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Liu Y, Wei Y, Chen X, Huang S, Gu Y, Yang Z, Guo X, Zheng H, Feng H, Huang M, Chen S, Xiao T, Hu L, Zhang Q, Zhang Y, Chen GB, Qiu X, Wei F, Zhen J, Liu S. Genetic study of intrahepatic cholestasis of pregnancy in Chinese women unveils East Asian etiology linked to historic HBV epidemic. J Hepatol 2024:S0168-8278(24)02708-9. [PMID: 39547589 DOI: 10.1016/j.jhep.2024.11.008] [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] [Received: 01/26/2024] [Revised: 10/25/2024] [Accepted: 11/05/2024] [Indexed: 11/17/2024]
Abstract
BACKGROUND & AIMS Intrahepatic cholestasis of pregnancy (ICP) is the most common and high-risk liver disorder during pregnancy, with varying prevalence across populations. Our understanding of the mechanisms underlying ICP and population-level differences remains limited. This study delves into the genetic etiology of ICP in East Asians, drawing comparisons with Europeans to comprehend ICP etiology in the context of genetic background and evolution. METHODS We conducted the hitherto largest-scale genome-wide association study on fasting total serum bile acids (TBA) and ICP in 98,269 Chinese pregnancies. The findings were replicated in three cohorts and compared with European populations. Additionally, phenome-wide association and spatio-temporal evolution analyses were employed to investigate the function and evolutionary patterns of ICP-associated loci. RESULTS We identified eight loci for fasting TBA and four for ICP, including ten novel loci. Notably, we discovered an East Asian-specific locus within a 0.4 Mbp region at 14q24.1, which increases fasting TBA by 6.12 μmol/L and ICP risk by 16.56-fold per risk allele (95% CI 16.43 to 16.69, p = 7.06×10-381). Phenome-wide association and spatial-temporal evolution analyses revealed that this 14q24.1 ICP risk locus confers resistance to hepatitis B and has become prevalent in East and Southeast Asia within the last 3,000 years. CONCLUSIONS We uncovered a distinct genetic etiology of ICP in East Asians, likely linked to a historic HBV epidemic in East and Southeast Asia within the last 3,000 years. These findings enhance our understanding of ICP pathophysiology and offer potential for more precise detection, assessment, and treatment of the disorder. IMPACT AND IMPLICATIONS This study provides novel insights into the genetic basis of intrahepatic cholestasis of pregnancy (ICP) in East Asian populations, where little was previously known. The identification of the East-Asian-specific 14q24.1 locus, associated with both fasting total serum bile acids and ICP, and its connection to a historical hepatitis B epidemic emphasize the importance of incorporating population-specific history into disease research. These findings are crucial for researchers studying pregnancy-related liver disorders and clinicians providing care to pregnant women, enabling more accurate screening, risk assessment, and targeted interventions for ICP.
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Affiliation(s)
- Yanhong Liu
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong 518107, China
| | - Yuandan Wei
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong 518107, China; Central Laboratory, Shenzhen Baoan Women's and Children's Hospital, Shenzhen, Guangdong 518102, China
| | - Xiaohang Chen
- The Genetics Laboratory, Longgang District Maternity & Child Healthcare Hospital of Shenzhen City (Longgang Maternity and Child Institute of Shantou University Medical College), Shenzhen, Guangdong, 518172, China
| | - Shujia Huang
- The Born in Guangzhou Cohort Study Group, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China; Department of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Yuqin Gu
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong 518107, China
| | - Zijing Yang
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong 518107, China; The Genetics Laboratory, Longgang District Maternity & Child Healthcare Hospital of Shenzhen City (Longgang Maternity and Child Institute of Shantou University Medical College), Shenzhen, Guangdong, 518172, China
| | - Xinxin Guo
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong 518107, China
| | - Hao Zheng
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong 518107, China
| | - Hanxiao Feng
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong 518107, China
| | - Mingxi Huang
- The Born in Guangzhou Cohort Study Group, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China; Department of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Shangliang Chen
- Department of transfusion, Shenzhen Baoan Women's and Children's Hospital, Shenzhen, Guangdong 518102, China
| | - Tiantian Xiao
- Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, China
| | - Liang Hu
- The Genetics Laboratory, Longgang District Maternity & Child Healthcare Hospital of Shenzhen City (Longgang Maternity and Child Institute of Shantou University Medical College), Shenzhen, Guangdong, 518172, China
| | - Quanfu Zhang
- Central Laboratory, Shenzhen Baoan Women's and Children's Hospital, Shenzhen, Guangdong 518102, China
| | - Yang Zhang
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong 518107, China
| | - Guo-Bo Chen
- Center for Reproductive Medicine, Department of Genetic and Genomic Medicine, Clinical Research Institute, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang, China
| | - Xiu Qiu
- The Born in Guangzhou Cohort Study Group, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China; Division of Women Health Care, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
| | - Fengxiang Wei
- The Genetics Laboratory, Longgang District Maternity & Child Healthcare Hospital of Shenzhen City (Longgang Maternity and Child Institute of Shantou University Medical College), Shenzhen, Guangdong, 518172, China.
| | - Jianxin Zhen
- Central Laboratory, Shenzhen Baoan Women's and Children's Hospital, Shenzhen, Guangdong 518102, China.
| | - Siyang Liu
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong 518107, China; Shenzhen Key Laboratory of Pathogenic Microbes and Biosafety, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China; GuangDong Engineering Technology Research Center of Nutrition Transformation, Sun Yat-sen University, Shenzhen, 518107, Guangdong Province, China.
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Katiyar H, Yadav S, Singh S, Mishra AK, Pradhan M, Lingaiah R, Goel A. Evaluation of Serum Calprotectin as an Alternative Diagnostic Marker for Intrahepatic Cholestasis of Pregnancy. J Clin Med 2024; 13:5644. [PMID: 39337132 PMCID: PMC11433286 DOI: 10.3390/jcm13185644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Revised: 09/22/2024] [Accepted: 09/22/2024] [Indexed: 09/30/2024] Open
Abstract
Background/Objectives: Intrahepatic cholestasis of pregnancy (ICP) is characterised by unexplained intense pruritus during pregnancy. While serum bile acid (BA) is the standard diagnostic marker for ICP, we explored the potential of serum calprotectin as an alternative diagnostic marker for ICP. Methods: Leftover serum specimens with known serum BA levels, collected from non-pregnant women and pregnant women with an ICP, were used to measure serum calprotectin levels using the Human calprotectin L1/S100-A8/A9 ELISA kit. Results: Serum calprotectin levels were measured in 79 pregnant women with ICP (median [interquartile range] 28 year; serum BA 20 [13.7-35.7] μMol/L; calprotectin159 pg/mL [122.2-212.3]); 43 pregnant women without ICP (age 28 years; serum BA 3.6 [2.1-5.8] μMol/L; calprotectin 146.5 pg/mL [75.8-194.8]), and 59 non-pregnant women (age 28 years; serum BA 3.5 [1.6-5.1 μMol/L; calprotectin 82.4 pg/mL [48.8-137.2]). Compared to non-pregnant women, calprotectin levels were significantly elevated among pregnant women with (p < 0.001) or without ICP (p = 0.01). Calprotectin levels were comparable between pregnant women with and without ICP (p = 0.15). The areas under the ROC curve, to differentiate the presence and absence of ICP, were 0.940 (0.903-0.977; p < 0.001) and 0.681 (0.604-0.759; p < 0.001) for BA and calprotectin, respectively. Conclusions: Serum calprotectin is raised in pregnant women regardless of the presence or absence of ICP and had an inferior diagnostic performance for ICP compared to BA. This information is crucial for understanding the challenges in ICP diagnosis and the limitations of serum calprotectin as an alternative marker.
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Affiliation(s)
- Harshita Katiyar
- Department of Hepatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India; (H.K.); (S.S.); (A.K.M.)
| | - Sangeeta Yadav
- Department of Maternal & Reproductive Health, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India; (S.Y.); (M.P.)
| | - Surender Singh
- Department of Hepatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India; (H.K.); (S.S.); (A.K.M.)
| | - Ajay Kumar Mishra
- Department of Hepatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India; (H.K.); (S.S.); (A.K.M.)
| | - Mandakini Pradhan
- Department of Maternal & Reproductive Health, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India; (S.Y.); (M.P.)
| | - Raghavendra Lingaiah
- Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India;
| | - Amit Goel
- Department of Hepatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India; (H.K.); (S.S.); (A.K.M.)
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Mao K, Jiang P, Cai W, Lin Y, Zhou Y, Li D. Association of gestational hepatitis B virus infection and antiviral therapy with pregnancy outcomes: A retrospective study. Int J Gynaecol Obstet 2024; 166:115-125. [PMID: 38831742 DOI: 10.1002/ijgo.15716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 04/29/2024] [Accepted: 05/23/2024] [Indexed: 06/05/2024]
Abstract
OBJECTIVE To explore the relationships between gestational hepatitis B virus (HBV) infection, antiviral therapy, and pregnancy outcomes. METHODS We retrospectively selected hepatitis B surface antigen (HBsAg)-positive pregnant women hospitalized for delivery at Fujian Medical University Affiliated Hospital from October 1, 2016 to October 1, 2020. The control group included randomly selected healthy pregnant women hospitalized for delivery during the same time. RESULTS Overall, 1115 participants were enrolled and grouped into control (n = 380) and HBsAg-positive groups (n = 735), which were further divided into groups I (n = 407; low viral load), II (n = 207; high viral load without antiviral therapy), and III (n = 121; high viral load with antiviral therapy). Pregnant women with HBV were positively correlated with the incidence of intrahepatic cholestasis of pregnancy (ICP) (adjusted odds ratio [aOR] 5.1, 95% confidence interval [CI] 2.62-9.92, P < 0.001), neonatal jaundice (aOR 10.56, 95% CI 4.49-24.83, P < 0.001), and neonatal asphyxia (aOR 5.03, 95% CI 1.46-17.27, P = 0.01). Aspartate aminotransferase (AST) greater than the upper limit of normal (ULN) was an independent risk factor for increased ICP incidence (aOR 3.49, 95% CI 1.26-9.67, P = 0.019). Antiviral therapy considerably reduced HBV DNA and improved liver function. High viral load and antiviral therapy did not correlate significantly with adverse pregnancy outcomes (P < 0.05). CONCLUSION Pregnant women with HBV have significantly elevated incidence of ICP, neonatal jaundice, and neonatal asphyxia not significantly correlated with viral load. AST greater than ULN independently increases the risk of ICP. Antiviral therapy effectively reduces viral replication and improves liver function without increasing the risk of adverse outcomes.
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Affiliation(s)
- Kaiyi Mao
- Department of Gastroenterology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Pingying Jiang
- Department of Gastroenterology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Weiqi Cai
- Department of Gastroenterology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Yongxu Lin
- Department of Gastroenterology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Yu Zhou
- Department of Obstetrics and Gynecology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Dan Li
- Department of Gastroenterology, Fujian Medical University Union Hospital, Fuzhou, China
- Fujian Clinical Research Center for Digestive System Tumors and Upper Gastrointestinal Diseases, Fuzhou, China
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Guan L, Wang Y, Lin L, Zou Y, Qiu L. Variations in Blood Copper and Possible Mechanisms During Pregnancy. Biol Trace Elem Res 2024; 202:429-441. [PMID: 37777692 DOI: 10.1007/s12011-023-03716-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Accepted: 05/24/2023] [Indexed: 10/02/2023]
Abstract
Copper (Cu), an essential trace element, is crucial for both the mother and fetus. Currently, an increasing number of studies have focused on blood copper levels during pregnancy. Studies have found that blood copper levels in pregnant women are higher than those in reproductive-age women, but the trend, mainly in the 2nd and 3rd trimester, is still controversial. Most studies showed that blood copper levels gradually increased during pregnancy, while some studies found that blood copper levels remained stable or even decreased in the 3rd trimester. The possible mechanisms of variations in blood copper during pregnancy include the influence of estrogen (hepatic uptake and excretion, ceruloplasmin synthesis, maternal-fetal transport, etc.), the interaction of other trace elements (Fe, Zn, etc.) and other factors. Among them, maternal-fetal copper transport caused by elevated estrogen may be the main reason for the inconsistencies observed in the 2nd and 3rd trimester during pregnancy. However, there are some mechanisms require further investigation. In the future, the trend and mechanisms of blood copper during pregnancy should be explored more deeply to help doctors better monitor copper status and detect copper abnormalities in time.
