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Basu S, Običan SG, Bertaggia E, Staab H, Izquierdo MC, Gyamfi-Bannerman C, Haeusler RA. Unresolved alterations in bile acid composition and dyslipidemia in maternal and cord blood after UDCA treatment for intrahepatic cholestasis of pregnancy. Am J Physiol Gastrointest Liver Physiol 2025; 328:G364-G376. [PMID: 39947696 DOI: 10.1152/ajpgi.00266.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 09/25/2024] [Accepted: 02/03/2025] [Indexed: 02/19/2025]
Abstract
Intrahepatic cholestasis of pregnancy (ICP) is characterized by elevated plasma bile acid levels. ICP is linked to adverse metabolic outcomes, including a reported increased risk of gestational diabetes. The standard therapeutic approach for managing ICP is treatment with ursodeoxycholic acid (UDCA) and induction of labor before 40 wk of gestation. To investigate bile acid and metabolic parameters after UDCA treatment, we enrolled 12 ICP patients with singleton pregnancies-half with and half without gestational diabetes-and 7 controls. Our study reveals that after UDCA treatment, notwithstanding a reduction in total bile acid and alanine aminotransferase levels, imbalances persist in the cholic acid (CA) to chenodeoxycholic acid (CDCA) ratio in maternal and cord blood plasma. This indicates a continued dysregulation of bile acid metabolism despite therapeutic intervention. Maternal plasma lipid analysis showed a distinct maternal dyslipidemia pattern among patients with ICP, marked by elevated cholesterol levels on VLDL particles and heightened triglyceride concentrations on LDL particles, persisting even after UDCA treatment. Cord plasma lipid profiles in patients with ICP exhibited elevated triglyceride and free fatty acid levels alongside a tendency toward increased β-hydroxybutyrate. The changes in lipid metabolism in both maternal and cord blood correlated with the high CA/CDCA ratio but not total bile acid levels or gestational diabetes status. Understanding the imbalances in maternal and cord bile acid and lipid profiles that persist after standard UDCA therapy provides insights for improving management strategies and mitigating the long-term consequences of ICP.NEW & NOTEWORTHY This study uncovers that despite ursodeoxycholic acid treatment, intrahepatic cholestasis of pregnancy (ICP) is associated with increases in the ratio of cholic acid to chenodeoxycholic acid in both maternal and cord blood, suggesting ongoing dysregulation of bile acid metabolism. The high cholic to chenodeoxycholic acid ratio is correlated with maternal dyslipidemia and high cord blood lipids. These findings may inform more targeted approaches to managing ICP.
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Affiliation(s)
- Srijani Basu
- Naomi Berrie Diabetes Center, Columbia University, New York, New York, United States
- Columbia University Digestive and Liver Disease Research Center, Columbia University, New York, New York, United States
- Department of Medicine, Columbia University, New York, New York, United States
| | - Sarah G Običan
- Department of Obstetrics and Gynecology, Columbia University, New York, New York, United States
- Department of Obstetrics and Gynecology, University of South Florida, Tampa, Florida, United States
| | - Enrico Bertaggia
- Naomi Berrie Diabetes Center, Columbia University, New York, New York, United States
- Department of Pathology and Cell Biology, Columbia University, New York, New York, United States
| | - Hannah Staab
- Naomi Berrie Diabetes Center, Columbia University, New York, New York, United States
| | - M Concepcion Izquierdo
- Naomi Berrie Diabetes Center, Columbia University, New York, New York, United States
- Department of Pathology and Cell Biology, Columbia University, New York, New York, United States
| | | | - Rebecca A Haeusler
- Naomi Berrie Diabetes Center, Columbia University, New York, New York, United States
- Columbia University Digestive and Liver Disease Research Center, Columbia University, New York, New York, United States
- Department of Medicine, Columbia University, New York, New York, United States
- Department of Pathology and Cell Biology, Columbia University, New York, New York, United States
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Zhang D, Li Y, He S, Shu J, Li T, Sun Q. Association between ABCB4 variants and intrahepatic cholestasis of pregnancy. Sci Rep 2025; 15:3300. [PMID: 39865141 PMCID: PMC11770179 DOI: 10.1038/s41598-025-87909-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2024] [Accepted: 01/22/2025] [Indexed: 01/28/2025] Open
Abstract
