Williamson C. The pathophysiology of intrahepatic cholestasis of pregnancy. Clin Res Hepatol Gastroenterol 2016; 40:141-53. [PMID: 26823041 DOI: 10.1016/j.clinre.2015.12.008] [Citation(s) in RCA: 116] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2015] [Revised: 12/02/2015] [Accepted: 12/10/2015] [Indexed: 02/06/2023]
Abstract
A number of liver disorders are specific to pregnancy. Amongst these, intrahepatic cholestasis of pregnancy (ICP), also known as obstetric cholestasis (OC), is the commonest, affecting approximately 1 in 140 UK pregnancies. Patients commonly present in the third trimester with severe pruritus and deranged serum liver tests; bile acids are elevated, in severe cases >40 μmol/L. Although the disease is considered relatively benign for the mother, increased rates of adverse fetal outcomes, including stillbirth, are associated with ICP. As our knowledge of the mechanisms underlying bile acid homeostasis has advanced in the last 15 years our understanding of ICP has grown, in particular with respect to genetic influences on susceptibility to the disease, the role of reproductive hormones and their metabolites and the possible identity of the pruritic agents. In this review, we will describe recent advances in the understanding of this condition with a particular emphasis on how aspects of genetic and reproductive hormone involvement in pathophysiology have been elucidated. We also review recent developments regarding our knowledge of placental and fetal pathophysiology and the long-term health consequences for the mother and child.
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Affiliation(s)
- Peter H Dixon
- Division of Women's Health, 2.30W Hodgkin Building, King's College London, Guy's Campus, SE1 1UL London, United Kingdom
| | - Catherine Williamson
- Division of Women's Health, 2.30W Hodgkin Building, King's College London, Guy's Campus, SE1 1UL London, United Kingdom.
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Abstract
Intrahepatic cholestasis of pregnancy (ICP) is characterized by maternal pruritus, and elevated serum transaminases and bile acids. Genetic defects in at least 6 canalicular transporters have been found. Association studies stress the variability of genotypes, different penetrance, and influence of environmental factors. Serum autotaxin is a sensitive, specific, and robust diagnostic marker. Elevated maternal bile acids correlate with fetal complications. Long-term sequelae for mothers include the gallstone risk and chronic liver disease. There is an association between ICP and hepatitis C. Current treatment is ursodeoxycholic acid, owing to benefits on pruritus, liver function, safety, and decreased rates of adverse effects.
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Affiliation(s)
- Annarosa Floreani
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Via Giustiniani, 2, Padova 35128, Italy.
| | - Maria Teresa Gervasi
- Department of Obstetrics and Gynecology, Azienda Ospedaliera, Via Giustiniani, 2, Padova 35128, Italy
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47
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Larson SP, Kovilam O, Agrawal DK. Immunological basis in the pathogenesis of intrahepatic cholestasis of pregnancy. Expert Rev Clin Immunol 2015; 12:39-48. [PMID: 26469633 DOI: 10.1586/1744666x.2016.1101344] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Intrahepatic cholestasis of pregnancy poses a great risk to both maternal and fetal health. Despite extensive research, much of the pathogenesis of this disorder is unknown. The increase in bile acids observed in patients with intrahepatic cholestasis of pregnancy has been noted to cause a change in the immune system from the normally mediated TH2 response to one that is more oriented towards TH1. In this literature review, we have critically reviewed the current literature regarding the changes in the immune system and the potential effects of immunological changes in the management of the patient. The current treatment, ursodeoxycholic acid, is also discussed along with potential combination therapies and future directions for research.
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Affiliation(s)
- Spencer P Larson
- a Center for Clinical & Translational Science , Creighton University School of Medicine , Omaha , NE , USA.,b Department of Obstetrics and Gynecology , Creighton University School of Medicine , Omaha , NE , USA
| | - Oormila Kovilam
- b Department of Obstetrics and Gynecology , Creighton University School of Medicine , Omaha , NE , USA
| | - Devendra K Agrawal
- a Center for Clinical & Translational Science , Creighton University School of Medicine , Omaha , NE , USA
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48
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Shekhar S, Diddi G. Liver disease in pregnancy. Taiwan J Obstet Gynecol 2015; 54:475-82. [DOI: 10.1016/j.tjog.2015.01.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/16/2015] [Indexed: 12/17/2022] Open
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49
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Korneenko TV, Pestov NB, Okkelman IA, Modyanov NN, Shakhparonov MI. [P4-ATP-ase Atp8b1/FIC1: structural properties and (patho)physiological functions]. RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY 2015; 41:3-12. [PMID: 26050466 DOI: 10.1134/s1068162015010070] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
P4-ATP-ases comprise an interesting family among P-type ATP-ases, since they are thought to play a major role in the transfer of phospholipids such as phosphatydylserine from the outer leaflet to the inner leaflet. Isoforms of P4-ATP-ases are partially interchangeable but peculiarities of tissue-specific expression of their genes, intracellular localization of proteins, as well as regulatory pathways lead to the fact that, on the organismal level, serious pathologies may develop in the presence of structural abnormalities in certain isoforms. Among P4-ATP-ases a special place is occupied by ATP8B1, for which several mutations are known that lead to serious hereditary diseases: two forms of congenital cholestasis (PFIC1 or Byler disease and benign recurrent intrahepatic cholestasis) with extraliver symptoms such as sensorineural hearing loss. The physiological function of the Atp8b1/FIC1 protein is known in general outline: it is responsible for transport of certain phospholipids (phosphatydylserine, cardiolipin) for the outer monolayer of the plasma membrane to the inner one. It is well known that perturbation of membrane asymmetry, caused by the lack of Atp8B1 activity, leads to death of hairy cells of the inner ear, dysfunction of bile acid transport in liver-cells that causes cirrhosis. It is also probable that insufficient activity of Atp8b1/FIC1 increases susceptibility to bacterial pneumonia.Regulatory pathways of Atp8b1/FIC1 activity in vivo remain to be insufficiently studied and this opens novel perspectives for research in this field that may allow better understanding of molecular processes behind the development of certain pathologies and to reveal novel therapeutical targets.
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50
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Abstract
Bile acids are the end products of cholesterol catabolism. Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Biliary secretion of bile acids generates bile flow and facilitates hepatobiliary secretion of lipids, lipophilic metabolites, and xenobiotics. In the intestine, bile acids are essential for the absorption, transport, and metabolism of dietary fats and lipid-soluble vitamins. Extensive research in the last 2 decades has unveiled new functions of bile acids as signaling molecules and metabolic integrators. The bile acid-activated nuclear receptors farnesoid X receptor, pregnane X receptor, constitutive androstane receptor, vitamin D receptor, and G protein-coupled bile acid receptor play critical roles in the regulation of lipid, glucose, and energy metabolism, inflammation, and drug metabolism and detoxification. Bile acid synthesis exhibits a strong diurnal rhythm, which is entrained by fasting and refeeding as well as nutrient status and plays an important role for maintaining metabolic homeostasis. Recent research revealed an interaction of liver bile acids and gut microbiota in the regulation of liver metabolism. Circadian disturbance and altered gut microbiota contribute to the pathogenesis of liver diseases, inflammatory bowel diseases, nonalcoholic fatty liver disease, diabetes, and obesity. Bile acids and their derivatives are potential therapeutic agents for treating metabolic diseases of the liver.
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Affiliation(s)
- Tiangang Li
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas (T.L.); and Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio (J.Y.L.C.)
| | - John Y L Chiang
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas (T.L.); and Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio (J.Y.L.C.)
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