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Affiliation(s)
- Lihua Guan
- Department of Laboratory Medicine, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing, 100730, People's Republic of China
| | - Yifei Wang
- Department of Laboratory Medicine, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing, 100730, People's Republic of China
| | - Liling Lin
- Department of Laboratory Medicine, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing, 100730, People's Republic of China
| | - Yutong Zou
- Department of Laboratory Medicine, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing, 100730, People's Republic of China
| | - Ling Qiu
- Department of Laboratory Medicine, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing, 100730, People's Republic of China.
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing, 100730, People's Republic of China.
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Sanchon-Sanchez P, Herraez E, Macias RIR, Estiu MC, Fortes P, Monte MJ, Marin JJG, Romero MR. Relationship between cholestasis and altered progesterone metabolism in the placenta-maternal liver tandem. Biochim Biophys Acta Mol Basis Dis 2024; 1870:166926. [PMID: 37956602 DOI: 10.1016/j.bbadis.2023.166926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 10/20/2023] [Accepted: 10/24/2023] [Indexed: 11/15/2023]
Abstract
BACKGROUND In intrahepatic cholestasis of pregnancy (ICP), there are elevated maternal serum levels of total bile acids, progesterone, and some sulfated metabolites, such as allopregnanolone sulfate, which inhibits canalicular function. AIM To investigate the relationship between cholestasis and the expression of crucial enzymes involved in progesterone metabolism in the liver and placenta. METHODS Obstructive cholestasis was induced by bile duct ligation (BDL). RT-qPCR (mRNA) and western blot (protein) were used to determine expression levels. Srd5a1 and Akr1c2 enzymatic activities were assayed by substrate disappearance (progesterone and 5α-dihydroprogesterone, respectively), measured by HPLC-MS/MS. RESULTS BDL induced decreased Srd5a1 and Akr1c2 expression and activity in rat liver, whereas both enzymes were up-regulated in rat placenta. Regarding sulfotransferases, Sult2b1 was also moderately up-regulated in the liver. In placenta from ICP patients, SRD5A1 and AKR1C2 expression was elevated, whereas both genes were down-regulated in liver biopsies collected from patients with several liver diseases accompanied by cholestasis. SRD5A1 and AKR1C2 expression was not affected by incubating human hepatoma HepG2 cells with FXR agonists (chenodeoxycholic acid and GW4064). Knocking-out Fxr in mice did not reduce Srd5a1 and Akr1c14 expression, which was similarly down-regulated by BDL. CONCLUSION SRD5A1 and AKR1C2 expression was markedly altered by cholestasis. This was enhanced in the placenta but decreased in the liver, which is not mediated by FXR. These results suggest that the excess of progesterone metabolites in the serum of ICP patients can involve both enhanced placental production and decreased hepatic clearance. The latter may also occur in other cholestatic conditions.
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Affiliation(s)
- Paula Sanchon-Sanchez
- Experimental Hepatology and Drug Targeting (HEVEPHARM), IBSAL, University of Salamanca, Salamanca, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Madrid, Spain
| | - Elisa Herraez
- Experimental Hepatology and Drug Targeting (HEVEPHARM), IBSAL, University of Salamanca, Salamanca, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Madrid, Spain
| | - Rocio I R Macias
- Experimental Hepatology and Drug Targeting (HEVEPHARM), IBSAL, University of Salamanca, Salamanca, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Madrid, Spain
| | - Maria C Estiu
- Ramon Sarda Mother's and Children's Hospital, Buenos Aires, Argentina
| | - Puri Fortes
- Foundation for Applied Medical Research (FIMA), School of Medicine, University of Navarra, Pamplona, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Madrid, Spain
| | - Maria J Monte
- Experimental Hepatology and Drug Targeting (HEVEPHARM), IBSAL, University of Salamanca, Salamanca, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Madrid, Spain
| | - Jose J G Marin
- Experimental Hepatology and Drug Targeting (HEVEPHARM), IBSAL, University of Salamanca, Salamanca, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Madrid, Spain.
| | - Marta R Romero
- Experimental Hepatology and Drug Targeting (HEVEPHARM), IBSAL, University of Salamanca, Salamanca, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Madrid, Spain
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Wang M, Chen L, Li J, You Y, Qian Z, Liu J, Jiang Y, Zhou T, Gu Y, Zhang Y. An omics review and perspective of researches on intrahepatic cholestasis of pregnancy. Front Endocrinol (Lausanne) 2024; 14:1267195. [PMID: 38260124 PMCID: PMC10801044 DOI: 10.3389/fendo.2023.1267195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Accepted: 12/19/2023] [Indexed: 01/24/2024] Open
Abstract
Intrahepatic cholestasis of pregnancy (ICP) is one of the common pregnancy complications that may threaten the health of both pregnant women and their fetuses. Hence, it is of vital importance to identify key moleculars and the associated functional pathways of ICP, which will help us to better understand the pathological mechanisms as well as to develop precise clinical biomarkers. The emerging and developing of multiple omics approaches enable comprehensive studies of the genome, transcriptome, proteome and metabolome of clinical samples. The present review collected and summarized the omics based studies of ICP, aiming to provide an overview of the current progress, limitations and future directions. Briefly, these studies covered a broad range of research contents by the comparing of different experimental groups including ICP patients, ICP subtypes, ICP fetuses, ICP models and other complications. Correspondingly, the studied samples contain various types of clinical samples, in vitro cultured tissues, cell lines and the samples from animal models. According to the main research objectives, we further categorized these studies into two groups: pathogenesis and diagnosis analyses. The pathogenesis studies identified tens of functional pathways that may represent the key regulatory events for the occurrence, progression, treatment and fetal effects of ICP. On the other hand, the diagnosis studies tested more than 40 potential models for the early-prediction, diagnosis, grading, prognosis or differential diagnosis of ICP. Apart from these achievements, we also evaluated the limitations of current studies, and emphasized that many aspects of clinical characteristics, sample processing, and analytical method can greatly affect the reliability and repeatability of omics results. Finally, we also pointed out several new directions for the omics based analyses of ICP and other perinatal associated conditions in the future.
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Affiliation(s)
- Min Wang
- Center for Reproductive Medicine, The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi, China
| | - Lingyan Chen
- Department of Gynaecology and Obstetrics, The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi, China
| | - Jingyang Li
- Department of Gynaecology and Obstetrics, The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi, China
| | - Yilan You
- Department of Gynaecology and Obstetrics, The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi, China
| | - Zhiwen Qian
- Department of Gynaecology and Obstetrics, The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi, China
| | - Jiayu Liu
- Wuxi Maternity and Child Health Care Hospital, Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Ying Jiang
- Department of Gynaecology and Obstetrics, The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi, China
| | - Tao Zhou
- Wuxi Maternity and Child Health Care Hospital, Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Ying Gu
- Department of Gynaecology and Obstetrics, The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi, China
- Wuxi Maternity and Child Health Care Hospital, Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Yan Zhang
- Department of Gynaecology and Obstetrics, The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi, China
- Wuxi Maternity and Child Health Care Hospital, Wuxi School of Medicine, Jiangnan University, Wuxi, China
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Roediger R, Fleckenstein J. Intrahepatic cholestasis of pregnancy. Clin Liver Dis (Hoboken) 2024; 23:e0119. [PMID: 38379768 PMCID: PMC10878546 DOI: 10.1097/cld.0000000000000119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Accepted: 10/22/2023] [Indexed: 02/22/2024] Open
Affiliation(s)
- Rebecca Roediger
- Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, New York City, New York, USA
| | - Jaquelyn Fleckenstein
- Department of Medicine, Division of Gastroenterology and Hepatology, Washington University School of Medicine, St. Louis, Missouri, USA
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Li X, Xie H, Chao JJ, Jia YH, Zuo J, An YP, Bao YR, Jiang X, Ying H. Profiles and integration of the gut microbiome and fecal metabolites in severe intrahepatic cholestasis of pregnancy. BMC Microbiol 2023; 23:282. [PMID: 37784030 PMCID: PMC10546765 DOI: 10.1186/s12866-023-02983-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 08/17/2023] [Indexed: 10/04/2023] Open
Abstract
BACKGROUND The pathogenesis of intrahepatic cholestasis of pregnancy (ICP) remains unknown. The gut microbiome and its metabolites play important roles in bile acid metabolism, and previous studies have indicated the association of the gut microbiome with ICP. METHODS We recruited a cohort of 5100 participants, and 20 participants were enrolled in the severe ICP group, matched with 20 participants in the mild ICP group and 20 controls. 16S rRNA sequencing and nontargeting metabolomics were adapted to explore the gut microbiome and fecal metabolites. RESULTS An increase in richness and a dramatic deviation in composition were found in the gut microbiome in ICP. Decreased Firmicutes and Bacteroidetes abundances and increased Proteobacteria abundances were found in women with severe but not mild ICP compared to healthy pregnant women. Escherichia-Shigella and Lachnoclostridium abundances increased, whereas Ruminococcaceae abundance decreased in ICP group, especially in severe ICP group. The fecal metabolite composition and diversity presented typical variation in severe ICP. A significant increase in bile acid, formate and succinate levels and a decrease in butyrate and hypoxanthine levels were found in women with severe ICP. The MIMOSA model indicated that genera Ruminococcus gnavus group, Lachnospiraceae FCS020 group, and Lachnospiraceae NK4A136 group contributed significantly to the metabolism of hypoxanthine, which was significantly depleted in subjects with severe ICP. Genus Acinetobacter contributed significantly to formate metabolism, which was significantly enriched in subjects with severe ICP. CONCLUSIONS Women with severe but not mild ICP harbored a unique gut microbiome and fecal metabolites compared to healthy controls. Based on these profiles, we hypothesized that the gut microbiome was involved in bile acid metabolism through metabolites, affecting ICP pathogenesis and development, especially severe ICP.
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Affiliation(s)
- Xiang Li
- Shanghai Key Laboratory of Maternal Fetal Medicine Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai, 200040, China
- Department of Obstetrics, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, No. 2699, West Gaoke Road, Shanghai, 200040, People's Republic of China
| | - Han Xie
- Shanghai Key Laboratory of Maternal Fetal Medicine Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai, 200040, China
- Department of Obstetrics, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, No. 2699, West Gaoke Road, Shanghai, 200040, People's Republic of China
| | - Jia-Jing Chao
- Shanghai Key Laboratory of Maternal Fetal Medicine Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai, 200040, China
- Department of Obstetrics, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, No. 2699, West Gaoke Road, Shanghai, 200040, People's Republic of China
| | - Yuan-Hui Jia
- Shanghai Key Laboratory of Maternal Fetal Medicine Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai, 200040, China
- Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 200040, China
| | - Jia Zuo
- Shanghai Key Laboratory of Maternal Fetal Medicine Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai, 200040, China
- Department of Obstetrics, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, No. 2699, West Gaoke Road, Shanghai, 200040, People's Republic of China
| | - Yan-Peng An
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, 200438, China
| | - Yi-Rong Bao
- Shanghai Key Laboratory of Maternal Fetal Medicine Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai, 200040, China
- Department of Obstetrics, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, No. 2699, West Gaoke Road, Shanghai, 200040, People's Republic of China
| | - Xiang Jiang
- Shanghai Key Laboratory of Maternal Fetal Medicine Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai, 200040, China.