The ABCB4 gene encodes multidrug resistance protein 3(MDR3), which is a phosphatidylcholine(PC) transfer enzyme that transfers lecithin from the inner part of the phospholipid bilayer to the extracellular bile. The occurrence of intrahepatic cholestasis of pregnancy(ICP) is closely related to ABCB4 variants, but there is limited research on this topic in southern Anhui, China. We sequenced ABCB4 in pregnant women with ICP and healthy pregnant women to explore the relationship. A total of 30 patients diagnosed with ICP were selected as the study objects and 90 healthy pregnant women were selected as the control group. DNA was extracted from peripheral blood of ICP patients and healthy pregnant women, 27 exons were sequencing by Sanger sequencing. Polymerase chain reaction (PCR) was used to amplify those exons. PolyPhen2, Mutation Taster, Provean, SIFT and Mutpred2 were used to predict protein structure, and Pymol software was used to predict the impact of missense variant c.1954 A > G(p.Arg652Gly) on proteins. Four exonic variants of ABCB4 gene were detected in ICP patients and healthy pregnant women, including synonymous variants c.175 C > T, c.504 C > T,c.711 A > T and missense variant c.1954 A > G(p.Arg652Gly). The incidence of the missense variant c.1954 A > G(p.Arg652Gly) was 6/90 in healthy pregnant womenand 8/30 in ICP patients.In healthy pregnant women with the missense variant c.1954 A > G(p.Arg652Gly), no other exonic variants were found. In ICP patients with missense variant c.1954 A > G(p.Arg652Gly), other exonic variants were found. PolyPhen2, Mutation Taster, Provean, SIFT and Mutpred2 were used to predict that the four exonic variants were benign, while Pymol was used to showed that the missense variant was located in the linker region of MDR3 and had a slight impact on protein function. Among ICP patients with missense variant c.1954 A > G(p.Arg652Gly), patients with three exonic variants(c.504 C > T, c.711 A > T, c.1954 A > G) had higher γ-GT, TBA, ALT and AST than those with two exonic variants. ABCB4 missense variant c.1954 A > G(p.Arg652Gly) requires the combination of other variants(c.175 C > T, c.504 C > T,c.711 A > T) to cause ICP symptoms, and when combined with other variants, it has a superimposed effect.
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Affiliation(s)
- Dekun Zhang
- Department of Gynecology and Obstetrics, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, People's Republic of China
- School of Basic Medical Sciences, Wannan Medical College, Wuhu, Anhui, People's Republic of China
| | - Yuhong Li
- Department of Gynecology and Obstetrics, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, People's Republic of China
- School of Basic Medical Sciences, Wannan Medical College, Wuhu, Anhui, People's Republic of China
| | - Shufeng He
- Department of Gynecology and Obstetrics, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, People's Republic of China
- School of Basic Medical Sciences, Wannan Medical College, Wuhu, Anhui, People's Republic of China
| | - Jing Shu
- School of Basic Medical Sciences, Wannan Medical College, Wuhu, Anhui, People's Republic of China
| | - Tiechen Li
- School of Basic Medical Sciences, Wannan Medical College, Wuhu, Anhui, People's Republic of China.
| | - Qing Sun
- Department of Gynecology and Obstetrics, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, People's Republic of China.
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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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Zöllner J, Williamson C, Dixon PH. Genetic issues in ICP. Obstet Med 2024; 17:157-161. [PMID: 39262913 PMCID: PMC11384815 DOI: 10.1177/1753495x241263441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Accepted: 06/05/2024] [Indexed: 09/13/2024] Open
Abstract
Intrahepatic cholestasis of pregnancy (ICP) is the commonest gestational liver disorder with variable global incidence. Genetic susceptibility, combined with hormonal and environmental influences, contributes to ICP aetiology. Adverse pregnancy outcomes linked to elevated serum bile acids highlight the importance of comprehensive risk assessment. ABCB4 and ABCB11 gene variants play a significant role in about 20% of severe ICP cases. Several other genes including ATP8B1, NR1H4, ABCC2, TJP2, SERPINA1, GCKR and HNF4A have also been implicated with ICP. Additionally, ABCB4 variants elevate the risk of drug-induced intrahepatic cholestasis, gallstone disease, gallbladder and bile duct carcinoma, liver cirrhosis and abnormal liver function tests. Genetic variations, both rare and common, intricately contribute to ICP susceptibility. Leveraging genetic insights holds promise for personalised management and intervention strategies. Further research is needed to elucidate variant-specific phenotypic expressions and therapeutic implications, advancing precision medicine in ICP management.