- Department of Obstetrics, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, No. 2699, West Gaoke Road, Shanghai, 200040, People's Republic of China.
- Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 200040, China.
| | - Hao Ying
- Shanghai Key Laboratory of Maternal Fetal Medicine Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai, 200040, China.
- Department of Obstetrics, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, No. 2699, West Gaoke Road, Shanghai, 200040, People's Republic of China.
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9
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Sun J, Wang W, Zhou X, Yang T, Ye M, Shi W, Liu Z, Zhang L, Zhou Q, Qin Y, Chen Y, Chen F, Huang H, Chen S, Xu C. Early characterisation and prediction of liver diseases in pregnancy by plasma cell-free RNAs. Clin Transl Med 2023; 13:e1439. [PMID: 37830149 PMCID: PMC10570770 DOI: 10.1002/ctm2.1439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 09/15/2023] [Accepted: 10/01/2023] [Indexed: 10/14/2023] Open
Affiliation(s)
| | | | - Xuanyou Zhou
- Obstetrics and Gynecology HospitalInstitute of Reproduction and DevelopmentFudan UniversityShanghaiShanghaiP. R. China
| | - Tingyu Yang
- BGI‐ShenzhenShenzhenGuangdongP. R. China
- College of Life SciencesUniversity of Chinese Academy of SciencesBeijingBeijingP. R. China
| | - Mujin Ye
- International Peace Maternity and Child Health HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiShanghaiP. R. China
| | - Weihui Shi
- Obstetrics and Gynecology HospitalInstitute of Reproduction and DevelopmentFudan UniversityShanghaiShanghaiP. R. China
| | | | - Lanlan Zhang
- International Peace Maternity and Child Health HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiShanghaiP. R. China
| | - Qing Zhou
- BGI‐ShenzhenShenzhenGuangdongP. R. China
| | - Yulong Qin
- BGI‐ShenzhenShenzhenGuangdongP. R. China
- College of Life SciencesUniversity of Chinese Academy of SciencesBeijingBeijingP. R. China
| | - Yiyao Chen
- International Peace Maternity and Child Health HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiShanghaiP. R. China
| | - Fang Chen
- BGI‐ShenzhenShenzhenGuangdongP. R. China
| | - Hefeng Huang
- Obstetrics and Gynecology HospitalInstitute of Reproduction and DevelopmentFudan UniversityShanghaiShanghaiP. R. China
- International Peace Maternity and Child Health HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiShanghaiP. R. China
- Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences (No. 2019RU056)ShanghaiChina
| | - Songchang Chen
- Obstetrics and Gynecology HospitalInstitute of Reproduction and DevelopmentFudan UniversityShanghaiShanghaiP. R. China
| | - Chenming Xu
- Obstetrics and Gynecology HospitalInstitute of Reproduction and DevelopmentFudan UniversityShanghaiShanghaiP. R. China
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10
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Granese R, Calagna G, Alibrandi A, Martinelli C, Romeo P, Filomia R, Ferraro MI, Piccione E, Ercoli A, Saitta C. Maternal and Neonatal Outcomes in Intrahepatic Cholestasis of Pregnancy. J Clin Med 2023; 12:4407. [PMID: 37445442 DOI: 10.3390/jcm12134407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Revised: 06/26/2023] [Accepted: 06/27/2023] [Indexed: 07/15/2023] Open
Abstract
The aims of our study were to evaluate the maternal and fetal outcomes of intrahepatic cholestasis of pregnancy (ICP). In this observational, retrospective case-control study, we included all pregnant women who gave birth with a diagnosis of ICP between January 2010 and December 2020 at the Unit of Obstetrics and Gynecology, University Hospital of Messina. The data were compared with those from a control group of pregnant women who did not have ICP. One hundred twenty-nine and eighty-five patients were included, respectively, in the study and in the control group. There was a significant difference between the two groups in the incidence of hypothyroidism, thrombophilia, gestational diabetes, gestational hypertension, postpartum hemorrhage, and preterm delivery, which were more frequent in the ICP patients. No neonatal adverse events were recorded, although a significant difference in the meconium-stained amniotic fluid condition was noted. After a 24-month follow-up, 48/129 patients with ICP accepted to be reassessed by liver ultrasound, elastographic examination, and liver function blood tests. No patient showed signs of chronic liver disease. This study confirmed a higher probability of adverse short-term maternal outcomes in ICP pregnant patients, but a lower probability of adverse short-term fetal outcomes and the absence of a long-term maternal risk of chronic liver disease.
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Affiliation(s)
- Roberta Granese
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University Hospital "G. Martino", Via Consolare Valeria 1, Gazzi, 98100 Messina, Italy
| | - Gloria Calagna
- Obstetrics and Gynecology, "Villa Sofia Cervello" Hospital, University of Palermo, Via Trabucco 180, 90127 Palermo, Italy
| | - Angela Alibrandi
- Department of Economics, Unit of Statistical and Mathematical Sciences, University of Messina, Via dei Verdi, 98166 Messina, Italy
| | - Canio Martinelli
- Department of Human Pathology in Adulthood and Childhood, University Hospital "G. Martino", Via Consolare Valeria 1, Gazzi, 98100 Messina, Italy
| | - Paola Romeo
- Department of Human Pathology in Adulthood and Childhood, University Hospital "G. Martino", Via Consolare Valeria 1, Gazzi, 98100 Messina, Italy
| | - Roberto Filomia
- Department of Clinical and Experimental Medicine, University Hospital "G. Martino", Via Consolare Valeria 1, Gazzi, 98100 Messina, Italy
| | | | - Eleonora Piccione
- Family Counseling, ASP Messina, Via Trento 8, Brolo, 98100 Messina, Italy
| | - Alfredo Ercoli
- Department of Human Pathology in Adulthood and Childhood, University Hospital "G. Martino", Via Consolare Valeria 1, Gazzi, 98100 Messina, Italy
| | - Carlo Saitta
- Department of Clinical and Experimental Medicine, University Hospital "G. Martino", Via Consolare Valeria 1, Gazzi, 98100 Messina, Italy
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11
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Jiang Y, Yin X, Xu Q, Tang X, Zhang H, Cao X, Lin J, Wang Y, Yang F, Khan NU, Shen L, Zhao D. SWATH proteomics analysis of placental tissue with intrahepatic cholestasis of pregnancy. Placenta 2023; 137:1-13. [PMID: 37054625 DOI: 10.1016/j.placenta.2023.04.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 02/26/2023] [Accepted: 04/07/2023] [Indexed: 04/15/2023]
Abstract
INTRODUCTION Intrahepatic cholestasis of pregnancy (ICP) usually occurs in the second and third trimesters. The disease's etiology and diagnostic criteria are currently unknown. Based on a sequence window to obtain all theoretical fragment ions (SWATH) proteomic approach, this study sought to identify potential proteins in placental tissue that may be involved in the pathogenesis of ICP and adverse fetal pregnancy outcomes. METHODS The postpartum placental tissue of pregnant women with ICP were chosen as the case group (ICP group) (subdivided into mild ICP group (MICP group) and severe ICP group (SICP group)), and healthy pregnant women were chosen as the control group (CTR). The hematoxylin-eosin (HE) staining was used to observe the histologic changes of placenta. The SWATH analysis combined with liquid chromatography-tandem mass spectrometry (LC-MS) was used to screen the differentially expressed proteins (DEPs) in ICP and CTR groups, and bioinformatics analysis was used to find out the biological process of these differential proteins. RESULTS Proteomic studies showed there were 126 DEPs from pregnant women with ICP and healthy pregnant women. Most of the identified proteins were functionally related to humoral immune response, cell response to lipopolysaccharide, antioxidant activity and heme metabolism. A subsequent examination of placentas from patients with mild and severe ICP revealed 48 proteins that were differentially expressed. Through death domain receptors and fibrinogen complexes, these DEPs primarily regulate extrinsic apoptotic signaling pathways, blood coagulation, and fibrin clot formation. The differential expressions of HBD, HPX, PDE3A, and PRG4 were down-regulated by Western blot analysis, which was consistent with proteomics. DISCUSSION This preliminary study helps us to understand the changes in the placental proteome of ICP patients, and provides new insights into the pathophysiology of ICP.
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Affiliation(s)
- Yuxuan Jiang
- Department of Obstetrics and Gynecology Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Xiaoping Yin
- Department of Obstetrics and Gynecology Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Qian Xu
- Department of Obstetrics and Gynecology Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Xiaoxiao Tang
- College of Life Science and Oceanography, Shenzhen University, Shenzhen, China
| | - Huajie Zhang
- College of Life Science and Oceanography, Shenzhen University, Shenzhen, China
| | - Xueshan Cao
- College of Life Science and Oceanography, Shenzhen University, Shenzhen, China
| | - Jing Lin
- College of Life Science and Oceanography, Shenzhen University, Shenzhen, China
| | - Yi Wang
- School of Public Health, The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, China
| | - Fei Yang
- Department of Obstetrics and Gynecology Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Naseer Ullah Khan
- College of Life Science and Oceanography, Shenzhen University, Shenzhen, China
| | - Liming Shen
- College of Life Science and Oceanography, Shenzhen University, Shenzhen, China.
| | - Danqing Zhao
- Department of Obstetrics and Gynecology Affiliated Hospital of Guizhou Medical University, Guiyang, China.
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12
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Lai H, Liu X, Xin S, Zheng J, Liu H, Ouyang Y, Yang H, Zeng Y, Zou Y, Zeng X. Identification of two novel pathogenic variants of the NR1H4 gene in intrahepatic cholestasis of pregnancy patients. BMC Med Genomics 2022; 15:90. [PMID: 35436901 PMCID: PMC9017038 DOI: 10.1186/s12920-022-01240-w] [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: 11/04/2021] [Accepted: 04/12/2022] [Indexed: 12/18/2022] Open
Abstract
Background Intrahepatic cholestasis of pregnancy (ICP) can cause adverse pregnancy outcomes, such as spontaneous preterm delivery and stillbirth. It is a complex disease influenced by multiple factors, including genetics and the environment. Previous studies have reported that functioning nuclear receptor subfamily 1 group H member 4 (NR1H4) plays an essential role in bile acid (BA) homeostasis. However, some novel variants and their pathogenesis have not been fully elucidated. Therefore, this research aimed to investigate the genetic characteristics of the NR1H4 gene in ICP.
Methods In this study, we sequenced the entire coding region of NR1H4 in 197 pregnant women with ICP disease. SIFT and PolyPhen2 were used to predict protein changes. Protein structure modelling and comparisons between NR1H4 reference and modified protein structures were performed by SWISS-MODEL and Chimera 1.14rc, respectively. T-tests were used to analyse the potential significant differences between NR1H4 mutations and wild types for 29 clinical features. Fisher’s test was conducted to test the significance of differences in mutation frequencies between ICP and the three databases. Results We identified four mutations: two novel missense mutations, p.S145F and p.M185L; rs180957965 (A230S); and rs147030757 (N275N). The two novel missense mutations were absent in 1029 controls and three databases, including the 1000 Genomes Project (1000G_ALL), Exome Aggregation Consortium (ExAC) and ChinaMAP. Two web-available tools, SIFT and PolyPhen2, predicted that these mutations are harmful to the function of the protein. Moreover, compared to the wild-type protein structure, the NR1H4 p.S145F and p.M185L protein structure showed a slight change in the chemical bond in two zinc finger structures. Combined clinical data indicate that the mutation group had higher levels of total bile acid (TBA) than the wild-type group. Therefore, we hypothesized that these two mutations altered the protein structure of NR1H4, which impaired the function of NR1H4 itself and its target gene and caused an increase in TBA. Conclusions To our knowledge, this is the first study to identify the novel p.S145F and p.M185L mutations in 197 ICP patients. Our present study provides new insights into the genetic architecture of ICP involving the two novel NR1H4 mutations. Supplementary Information The online version contains supplementary material available at 10.1186/s12920-022-01240-w.
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Affiliation(s)
- Hua Lai
- Key Laboratory of Women's Reproductive Health of Jiangxi Province, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, China.,Department of Obstetrics, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, China
| | - Xianxian Liu
- Key Laboratory of Women's Reproductive Health of Jiangxi Province, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, China.,Central Lab, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, China
| | - Siming Xin
- Key Laboratory of Women's Reproductive Health of Jiangxi Province, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, China.,Department of Obstetrics, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, China
| | - Jiusheng Zheng
- Key Laboratory of Women's Reproductive Health of Jiangxi Province, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, China.,Department of Obstetrics, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, China
| | - Huai Liu
- Key Laboratory of Women's Reproductive Health of Jiangxi Province, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, China.,Department of Obstetrics, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, China
| | - Yu Ouyang
- Key Laboratory of Women's Reproductive Health of Jiangxi Province, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, China.,Department of Obstetrics, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, China
| | - Huoxiu Yang
- Key Laboratory of Women's Reproductive Health of Jiangxi Province, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, China.,Department of Obstetrics, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, China
| | - Yang Zeng
- Key Laboratory of Women's Reproductive Health of Jiangxi Province, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, China.,Central Lab, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, China
| | - Yang Zou
- Key Laboratory of Women's Reproductive Health of Jiangxi Province, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, China. .,Central Lab, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, China.
| | - Xiaoming Zeng
- Key Laboratory of Women's Reproductive Health of Jiangxi Province, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, China. .,Department of Obstetrics, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, China.
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13
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Zhu H, Wang S, Li L, Geng W, Wan X, Hua R, Wang D, Gao P. Case Report: A rare case of young adult progressive familial intrahepatic cholestasis-type 3 with a novel heterozygous pathogenic variant of ABCB4. Front Pediatr 2022; 10:1012825. [PMID: 36330364 PMCID: PMC9622764 DOI: 10.3389/fped.2022.1012825] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 09/28/2022] [Indexed: 12/02/2022] Open
Abstract
Progressive familial intrahepatic cholestasis type 3 (PFIC-3) is a rare autosomal recessive disorder with poor prognosis. It is caused by pathogenic variants of the ATP binding cassette subfamily B member 4 (ABCB4) gene and usually progresses from chronic cholestasis with or without jaundice to portal hypertension and end-stage liver disease within the first to second decade of life. Few reported PFIC-3 patients presented with atypical clinical symptoms, therefore, often misdiagnosed if without family history. Herein, we report a 16-year-old male who was admitted to our hospital due to acute episodes of jaundice and intense pruritus, subsequently progressed to end-stage liver disease. Laboratory examinations showed no evidence of liver injury caused by viral, autoimmune, drug or liver tumors. Ursodeoxycholic acid and dexamethasone did not relieve his symptoms and he underwent liver transplantation successfully. Targeted next-generation sequencing identified that the patient was a compound heterozygote for two missense mutations (c.959C > T/c.1429C > A) in the ABCB4 gene. The mutation c.1429C > A (p.Q477K) is a novel heterozygous mutation. We constructed a three-dimensional model of this novel pathogenic variant using the SWISS MODEL program and found that the patient's ABCB4 protein is an ATP hydrolysis deficient mutant. The postoperative pathological diagnosis showed intrahepatic cholestasis with progression to cirrhosis. Negative liver tissue immunohistochemistry of MDR3 was found in the explanted liver. The patient was diagnosed with PFIC-3, and his symptoms improved dramatically with liver transplantation. In conclusion, for young patients with acute cholestasis, pruritus, jaundice, growth retardation, and enlargement of the liver and spleen, the possibility of inherited metabolic liver diseases should be considered, detailed medical and family history should be collected, and metabolic screening tests as well as gene tests are necessary for correct diagnosis. Increasing the coverage of PFIC3 is meaningful and thus can improve the current understanding of this disease.
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Affiliation(s)
- Hao Zhu
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
| | - Shengnan Wang
- Department of Neurology, The First Hospital of Jilin University, Changchun, China
| | - Li Li
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
| | - Wenqian Geng
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
| | - Xiaoqiang Wan
- Department of Interventional Therapy, The First Hospital of Jilin University, Changchun, China
| | - Rui Hua
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
| | - Dong Wang
- Department of Neurology, The First Hospital of Jilin University, Changchun, China
| | - Pujun Gao
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
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14
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Triggers of benign recurrent intrahepatic cholestasis and its pathophysiology: a review of literature. Acta Gastroenterol Belg 2021; 84:477-486. [PMID: 34599573 DOI: 10.51821/84.3.013] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Benign recurrent intrahepatic cholestasis (BRIC) is a rare genetic disorder that is characterized by episodes of cholestasis followed by complete resolution. The episodic nature of BRIC raises concerns about its possible trigger factors. Indeed, case reports of this orphan disease have associated BRIC to some triggers. In the absence of any reviews, we reviewed BRIC trigger factors and its pathophysiology. The study consisted of a systematic search for case reports using PubMed. Articles describing a clear case of BRIC associated with a trigger were included resulting in 22 articles that describe 35 patients. Infection was responsible for 54.3% of triggered episodes, followed by hormonal, drugs, and miscellaneous causes reporting as 30%, 10%, and 5.7% respectively. Females predominated with 62.9%. The longest episode ranged between 3 months to 2 years with a mean of 32.37 weeks. The mean age of the first episode was 14.28 ranging between 3 months to 48 years. Winter and autumn were the major seasons during which episodes happened. Hence, BRIC is potentially triggered by infection, which is most commonly a viral infection, hormonal disturbances as seen in oral contraceptive pills and pregnancy state, and less commonly by certain drugs and other causes. The appearance of cholestasis during the first two trimesters of pregnancy compared to intrahepatic cholestasis of pregnancy could help to differentiate between the two conditions. The possible mechanism of BRIC induction implicates a role of BSEP and ATP8B1. While estrogen, drugs, and cytokines are known to affect BSEP, less is known about their action on ATP8B1.
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15
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Molecular Pathogenesis of Intrahepatic Cholestasis of Pregnancy. Can J Gastroenterol Hepatol 2021; 2021:6679322. [PMID: 34195157 PMCID: PMC8181114 DOI: 10.1155/2021/6679322] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Accepted: 05/22/2021] [Indexed: 12/12/2022] Open
Abstract
Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disease. The maternal symptoms are characterized by skin pruritus and elevated bile acids, causing several adverse outcomes for fetuses, including an increased risk of preterm birth, meconium-stained amniotic fluid, neonatal depression, respiratory distress syndrome, and stillbirth. Genetic, hormonal, immunological, and environmental factors contribute to the pathogenesis of ICP, and the estrogen-bile acid axis is thought to play a dominant role. The advances in the past 10 years uncover more details of this axis. Moreover, dysregulation of extracellular matrix and oxygen supply, organelle dysfunction, and epigenetic changes are also found to cause ICP, illuminating more potential drug targets for interfering with. Here, we summarize the molecular pathogenesis of ICP with an emphasis on the advancement in the past 10 years, aiming to give an updated full view of this field.
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16
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Langedijk JAGM, Beuers UH, Oude Elferink RPJ. Cholestasis-Associated Pruritus and Its Pruritogens. Front Med (Lausanne) 2021; 8:639674. [PMID: 33791327 PMCID: PMC8006388 DOI: 10.3389/fmed.2021.639674] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 02/12/2021] [Indexed: 12/17/2022] Open
Abstract
Pruritus is a debilitating symptom of various cholestatic disorders, including primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and inherited progressive familial intrahepatic cholestasis (PFIC). The molecular mechanisms leading to cholestasis-associated pruritus are still unresolved and the involved pruritogens are indecisive. As a consequence of pruritus, patients suffer from sleep deprivation, loss of daytime concentration, auto-mutilation and sometimes even suicidal ideations. Current guideline-approved therapy of cholestasis-associated pruritus includes stepwise administration of several medications, which may alleviate complaints in some, but not all affected patients. Therefore, also experimental therapeutic approaches are required to improve patients' quality of life. This article reviews the current state of research on pruritogens and their receptors, and shortly discusses the most recent experimental therapies.
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Affiliation(s)
| | | | - Ronald P. J. Oude Elferink
- Amsterdam University Medical Centers, Tytgat Institute for Liver and Intestinal Research, Research Institute Amsterdam Gastroenterology, Endocrinology and Metabolism (AGEM), University of Amsterdam, Amsterdam, Netherlands
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17
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Turhan U, Şahin B, Dağ İ. Lysyl oxidase like protein-2 (LOXL-2); a novel marker for prediction of intrahepatic cholestasis of pregnancy. J Matern Fetal Neonatal Med 2021; 34:2363-2368. [PMID: 33627052 DOI: 10.1080/14767058.2021.1885646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
OBJECTIVE Lysyl oxidase like protein 2 (LOXL-2) is an enzyme that is involved in the development of hepatic fibrosis and bile duct epithelial injury in hepatic cholestasis. Our aim was to investigate maternal serum levels of LOXL-2 and their relationship with fasting total bile acid (FTBA) levels in patients with intrahepatic cholestasis of pregnancy (ICP). MATERIALS AND METHODS Thirty-five pregnant women with ICP and 35 healthy women with uncomplicated pregnancies as the control group, were included in this cross-sectional study. Maternal serum LOXL-2, FTBA and other liver function test levels were compared between the two groups. The predictive cutoff value for LOXL-2 level in ICP was specified. RESULTS Serum LOXL-2 levels were found to be higher in the ICP group compared to the control group (225.699 ± 142.453 vs. 127.731 ± 63.419 pg/mL, p = .001). There was a significant positive correlation between serum LOXL-2 levels and FTBA levels (r = 0.330, p = .003). The optimal cutoff point for LOXL-2 for identifying increased risk of ICP was found to be ≥102 pg/mL, for which the sensitivity and specificity were 96.87% and 48.57%, respectively (p < .001). CONCLUSIONS Maternal serum LOXL-2 levels were significantly higher in women with ICP. LOXL-2 may be both an initiating factor in the pathophysiology of ICP and a marker in the prediction. It may also be a target in terms of preventing strategies in ICP.
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Affiliation(s)
- Uğur Turhan
- Private Clinic, Perinatology, Samsun, Turkey
| | - Banuhan Şahin
- Amasya University, Sabuncuoğlu Şerefeddin Training and Research Hospital, Gynecology and Obstetrics Department, Amasya, Turkey
| | - İsmail Dağ
- Eyüp State Hospital, Biochemistry Department, İstanbul, Turkey
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18
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Tian X, Niu K, Cao H, Zhan G, Zhang Y, Xu F, Shangguan W, Gao Y. Pruritus after continuous administration of epidural morphine for post-cesarean delivery analgesia: a case control study. BMC Pregnancy Childbirth 2021; 21:60. [PMID: 33451285 PMCID: PMC7811233 DOI: 10.1186/s12884-020-03522-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 12/22/2020] [Indexed: 02/08/2023] Open
Abstract
Background Pruritus is one of the most common side effects of epidural morphine administered for post-surgery analgesia, and pregnant women tend to be highly susceptible. The relative contributions of morphine concentration, local anesthetics, and level of pain to pruritus after epidural morphine for post-cesarean delivery analgesia remain unclear. Accordingly, the present study aimed to identify risk factors for pruritus after continuous administration of epidural morphine for post-cesarean delivery analgesia. Methods This case control study was based on routinely collected clinical data. Participants included women who had undergone cesarean section and adopted a patient-controlled analgesia pump for postoperative analgesia. A series of logistic regression analyses were performed. Interaction terms were added to explore the moderation effects of combined local anesthetics and pain level on associations between morphine concentration and pruritus. Robustness of the results was checked through sensitivity analysis using propensity scores matching approach. Results Higher morphine concentration, assisted reproductive treatment, and multipara and cesarean section history were significantly more prevalent in the pruritus group than in the control group. The probabilities of pruritus at morphine concentrations of 10, 15, 20, 25, 30 and 40 μg/mL increased sequentially from 0.05, 0.1, 0.2, 0.35, 0.54 to 0.84, respectively. The trend remained steep in the ropivacaine stratum and became flatter when combined with levobupivacaine. At mild pain combined with levobupivacaine, the incidence of pruritus increased from 0.33 (95% confidence interval [CI] 0.1–0.68) in the 10 μg/mL morphine group to 0.48 (95% CI 0.1–0.88) in the 40 μg/mL morphine group. In the stratum of moderate pain combined with levobupivacaine, the incidence increased from 0.4 (95% CI 0.04–0.92) to 0.56 (95% CI 0.03–0.98). The results in the sensitivity analysis were in consistent with above findings. Conclusions Higher concentrations of morphine, multipara, and assisted reproductive treatment were factors associated with a higher probability of pruritus. Pain level or combined local anesthetics could moderate the association between morphine concentration and pruritus.