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Basu S, Običan SG, Bertaggia E, Staab H, Izquierdo MC, Gyamfi-Bannerman C, Haeusler RA. Unresolved alterations in bile acid composition and dyslipidemia in maternal and cord blood after ursodeoxycholic acid treatment for intrahepatic cholestasis of pregnancy. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.08.21.24312246. [PMID: 39228704 PMCID: PMC11370516 DOI: 10.1101/2024.08.21.24312246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/05/2024]
Abstract
Intrahepatic cholestasis of pregnancy (ICP) is characterized by elevated plasma bile acid levels. ICP is linked to adverse metabolic outcomes, including a reported increased risk of gestational diabetes. The standard therapeutic approach for managing ICP is treatment with ursodeoxycholic acid (UDCA) and induction of labor prior to 40 weeks of gestation. To investigate bile acid and metabolic parameters after UDCA treatment, we enrolled 12 ICP patients with singleton pregnancies-half with and half without gestational diabetes-and 7 controls. Our study reveals that after UDCA treatment, notwithstanding a reduction in total bile acid and ALT levels, imbalances persist in the cholic acid (CA) to chenodeoxycholic acid (CDCA) ratio in maternal and cord blood plasma. This indicates a continued dysregulation of bile acid metabolism despite therapeutic intervention. Maternal plasma lipid analysis showed a distinct maternal dyslipidemia pattern among ICP patients, marked by elevated cholesterol levels on VLDL particles and heightened triglyceride concentrations on LDL particles, persisting even after UDCA treatment. Cord plasma lipid profiles in ICP patients exhibited elevated triglyceride and free fatty acid levels alongside a tendency toward increased β-hydroxybutyrate. The changes in lipid metabolism in both maternal and cord blood correlated with the high CA/CDCA ratio, but not total bile acid levels or gestational diabetes status. Understanding the imbalances in maternal and cord bile acid and lipid profiles that persist after standard UDCA therapy provides insights for improving management strategies and mitigating the long-term consequences of ICP. News and Noteworthy This study uncovers that despite ursodeoxycholic acid treatment, intrahepatic cholestasis of pregnancy (ICP) is associated with increases in the ratio of cholic acid to chenodeoxycholic acid in both maternal and cord blood, suggesting ongoing dysregulation of bile acid metabolism. The high cholic to chenodeoxycholic acid ratio is correlated with maternal dyslipidemia and high cord blood lipids. These findings may inform more targeted approaches to managing ICP.
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Cai J, Tang M, Deng Y, Xiong L, Luo M, Huang C, Yang L, Yang X. Global research status of intrahepatic cholestasis of pregnancy: A bibliometric analysis of hotspots, bursts, and trends. Heliyon 2024; 10:e33940. [PMID: 39055843 PMCID: PMC11269835 DOI: 10.1016/j.heliyon.2024.e33940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 06/28/2024] [Accepted: 07/01/2024] [Indexed: 07/28/2024] Open
Abstract
Background Research on intrahepatic cholestasis of pregnancy (ICP) has recently gained attention. However, no bibliometric analysis was performed in the ICP research field. Therefore, the present study aimed to use bibliometric analysis to analyze the current research hotspots and identify global research status in ICP to reference for future research directions. Methods We comprehensively searched the Web of Science Core Collection (WoSCC) database from its inception to December 31, 2023. Articles and reviews related to ICP were downloaded as plain text file records. We used the VOSviewer and Citespace to perform the bibliometric analysis and visualization. The main bibliometric features were tabulated and calculated. Results A total of 1092 documents, including 921 original articles and 171 reviews, were identified in WoSCC. These publications were published in 395 journals by 4751 authors from 1250 institutions and 61 countries/regions. The global publication numbers exhibited a gradual upward trend. China, the United States, and the United Kingdom were top contributors to scientific research on ICP. King's College London, London Imperial Coll Sci Technol & Med, and Sichuan University were the most productive institutions. Catherine Williamson had published the most papers and received the most total citations. The most productive journal was Journal of Maternal-Fetal & Neonatal Medicine. The most cited paper was Beuers et al. in the Journal of Hepatology (2009). Citation burst terms showed that "risk factors" and "perinatal outcomes" were hotspots. "Inflammation", "risk factors", "perinatal outcomes", and "bile acid" have gained attention in more recent research. Conclusion The present study comprehensively summarizes the global research status and research trends in ICP. Our study identifies hotspots, collaborative networks, and trends that will provide new insights and guidance for further research in the field.