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Affiliation(s)
- Xinyi Tian
- Department of Anesthesia, Pain and Critical Care Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China
| | - Kaifan Niu
- West China School of Medicine, West China Hospital, Sichuan University, Chengdu, 610041, P. R. China
| | - Hong Cao
- Department of Anesthesia, Pain and Critical Care Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China
| | - Gonghao Zhan
- Department of Anesthesia, Pain and Critical Care Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China
| | - Yan Zhang
- School of Public Health, Fudan University, Shanghai, China.,NHC Key Lab. of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Fudan University, Shanghai, China
| | - Feng Xu
- Department of Anesthesia, Pain and Critical Care Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China
| | - Wangning Shangguan
- Department of Anesthesia, Pain and Critical Care Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China.
| | - Ye Gao
- Department of Anesthesia, Pain and Critical Care Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China.
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19
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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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Can the Severity of Intrahepatic Cholestasis of Pregnancy be Predicted by Second Trimester Screening Test Parameters? JOURNAL OF FETAL MEDICINE 2020. [DOI: 10.1007/s40556-020-00261-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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Gümüş Güler B, Özler S. Increased syndecan-1 and glypican-3 predict poor perinatal outcome and treatment resistance in intrahepatic cholestasis. Hepatobiliary Pancreat Dis Int 2020; 19:271-276. [PMID: 31919038 DOI: 10.1016/j.hbpd.2019.12.001] [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] [Received: 02/09/2019] [Accepted: 12/10/2019] [Indexed: 02/05/2023]
Abstract
BACKGROUND Intrahepatic cholestasis of pregnancy (ICP) increases the risk of adverse pregnancy outcomes. This study aimed to explore the association between serum syndecan-1 and glypican-3 levels and the adverse perinatal outcome as well as the responses to the treatment of ursodeoxycholic acid (UDCA). METHODS This prospective, case control study included 88 pregnant women (44 women with ICP and 44 healthy controls). The primary end points were the perinatal outcome and the response to UDCA therapy. A logistic regression model was used to identify the independent risk factors of adverse pregnancy outcomes and reduced response to UDCA therapy. RESULTS Women with ICP had significantly higher serum syndecan-1 (1.27 ± 0.36 ng/mL vs. 0.98 ± 0.50 ng/mL; P = 0.003), glypican-3 (1.78 ± 0.13 ng/mL vs.1.69 ± 0.16 ng/mL; P = 0.004), AST (128.59 ± 1.44 vs. 13.29 ± 1.32 U/L; P < 0.001), and ALT (129.84 ± 1.53 vs. 8.00 ± 3.67 U/L; P < 0.001) levels compared with the controls. The increased levels of syndecan-1 (OR = 4.715, 95% CI: 1.554-14.310; P = 0.006), glypican-3 (OR = 8.465, 95% CI: 3.372-21.248; P = 0.007), ALT (OR = 1.382, 95% CI: 1.131-1.690; P = 0.002), and postprandial bile acid (PBA) (OR = 3.392, 95% CI: 1.003-12.869; P = 0.026) were correlated to ICP. The adverse neonatal outcome was related to increased glypican-3 (OR = 4.275, 95% CI: 2.726-5.635; P = 0.039), and PBA (OR = 3.026, 95% CI: 1.069-13.569; P = 0.037). Increases of syndecan-1 (OR = 7.464, 95% CI: 2.130-26.153, P = 0.017) and glypican-3 (OR = 6.194, 95% CI: 2.951-13.002; P = 0.025) were the risk factors of decreased response to UDCA treatment. CONCLUSION Syndecan-1 and glypican-3 might be powerful determinants in predicting adverse perinatal outcome in patients with ICP, and they can be used to predict the response to the UDCA treatment.
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Affiliation(s)
- Başak Gümüş Güler
- Department of Health Sciences, Istinye University, Istanbul 34010, Turkey
| | - Sibel Özler
- Department of Perinatology, Selcuk University Faculty of Medicine, Konya 42130, Turkey.
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Juusela AL, Cordero L, Gimovsky M, Nazir M. Correlation of bile acids and aspartate-aminotransferase with outcomes in cholestasis of pregnancy. J Neonatal Perinatal Med 2020; 13:513-519. [PMID: 31796691 DOI: 10.3233/npm-190276] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
OBJECTIVE To identify laboratory data that correlates with poor perinatal outcomes. METHODS A retrospective chart review of women with intrahepatic cholestasis of pregnancy (ICP), admitted for delivery between January 1, 2013 and December 31, 2017, was performed. Chi-square, student's t-test, and ANOVA statistical analysis was performed. The receiver-operator characteristic curves were plotted for the prediction of each category of perinatal outcome and the areas under the curves were determined. All p-values were two-sided, and p < 0.05 was considered statistically significant. RESULTS Analysis of the 61 ICP cases showed no occurrence of the intrauterine fetal demise (IUFD), stillbirth, abruption, or neonatal demise. ROC curve analysis revealed a statistically significant correlation between bile acid and AST levels and perinatal outcomes. A bile acid (BA) level equal to or greater than 37μmol/L strongly predicted spontaneous preterm labor in women affected by ICP with a sensitivity of 100% and specificity of 60.70% (p = 0.002). A BA level equal to or greater than 42μmol/L strongly predicted meconium-stained amniotic fluid with a sensitivity of 85.70% and specificity of 66.70% (p = 0.006). AST levels equal to or greater than 62 IU/L strongly predicted NICU admission with a sensitivity of 81.30% and specificity of 62.20% (p = 0.002). AST levels equal to or greater than 75 IU/L strongly predicted hyperbilirubinemia in the neonates with a sensitivity of 87.50% and specificity of 69.80% (p = 0.001). CONCLUSIONS There is a statistically significant correlation between elevated BA and elevated AST levels and adverse perinatal outcomes.
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Affiliation(s)
- A L Juusela
- Newark Beth Israel Medical Center, Newark, NJ, USA
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Obeticholic Acid Protects against Gestational Cholestasis-Induced Fetal Intrauterine Growth Restriction in Mice. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:7419249. [PMID: 31827696 PMCID: PMC6885290 DOI: 10.1155/2019/7419249] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Revised: 04/25/2019] [Accepted: 09/23/2019] [Indexed: 12/18/2022]
Abstract
Gestational cholestasis is a common disease and is associated with adverse pregnancy outcomes. However, there are still no effective treatments. We investigated the effects of obeticholic acid (OCA) on fetal intrauterine growth restriction (IUGR) during 17α-ethynylestradiol- (E2-) induced gestational cholestasis in mice. All pregnant mice except controls were subcutaneously injected with E2 (0.625 mg/kg) daily from gestational day (GD) 13 to GD17. Some pregnant mice were orally administered with OCA (5 mg/kg) daily from GD12 to GD17. As expected, OCA activated placental, maternal, and fetal hepatic FXR signaling. Additionally, exposure with E2 during late pregnancy induced cholestasis, whereas OCA alleviated E2-induced cholestasis. Gestational cholestasis caused reduction of fetal weight and crown-rump length and elevated the incidence of IUGR. OCA decreased the incidence of IUGR during cholestasis. Interestingly, OCA attenuated reduction of blood sinusoid area in placental labyrinth layer and inhibited downregulation of placental sodium-coupled neutral amino acid transporter- (SNAT-) 2 during cholestasis. Additional experiment found that OCA attenuated glutathione depletion and lipid peroxidation in placenta and fetal liver and placental protein nitration during cholestasis. Moreover, OCA inhibited the upregulation of placental NADPH oxidase-4 and antioxidant genes during cholestasis. OCA activated antioxidant Nrf2 signaling during cholestasis. Overall, we demonstrated that OCA treatment protected against gestational cholestasis-induced placental dysfunction and IUGR through suppressing placental oxidative stress and maintaining bile acid homeostasis.
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Cabrera D, Arab JP, Arrese M. UDCA, NorUDCA, and TUDCA in Liver Diseases: A Review of Their Mechanisms of Action and Clinical Applications. Handb Exp Pharmacol 2019; 256:237-264. [PMID: 31236688 DOI: 10.1007/164_2019_241] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Bile acids (BAs) are key molecules in generating bile flow, which is an essential function of the liver. In the last decades, there have been great advances in the understanding of BA physiology, and new insights have emerged regarding the role of BAs in determining cell damage and death in several liver diseases. This new knowledge has helped to better delineate the pathophysiology of cholestasis and the adaptive responses of hepatocytes to cholestatic liver injury as well as of the mechanisms of injury of biliary epithelia. In this context, therapeutic approaches for liver diseases using hydrophilic BA (i.e., ursodeoxycholic acid, tauroursodeoxycholic, and, more recently, norursodeoxycholic acid), have been revamped. In the present review, we summarize current experimental and clinical data regarding these BAs and its role in the treatment of certain liver diseases.
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Affiliation(s)
- Daniel Cabrera
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
- Departamento de Ciencias Químicas y Biológicas, Facultad de Salud, Universidad Bernardo O'Higgins, Santiago, Chile
| | - Juan Pablo Arab
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Marco Arrese
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
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Tayyar AT, Tayyar A, Kozali S, Karakus R, Koroglu N, Yuksel IT, Yildirim GY, Dag I, Eroglu M. Evaluation of FGF-19 and β-klotho as biomarkers in patients with intrahepatic cholestasis of pregnancy. Arch Med Sci 2019; 15:113-119. [PMID: 30697260 PMCID: PMC6348354 DOI: 10.5114/aoms.2017.72424] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2017] [Accepted: 12/19/2017] [Indexed: 12/27/2022] Open
Abstract
INTRODUCTION Fibroblast growth factor-19 (FGF-19) and its co-receptor, beta-klotho, regulate bile acid synthesis in the liver as an enterohepatic feedback mechanism. In this study, our aim was to investigate the circulating FGF-19 and β-klotho levels in intrahepatic cholestasis of pregnancy (ICP) cases. MATERIAL AND METHODS A cross-sectional study including 40 women whose pregnancies were complicated with ICP were recruited for the study group. Forty randomly selected healthy pregnant women comprised the control group. The patient characteristics, including maternal age, gravidity, parity, gestational age at the time of diagnosis, body mass index (BMI), and obstetric history, were recorded. The serum FGF-19 and β-klotho concentrations were measured using an enzyme-linked immunosorbent assay. RESULTS Maternal age, gravidity, parity, body mass index at assessment, and gestational age at blood sampling were similar between the two groups (p > 0.05). Moreover, there were no significant differences in the FGF-19 and β-klotho concentrations between the two groups (p = 0.341 and p = 0.086, respectively). A positive correlation was detected between the β-klotho and FGF-19 levels, as well as between the FGF-19 level and BMI (r = 0.368, p = 0.020 and r = 0.389, p = 0.013, respectively). CONCLUSIONS The serum FGF-19 and β-klotho concentrations did not differ between the pregnancies with ICP and the healthy controls. However, in some cases, abnormalities in the FGF-19, β-klotho, and FGFR4 signaling system may play roles in the pathogenesis of ICP.
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Affiliation(s)
- Ahter Tanay Tayyar
- Department of Obstetrics and Gynecology, Health Sciences University Zeynep Kamil Maternity and Children’s Research Hospital, Istanbul, Turkey
| | - Ahmet Tayyar
- Department of Obstetrics and Gynecology, Health Sciences University Kanuni Sultan Suleyman Training and Research Hospital, Istanbul, Turkey
| | - Sukran Kozali
- Department of Obstetrics and Gynecology, Health Sciences University Zeynep Kamil Maternity and Children’s Research Hospital, Istanbul, Turkey
| | - Resul Karakus
- Department of Obstetrics and Gynecology, Health Sciences University Zeynep Kamil Maternity and Children’s Research Hospital, Istanbul, Turkey
| | - Nadiye Koroglu
- Department of Obstetrics and Gynecology, Health Sciences University Kanuni Sultan Suleyman Training and Research Hospital, Istanbul, Turkey
| | - Ilkbal Temel Yuksel
- Department of Obstetrics and Gynecology, Health Sciences University Kanuni Sultan Suleyman Training and Research Hospital, Istanbul, Turkey
| | - Gonca Yetkin Yildirim
- Department of Obstetrics and Gynecology, Health Sciences University Kanuni Sultan Suleyman Training and Research Hospital, Istanbul, Turkey
| | - Ismail Dag
- Department of Clinical Biochemistry, Eyup State Hospital, Istanbul, Turkey
| | - Mustafa Eroglu
- Department of Obstetrics and Gynecology, Health Sciences University Zeynep Kamil Maternity and Children’s Research Hospital, Istanbul, Turkey
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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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Macias RIR, Matilla S, Lozano E, Estiú MC, Oude Elferink RP, Marin JJG. Role of the placenta in serum autotaxin elevation during maternal cholestasis. Am J Physiol Gastrointest Liver Physiol 2018; 315:G399-G407. [PMID: 29927323 DOI: 10.1152/ajpgi.00112.2018] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Intrahepatic cholestasis of pregnancy (ICP) is frequently accompanied by pruritus, whose etiology has been associated with an enhanced production of lysophosphatidic acid (LPA) by the combined action of phospholipase A1/A2 (PLA1/PLA2) and autotaxin (ATX). Here, we have investigated whether the placenta is involved in LPA release to maternal circulation during ICP. Serum levels of ATX and LPA (determined by ELISA) were elevated in women with ICP, and a correlation between both parameters was found. No relationship between serum levels of ATX or LPA and bile acids was found. Expression levels of ATX and PLA2 were determined by RT-qPCR and Western blot. Placenta ATX but not PLA2 was significantly upregulated in ICP, and a tendency to increase was found at the protein level. A correlation between serum ATX and placental ATX mRNA levels was found. In human placenta at term, ATX was clearly detected (by immunofluorescence) in Hofbauer cells, but only faintly in trophoblast cells. In pregnant rats, the expression of Atx and Pla2 in placenta was lower than in liver. When obstructive cholestasis was imposed by bile duct ligation from day 14 of gestation until term, placenta Atx and Pla2 expression was markedly enhanced, and overexpression was confirmed at the protein level for Pla2, whereas Atx protein was not detected. In conclusion, the placenta substantially participates in LPA production during gestation. This contribution is markedly higher during maternal cholestasis and hence, may be involved in ICP-associated pruritus. NEW & NOTEWORTHY Fetal placental macrophages and, to a lesser extent, trophoblast cells express high levels of autotaxin at term. An increased expression of mRNA and protein autotaxin, the key secretory enzyme responsible for the production of lysophosphatidic acid in serum, has been observed in placentas of women with cholestasis of pregnancy, which supports that the placenta can contribute to an increased production of this pruritogenic compound in women suffering from this liver disease.
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Affiliation(s)
- Rocio I R Macias
- Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca , Salamanca , Spain.,Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health , Madrid , Spain
| | - Sonia Matilla
- Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca , Salamanca , Spain
| | - Elisa Lozano
- Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca , Salamanca , Spain.,Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health , Madrid , Spain
| | - Maria C Estiú
- Ramón Sardá Mother's and Children's Hospital , Buenos Aires , Argentina
| | - Ronald P Oude Elferink
- Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam , Amsterdam , The Netherlands
| | - Jose J G Marin
- Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca , Salamanca , Spain.,Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health , Madrid , Spain
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Mikolasevic I, Filipec-Kanizaj T, Jakopcic I, Majurec I, Brncic-Fischer A, Sobocan N, Hrstic I, Stimac T, Stimac D, Milic S. Liver Disease During Pregnancy: A Challenging Clinical Issue. Med Sci Monit 2018; 24:4080-4090. [PMID: 29905165 PMCID: PMC6034557 DOI: 10.12659/msm.907723] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
One of the least studied topics in the field of obstetrics is liver disease during pregnancy, which creates a challenge for both gynecologists and hepatologists. Approximately 3% of pregnant women are affected by some form of liver disease during pregnancy. Some of these conditions can be fatal for both the mother and child. In addition, 3 types of liver disease need to be differentiated during pregnancy. One type is liver disease directly related to pregnancy, which can occur at a specific time during pregnancy. Another type is liver disease not related to pregnancy, which can occur at any time, such as viral- or drug-induced hepatitis. Furthermore, pregnancy can occur in women with pre-existing liver disease. It is essential that the clinicians are familiar with this disorder so they can respond promptly and appropriately in all of these situations, especially when emergency delivery is needed and must not be postponed.
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Affiliation(s)
- Ivana Mikolasevic
- Department of Gastroenterology, University Hospital Center (UHC) Rijeka, School of Medicine, University of Rijeka, Rijeka, Croatia
| | - Tajana Filipec-Kanizaj
- Department of Gastroenterology, University Hospital Merkur, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Ivan Jakopcic
- Department of Gastroenterology, University Hospital Center (UHC) Rijeka, School of Medicine, University of Rijeka, Rijeka, Croatia
| | - Iva Majurec
- Department of Anesthesiology and Intensive Care Unit, University Hospital Merkur, Zagreb, Croatia
| | - Alemka Brncic-Fischer
- Department of Obstetrics and Gynecology, University Hospital Center (UHC) Rijeka, Rijeka, Croatia
| | - Nikola Sobocan
- Department of Gastroenterology, University Hospital Merkur, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Irena Hrstic
- Department of Internal Medicine, General Hospital Pula, Pula, Croatia
| | - Tea Stimac
- Department of Obstetrics and Gynecology, University Hospital Center (UHC) Rijeka, Rijeka, Croatia
| | - Davor Stimac
- Department of Gastroenterology, University Hospital Center (UHC) Rijeka, School of Medicine, University of Rijeka, Rijeka, Croatia
| | - Sandra Milic
- Department of Gastroenterology, University Hospital Center (UHC) Rijeka, School of Medicine, University of Rijeka, Rijeka, Croatia
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Tayyar AT, Tayyar A, Atakul T, Yayla CA, Kilicci C, Eser A, Karakus R, Herkiloglu D, Cundubey CR, Tayyar M. Could first- and second-trimester biochemical markers for Down syndrome have a role in predicting intrahepatic cholestasis of pregnancy? Arch Med Sci 2018; 14:846-850. [PMID: 30002703 PMCID: PMC6040116 DOI: 10.5114/aoms.2017.69865] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2017] [Accepted: 08/24/2017] [Indexed: 01/08/2023] Open
Abstract
INTRODUCTION The aim of this study is to compare first- and second-trimester Down syndrome biochemical screening markers in intrahepatic cholestasis of pregnancy (ICP) and normal pregnancies. MATERIAL AND METHODS This observational case-control study was conducted at Health Sciences University Zeynep Kamil Maternity and Children's Health Training and Research Hospital and the Department of Obstetrics and Gynecology at Erciyes University Medical Faculty during 2016-2017. The study included 165 patients, and consisted of 62 women who had been diagnosed with ICP (the ICP-diagnosed group) and 103 healthy pregnant women (the control group). First-trimester free β-human chorionic gonadotropin (β-hCG), pregnancy-associated plasma protein-A (PAPP-A) and second-trimester total β-hCG, estriol (E3), α-fetoprotein (AFP), and inhibin A levels were compared between the two groups. RESULTS The mean patient age was 28.67 ±5.96 years, with no significant difference between the groups (p > 0.05). Average PAPP-A levels were significantly lower in the ICP-diagnosed group (p < 0.001). When the cut-off value for PAPP-A was taken as ≤ 0.93 multiple of median (MoM), the sensitivity and specificity values for ICP were 73.8% and 56.3%, respectively (95% CI, AUC ± SE: 0.663 ±0.042). CONCLUSIONS The decrease in PAPP-A MoM value indicates an increase in the risk of developing ICP, while changes in other markers were not sufficient to predict ICP.
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Affiliation(s)
- Ahter Tanay Tayyar
- Department of Obstetrics and Gynecology, Health Sciences University, Zeynep Kamil Maternity and Children’s Training and Research Hospital, Istanbul, Turkey
| | - Ahmet Tayyar
- Department of Obstetrics and Gynecology, Health Sciences University, Kanuni Sultan Süleyman Education and Research Hospital, Istanbul, Turkey
| | - Tolga Atakul
- Department of Obstetrics and Gynecology, Faculty of Medicine, Adnan Menderes University, Aydın, Turkey
| | - Cigdem Abide Yayla
- Department of Obstetrics and Gynecology, Health Sciences University, Zeynep Kamil Maternity and Children’s Training and Research Hospital, Istanbul, Turkey
| | - Cetin Kilicci
- Department of Obstetrics and Gynecology, Health Sciences University, Zeynep Kamil Maternity and Children’s Training and Research Hospital, Istanbul, Turkey
| | - Ahmet Eser
- Department of Obstetrics and Gynecology, Health Sciences University, Zeynep Kamil Maternity and Children’s Training and Research Hospital, Istanbul, Turkey
| | - Resul Karakus
- Department of Obstetrics and Gynecology, Health Sciences University, Zeynep Kamil Maternity and Children’s Training and Research Hospital, Istanbul, Turkey
| | - Dilsat Herkiloglu
- Department of Obstetrics and Gynecology, Health Sciences University, Zeynep Kamil Maternity and Children’s Training and Research Hospital, Istanbul, Turkey
| | - Cevat Rifat Cundubey
- Department of Obstetrics and Gynecology, Faculty of Medicine, Erciyes University, Kayseri, Turkey
| | - Mehmet Tayyar
- Department of Obstetrics and Gynecology, Faculty of Medicine, Erciyes University, Kayseri, Turkey
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Feng C, Li WJ, He RH, Sun XW, Wang G, Wang LQ. Impacts of different methods of conception on the perinatal outcome of intrahepatic cholestasis of pregnancy in twin pregnancies. Sci Rep 2018; 8:3985. [PMID: 29507303 PMCID: PMC5838236 DOI: 10.1038/s41598-018-22387-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Accepted: 02/22/2018] [Indexed: 12/15/2022] Open
Abstract
Twin pregnancies have a higher prevalence of intrahepatic cholestasis of pregnancy (ICP) than single pregnancies. It is unknown whether in vitro fertilization-embryo transfer (IVF-ET) influences the fetal outcomes in twin pregnancies complicated by ICP. This study aimed to explore the impact of IVF-ET on the perinatal outcomes of ICP in twin pregnancy. Clinical data from 142 twin pregnant women complicated with ICP were retrospectively analyzed, including 51 patients who conceived through IVF-ET (IVF group) and 91 patients with spontaneous conception (SC group). Several biochemical indicators and perinatal outcomes were analyzed. Compared to the SC group, the IVF group had a higher incidence of early-onset ICP (P = 0.015) and more frequent clinical symptoms (P = 0.020), including skin pruritus, skin scratch, and jaundice. Furthermore, the IVF group had higher rates of neonatal asphyxia (IVF vs. SC, 9.80% vs. 1.10%, P = 0.023) and premature delivery (IVF vs. SC, 96.08% vs. 83.52%, P = 0.027) compared to the SC group. The IVF-conceived twin pregnancy group had a higher risk of early-onset ICP and suffered from clinical symptoms and poor perinatal outcomes.
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Affiliation(s)
- Chun Feng
- The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, China.,The Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310006, China
| | - Wen-Juan Li
- The Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310006, China
| | - Rong-Huan He
- The Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310006, China
| | - Xi-Wen Sun
- The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, China
| | - Guirong Wang
- Department of Surgery, SUNY Upstate Medical University, Syracuse, New York, 13210, USA
| | - Li-Quan Wang
- The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, China. .,The Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310006, China.
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Lin J, Gu W, Hou Y. Diagnosis and prognosis of early-onset intrahepatic cholestasis of pregnancy: a prospective study. J Matern Fetal Neonatal Med 2017; 32:997-1003. [PMID: 29065754 DOI: 10.1080/14767058.2017.1397124] [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: 12/25/2022]
Abstract
OBJECTIVE To explore the gestational age of early-onset intrahepatic cholestasis (ICP) of pregnancy, and to analyze the relationship between the clinical biochemical indices and pregnancy outcomes in order to arrive at a reasonable diagnosis and administer appropriate treatment. DESIGN This is a retrospective clinical study. POPULATION OR SAMPLE We selected 47,260 pregnant women who received prenatal care and underwent childbirth at the International Peace Maternity and Child Health Hospital affiliated to Shanghai Jiao Tong University from January 2014 to December 2016 for participating in this study. Of these 47,260 women, 407 developed ICP. METHODS To calculate the gestational week cutoff between early- and late-onset ICP by the receiver-operating characteristic (ROC) curve and Youden's index. Two independent samples t tests and chi square test were used to compare the differences in biochemical indices and pregnancy outcomes between the two groups. RESULTS We found that 34 weeks is the most appropriate cutoff gestational age for the diagnosis of early-onset ICP. Early-onset ICP is characterized by early onset, long disease duration and a higher incidence of preterm labor, fetal distress, and fetal low birth weight compared to late-onset ICP. CONCLUSIONS Thirty-four weeks is the most appropriate cutoff gestational age for the diagnosis of early-onset ICP. And to reduce the adverse pregnancy outcomes in cases of early-onset ICP, we suggest prolonging gestation up to 37 weeks as far as possible before selecting iatrogenic birth.
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Affiliation(s)
- Jing Lin
- a Department of Obstetrics, The International Peace Maternity and Child Health Hospital, Shanghai Jiaotong University School of Medicine , Shanghai , China
| | - Wei Gu
- a Department of Obstetrics, The International Peace Maternity and Child Health Hospital, Shanghai Jiaotong University School of Medicine , Shanghai , China
| | - Yanyan Hou
- a Department of Obstetrics, The International Peace Maternity and Child Health Hospital, Shanghai Jiaotong University School of Medicine , Shanghai , China
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Park JE, Ryoo G, Lee W. Alternative Splicing: Expanding Diversity in Major ABC and SLC Drug Transporters. AAPS JOURNAL 2017; 19:1643-1655. [DOI: 10.1208/s12248-017-0150-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Accepted: 09/10/2017] [Indexed: 01/18/2023]
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Lactation during cholestasis: Role of ABC proteins in bile acid traffic across the mammary gland. Sci Rep 2017; 7:7475. [PMID: 28785115 PMCID: PMC5547141 DOI: 10.1038/s41598-017-06315-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Accepted: 06/12/2017] [Indexed: 12/27/2022] Open
Abstract
Transporters involved in bile acid (BA) handling by the mammary gland are poorly understood. Here we have investigated the role of ABC proteins in blood-milk BA traffic and its sensitivity to maternal cholestasis. BA concentrations in rat and mouse serum were higher than in milk. BA profiles in both fluids were also different. In mammary gland, mRNA levels of ABC pumps transporting BAs were high for Bcrp, less abundant for Mrp1, Mrp3 and Mrp4 and negligible for Bsep and Mrp2. Milk BA concentrations were lower in Abcg2 -/- than in wild-type mice. Taurocholate administration (5 µmol, i.p.) increased 20-fold BA concentrations in serum, but only moderately in milk, even in Abcg2 -/- mice. Bile duct ligation (BDL) in pregnant rats markedly increased serum BA concentrations, which was not proportionally reflected in milk. In rat mammary tissue, Mrp4 was up-regulated by BDL. Serum BA levels were 2-fold higher in 10-day-old neonates of the BDL group, whereas their body weight was lower. The exchange of breastfeeding mothers immediately after birth reverted the situation without changes in endogenous BA synthesis. In conclusion, Bcrp is involved in BA secretion into milk, whereas Mrp4 participates in a blood-milk barrier that protects neonates from maternal hypercholanemia during breastfeeding.
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Relationship between early onset severe intrahepatic cholestasis of pregnancy and higher risk of meconium-stained fluid. PLoS One 2017; 12:e0176504. [PMID: 28437442 PMCID: PMC5402936 DOI: 10.1371/journal.pone.0176504] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2017] [Accepted: 04/11/2017] [Indexed: 12/27/2022] Open
Abstract
Background Intrahepatic cholestasis of pregnancy (ICP) is the commonest gestational liver disease. The risk of adverse fetal outcome has been associated with the severity of maternal hypercholanemia after diagnosis. Objective To investigate whether there is a relationship between the severity and timing of onset of hypercholanemia and the risk of meconium-stained amniotic fluid (MSAF) and adverse neonatal events. Study design The study included 382 pregnancies complicated by ICP managed at a referral hospital in Buenos Aires (Argentina) between June 2009 and December 2013. The patients were classified into three groups according to the severity of hypercholanemia at diagnosis; mild (10–19.9 μmol/L), moderate (20–39.9 μmol/L) and severe (≥40 μmol/L). Their clinical characteristics and pregnancy outcomes were investigated in a prospective observational study. Results Higher risk of MSAF was observed when ICP appeared early in gestation or when hypercholanemia was more severe. Taking both parameters into account an MSAF risk factor (MRF) was defined. Based on a model of positive/negative predictive values, a cut-off point of MRF = 3 was selected, which prioritized sensitivity versus specificity. In ICP patients with MRF>3, the probability of MSAF was enhanced 4-fold. An increase in the frequency of MSAF was also associated with higher serum levels at diagnosis of alanine transaminase, alkaline phosphatase and direct bilirubin. Conclusions The risk of MSAF is associated not only with the magnitude of hypercholanemia at diagnosis but also with the early gestational onset of raised maternal serum bile acids.
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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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Abstract
Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disease during pregnancy, characterized by otherwise unexplained pruritus in late second and third trimester of pregnancy and elevated bile acids and/or transaminases. ICP is associated with an increased risk of adverse perinatal outcomes for the fetus and the later development of hepatobiliary disease for the mother. Bile acids should be monitored throughout pregnancy since fetal risk is increased at serum bile acids >40 µmol/l. Management of ICP consists of treatment with ursodeoxycholic acid, which reduces pruritus. Early elective delivery is common practice but should be performed on an individualized basis as long as strong evidence supporting this practice is lacking. Mothers should be followed-up for normalization of liver function tests 6-12 weeks after delivery. Future research in large-scale studies is needed to address the impact of ursodeoxycholic acid and early elective delivery on fetal outcome.
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Affiliation(s)
- Hanns-Ulrich Marschall
- a Department of Molecular and Clinical Medicine, University of Gothenburg, Sahlgrenska Academy, Institute of Medicine, S-41345 Gothenburg, Sweden
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37
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Immunology of hepatic diseases during pregnancy. Semin Immunopathol 2016; 38:669-685. [PMID: 27324237 DOI: 10.1007/s00281-016-0573-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2016] [Accepted: 05/18/2016] [Indexed: 02/06/2023]
Abstract
The mother's immune system has to adapt to pregnancy accepting the semi-allograft fetus and preventing harmful effects to the developing child. Aberrations in feto-maternal immune adaptation may result in disease of the mother, such as liver injury. Five pregnancy-associated liver disorders have been described so far, however, little is known concerning immune alterations promoting the respective disease. These liver disorders are pre-eclampsia, hemolysis, elevated liver enzymes, low platelet count (HELLP), acute fatty liver, hyperemesis gravidarum, and intrahepatic cholestasis of pregnancy. On the other hand, pre-existing autoimmune liver injury of the mother can be affected by pregnancy. This review intends to summarize current knowledge linking feto-maternal immunology and liver inflammation with a special emphasis on novel potential biomarkers.
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Abstract
Neither the mechanisms of parturition nor the pathogenesis of preterm birth are well understood. Poor nutritional status has been suspected as a major causal factor, since vitamin A concentrations are low in preterm infants. However, even large enteral doses of vitamin A from birth fail to increase plasma concentrations of vitamin A or improve outcomes in preterm and/or extremely low birthweight infants. These findings suggest an underlying impairment in the secretion of vitamin A from the liver, where about 80% of the vitamin is stored. Vitamin A accumulates in the liver and breast during pregnancy in preparation for lactation. While essential in low concentration for multiple biological functions, vitamin A in higher concentration can be pro-oxidant, mutagenic, teratogenic and cytotoxic, acting as a highly surface-active, membrane-seeking and destabilizing compound. Regarding the mechanism of parturition, it is conjectured that by nine months of gestation the hepatic accumulation of vitamin A (retinol) from the liver is such that mobilization and secretion are impaired to the point where stored vitamin A compounds in the form of retinyl esters and retinoic acid begin to spill or leak into the circulation, resulting in amniotic membrane destabilization and the initiation of parturition. If, however, the accumulation and spillage of stored retinoids reaches a critical threshold prior to nine months, e.g., due to cholestatic liver disease, which is common in mothers of preterm infants, the increased retinyl esters and/or retinoic acid rupture the fetal membranes, inducing preterm birth and its complications, including retinopathy, necrotizing enterocolitis and bronchopulmonary dysplasia. Subject to testing, the model suggests that measures taken prior to and during pregnancy to improve liver function could reduce the risk of adverse birth outcomes, including preterm birth.
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Affiliation(s)
- Anthony R Mawson
- Interim Chair, Department of Epidemiology & Biostatistics, School of Public Health, Jackson State University, 350 West Woodrow Wilson Avenue, Room 229, Jackson, MS 39213, 601-991-3811
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Rodríguez M, Moreno J, Márquez R, Eltit R, Martinez F, Sepúlveda-Martínez A, Parra-Cordero M. Increased PR Interval in Fetuses of Patients with Intrahepatic Cholestasis of Pregnancy. Fetal Diagn Ther 2016; 40:298-302. [DOI: 10.1159/000444297] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2015] [Accepted: 01/26/2016] [Indexed: 11/19/2022]
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Abstract
Determining the optimal timing for induction of labor is critical in minimizing the risks to maternal and fetal health. While data are available to guide us in some clinical situations, such as hypertension and diabetes, many gaps in knowledge still exist in others, including cholestasis of pregnancy, fetal anomalies, and placental abruption. This review of the currently available literature assesses the risks and benefits of preterm and early term induction in a wide variety of maternal and fetal conditions.
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Affiliation(s)
- Stephen J Bacak
- Department of Obstetrics and Gynecology, University of Rochester, Elmwood Ave, Box 668, Rochester, NY 14642
| | - Courtney Olson-Chen
- Department of Obstetrics and Gynecology, University of Rochester, Elmwood Ave, Box 668, Rochester, NY 14642
| | - Eva Pressman
- Department of Obstetrics and Gynecology, University of Rochester, Elmwood Ave, Box 668, Rochester, NY 14642.
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41
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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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42
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Estiú MC, Monte MJ, Rivas L, Moirón M, Gomez-Rodriguez L, Rodriguez-Bravo T, Marin JJG, Macias RIR. Effect of ursodeoxycholic acid treatment on the altered progesterone and bile acid homeostasis in the mother-placenta-foetus trio during cholestasis of pregnancy. Br J Clin Pharmacol 2015; 79:316-29. [PMID: 25099365 DOI: 10.1111/bcp.12480] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
AIM Intrahepatic cholestasis of pregnancy (ICP) is characterized by pruritus and elevated bile acid concentrations in maternal serum. This is accompanied by an enhanced risk of intra-uterine and perinatal complications. High concentrations of sulphated progesterone metabolites (PMS) have been suggested to be involved in the multifactorial aetiopathogenesis of ICP. The aim of this study was to investigate further the mechanism accounting for the beneficial effect of oral administration of ursodeoxycholic acid (UDCA), which is the standard treatment, regarding bile acid and PMS homeostasis in the mother-placenta-foetus trio. METHOD Using HPLC-MS/MS bile acids and PMS were determined in maternal and foetal serum and placenta. The expression of ABC proteins in placenta was determined by real time quantitative PCR (RT-QPCR) and immunofluorescence. RESULTS In ICP, markedly increased concentrations of bile acids (tauroconjugates > glycoconjugates >> unconjugated), progesterone and PMS in placenta and maternal serum were accompanied by enhanced concentrations in foetal serum of bile acids, but not of PMS. UDCA treatment reduced bile acid accumulation in the mother-placenta-foetus trio, but had no significant effect on progesterone and PMS concentrations. ABCG2 mRNA abundance was increased in placentas from ICP patients vs. controls and remained stable following UDCA treatment, despite an apparent further increase in ABCG2. CONCLUSION UDCA administration partially reduces ICP-induced bile acid accumulation in mothers and foetuses despite the lack of effect on concentrations of progesterone and PMS in maternal serum. Up-regulation of placental ABCG2 may play an important role in protecting the foetus from high concentrations of bile acids and PMS during ICP.
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Affiliation(s)
- Maria C Estiú
- Ramón Sardá Mother' and Children's Hospital, Buenos Aires, Argentina
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43
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Wu WB, Xu YY, Cheng WW, Wang YX, Liu Y, Huang D, Zhang HJ. Agonist of farnesoid X receptor protects against bile acid induced damage and oxidative stress in mouse placenta--a study on maternal cholestasis model. Placenta 2015; 36:545-51. [PMID: 25747729 DOI: 10.1016/j.placenta.2015.02.005] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2014] [Revised: 01/21/2015] [Accepted: 02/09/2015] [Indexed: 12/20/2022]
Abstract
INTRODUCTION Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific disorder, which is characterized by raised serum bile acid level and potential adverse fetal outcome. Farnesoid X receptor (FXR), also known as a bile acid receptor, was found to be expressed in placenta with low level. Whether activation of FXR by specific agonists could regulate the pathogenesis of ICP is still unclear. METHODS A model of maternal cholestasis was induced by administration of 17α-ethynylestradiol (E2) in pregnant mice for 6 days. We explored the regulatory effect of WAY-362450 (W450), a highly selective and potent FXR agonist on placenta. RESULTS In this study, we demonstrated that administration of E2 increased bile acid levels in mouse serum, liver and amniotic fluid. Bile acid levels were significantly decreased after W450 treatment. W450 protected against the impairment of placentas induced by E2, including severe intracellular edema and apoptosis of trophoblasts. Moreover, W450 significantly induced the expressions of FXR target bile acid transport gene ATP-binding cassette, sub-family B (MDR/TAP), member 11 (Abcb11;Bsep) in placenta. W450 could also attenuate placental oxidative stress and increase the expressions of antioxidant enzymes Prdx1 and Prdx3. DISCUSSION AND CONCLUSION In conclusion, our data demonstrated that FXR agonist W450 modulated bile acid balance and protected against placental oxidative stress. Thus, our results support that potent FXR agonists might represent promising drugs for the treatment of ICP.
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Affiliation(s)
- W B Wu
- Departments of Pathology and Bio-Bank, the International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Y Y Xu
- Departments of Pathology and Bio-Bank, the International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - W W Cheng
- Department of Obstetrics and Gynecology, the International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Y X Wang
- Departments of Pathology and Bio-Bank, the International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Y Liu
- Departments of Pathology and Bio-Bank, the International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - D Huang
- Department of Obstetrics and Gynecology, the International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - H J Zhang
- Departments of Pathology and Bio-Bank, the International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
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Bacq Y, Sentilhes L. Intrahepatic cholestasis of pregnancy: Diagnosis and management. Clin Liver Dis (Hoboken) 2014; 4:58-61. [PMID: 30992922 PMCID: PMC6448735 DOI: 10.1002/cld.398] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2014] [Revised: 06/05/2014] [Accepted: 06/14/2014] [Indexed: 02/04/2023] Open
Affiliation(s)
- Yannick Bacq
- Department of HepatogastroenterologyTours University Hospital CenterToursFrance
| | - Loïc Sentilhes
- Department of Obstetrics and GynecologyAngers University HospitalAngersFrance
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45
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Marrone J, Lehmann GL, Soria LR, Pellegrino JM, Molinas S, Marinelli RA. Adenoviral transfer of human aquaporin -1 gene to rat liver improves bile flow in estrogen-induced cholestasis. Gene Ther 2014; 21:1058-64. [DOI: 10.1038/gt.2014.78] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2014] [Revised: 07/01/2014] [Accepted: 07/09/2014] [Indexed: 12/29/2022]
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Zucchini C, Montesanto I, Falcone V, Azzaroli F, Pittalis MC, Farina A. Intrahepatic Cholestasis of Pregnancy: mRNAs for LIPF and ELOVL4 Genes Are Not Detectable in Circulating Maternal Plasma. Fetal Diagn Ther 2014; 38:238-40. [PMID: 25059952 DOI: 10.1159/000361018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2013] [Accepted: 02/28/2014] [Indexed: 11/19/2022]
Affiliation(s)
- Cinzia Zucchini
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
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47
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Du Q, Pan Y, Zhang Y, Zhang H, Zheng Y, Lu L, Wang J, Duan T, Chen J. Placental gene-expression profiles of intrahepatic cholestasis of pregnancy reveal involvement of multiple molecular pathways in blood vessel formation and inflammation. BMC Med Genomics 2014; 7:42. [PMID: 25001852 PMCID: PMC4105836 DOI: 10.1186/1755-8794-7-42] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Accepted: 07/03/2014] [Indexed: 02/08/2023] Open
Abstract
Background Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-associated liver disease with potentially deleterious consequences for the fetus, particularly when maternal serum bile-acid concentration >40 μM. However, the etiology and pathogenesis of ICP remain elusive. To reveal the underlying molecular mechanisms for the association of maternal serum bile-acid level and fetal outcome in ICP patients, DNA microarray was applied to characterize the whole-genome expression profiles of placentas from healthy women and women diagnosed with ICP. Methods Thirty pregnant women recruited in this study were categorized evenly into three groups: healthy group; mild ICP, with serum bile-acid concentration ranging from 10–40 μM; and severe ICP, with bile-acid concentration >40 μM. Gene Ontology analysis in combination with construction of gene-interaction and gene co-expression networks were applied to identify the core regulatory genes associated with ICP pathogenesis, which were further validated by quantitative real-time PCR and histological staining. Results The core regulatory genes were mainly involved in immune response, VEGF signaling pathway and G-protein-coupled receptor signaling, implying essential roles of immune response, vasculogenesis and angiogenesis in ICP pathogenesis. This implication was supported by the observed aggregated immune-cell infiltration and deficient blood vessel formation in ICP placentas. Conclusions Our study provides a system-level insight into the placental gene-expression profiles of women with mild or severe ICP, and reveals multiple molecular pathways in immune response and blood vessel formation that might contribute to ICP pathogenesis.
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Affiliation(s)
| | | | | | | | | | | | | | - Tao Duan
- Department of Obstetrics, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 200040, China.
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Baghdasaryan A, Chiba P, Trauner M. Clinical application of transcriptional activators of bile salt transporters. Mol Aspects Med 2014; 37:57-76. [PMID: 24333169 PMCID: PMC4045202 DOI: 10.1016/j.mam.2013.12.001] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2013] [Revised: 11/21/2013] [Accepted: 12/01/2013] [Indexed: 02/07/2023]
Abstract
Hepatobiliary bile salt (BS) transporters are critical determinants of BS homeostasis controlling intracellular concentrations of BSs and their enterohepatic circulation. Genetic or acquired dysfunction of specific transport systems causes intrahepatic and systemic retention of potentially cytotoxic BSs, which, in high concentrations, may disturb integrity of cell membranes and subcellular organelles resulting in cell death, inflammation and fibrosis. Transcriptional regulation of canalicular BS efflux through bile salt export pump (BSEP), basolateral elimination through organic solute transporters alpha and beta (OSTα/OSTβ) as well as inhibition of hepatocellular BS uptake through basolateral Na(+)-taurocholate cotransporting polypeptide (NTCP) represent critical steps in protection from hepatocellular BS overload and can be targeted therapeutically. In this article, we review the potential clinical implications of the major BS transporters BSEP, OSTα/OSTβ and NTCP in the pathogenesis of hereditary and acquired cholestatic syndromes, provide an overview on transcriptional control of these transporters by the key regulatory nuclear receptors and discuss the potential therapeutic role of novel transcriptional activators of BS transporters in cholestasis.
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Affiliation(s)
- Anna Baghdasaryan
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria; Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Austria
| | - Peter Chiba
- Institute of Medical Chemistry, Medical University of Vienna, Austria
| | - Michael Trauner
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria.
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Ahmed KT, Almashhrawi AA, Rahman RN, Hammoud GM, Ibdah JA. Liver diseases in pregnancy: Diseases unique to pregnancy. World J Gastroenterol 2013; 19:7639-7646. [PMID: 24282353 PMCID: PMC3837262 DOI: 10.3748/wjg.v19.i43.7639] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2013] [Revised: 08/05/2013] [Accepted: 09/05/2013] [Indexed: 02/06/2023] Open
Abstract
Pregnancy is a special clinical state with several normal physiological changes that influence body organs including the liver. Liver disease can cause significant morbidity and mortality in both pregnant women and their infants. This review summarizes liver diseases that are unique to pregnancy. We discuss clinical conditions that are seen only in pregnant women and involve the liver; from Hyperemesis Gravidarum that happens in 1 out of 200 pregnancies and Intrahepatic Cholestasis of Pregnancy (0.5%-1.5% prevalence), to the more frequent condition of preeclampsia (10% prevalence) and its severe form; hemolysis, elevated liver enzymes, and a low platelet count syndrome (12% of pregnancies with preeclampsia), to the rare entity of Acute Fatty Liver of Pregnancy (incidence of 1 per 7270 to 13000 deliveries). Although pathogeneses behind the development of these aliments are not fully understood, theories have been proposed. Some propose the special physiological changes that accompany pregnancy as a precipitant. Others suggest a constellation of factors including both the mother and her fetus that come together to trigger those unique conditions. Reaching a timely and accurate diagnosis of such conditions can be challenging. The timing of the condition in relation toward which trimester it starts at is a key. Accurate diagnosis can be made using specific clinical findings and blood tests. Some entities have well-defined criteria that help not only in making the diagnosis, but also in classifying the disease according to its severity. Management of these conditions range from simple medical remedies to measures such as immediate termination of the pregnancy. In specific conditions, it is prudent to have expert obstetric and medical specialists teaming up to help improve the outcomes.
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Keitel V, Spomer L, Marin J, Williamson C, Geenes V, Kubitz R, Häussinger D, Macias R. Effect of maternal cholestasis on TGR5 expression in human and rat placenta at term. Placenta 2013; 34:810-6. [DOI: 10.1016/j.placenta.2013.06.302] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2013] [Revised: 05/31/2013] [Accepted: 06/18/2013] [Indexed: 01/26/2023]
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