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Affiliation(s)
- Jianghui Cai
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, 611731, China
- Department of Pharmacy, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Mi Tang
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, 611731, China
- Office of Good Clinical Practice, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Yi Deng
- Department of Pharmacy, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Liling Xiong
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, 611731, China
- Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Mengqiu Luo
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Cheng Huang
- Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Li Yang
- Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Xiao Yang
- Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 611731, China
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Liu LW, Chen Y, Zhu LJ, Xu QX, Xu S, Ding Y, Yin B. A study on the relationship between gut microbiota and intrahepatic cholestasis of pregnancy. Heliyon 2024; 10:e25861. [PMID: 38384504 PMCID: PMC10878930 DOI: 10.1016/j.heliyon.2024.e25861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 02/04/2024] [Accepted: 02/05/2024] [Indexed: 02/23/2024] Open
Abstract
Objective Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disease associated with a high incidence of complications in the mid and late stages of gestation. This study investigates differences in the composition of intestinal flora among pregnant women diagnosed with ICP, employing Illumina MiSeq high-throughput sequencing technology. Methods This case-control study obtained patient data from the hospital information system (HIS) and the laboratory information system (LIS). Fecal samples were collected from 25 pregnant women who did not undergo intestinal preparation before delivery between December 2020 and March 2021. Whole-genome analysis was performed. PCR was used to amplify the 16S rRNA V3-V4 variable region, which was then sequenced. Alpha and beta diversity were computed, and the maternal intestinal flora's abundance and composition characteristics were analyzed. Differences in intestinal flora between the two sample groups were examined. Results Bacteroides and Proteobacteria exhibited positive correlations with TBIL and IBIL. Betaproteobacteria, Gammaproteobacteria, and Erysipeiotrichi showed positive correlations with TBIL, IBIL, and DBIL, while Lactobacillus, Delftia, and Odoribacter demonstrated positive correlations with ALT. Conclusion The ICP group displayed significantly higher levels of total bile acid and ALT compared to the control group. The intestinal flora composition comprised four primary phyla: Firmicutes, Actinobacteria, Bacteroidetes, and Proteobacteria. ICP patients exhibited a lower relative abundance of intestinal flora across different levels of community composition when compared to the control group. Specific correlations between certain intestinal flora and clinical liver parameters were identified.
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Affiliation(s)
- Li-wen Liu
- Department of Anesthesia, The Reproductive Hospital of Guangxi Zhuang Autonomous Region, Nanning City, 530000, China
| | - Yan Chen
- Department of Obstetrical, Guangzhou Women and Children's Hospital Liuzhou Hospital, Liuzhou City, 545000, China
| | - Liu-jing Zhu
- Department of Obstetrical, Guangzhou Women and Children's Hospital Liuzhou Hospital, Liuzhou City, 545000, China
| | - Qun-xiang Xu
- Department of Breast, Guangzhou Women and Children's Hospital Liuzhou Hospital, Liuzhou City, 545000, China
| | - Shaolin Xu
- Department of Laboratory, Guangzhou Women and Children's Hospital Liuzhou Hospital, Liuzhou City, 545000, China
| | - Yanling Ding
- Department of Laboratory, Guangzhou Women and Children's Hospital Liuzhou Hospital, Liuzhou City, 545000, China
| | - Biao Yin
- Department of Eugenic Genetics, The Reproductive Hospital of Guangxi Zhuang Autonomous Region, Nanning City, 530000, China
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Tang M, Xiong L, Cai J, Fu J, Liu H, Ye Y, Yang L, Xing S, Yang X. Intrahepatic cholestasis of pregnancy: insights into pathogenesis and advances in omics studies. Hepatol Int 2024; 18:50-62. [PMID: 37957532 DOI: 10.1007/s12072-023-10604-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Accepted: 09/28/2023] [Indexed: 11/15/2023]
Abstract
Intrahepatic cholestasis of pregnancy (ICP) is the most common pregnancy-specific liver disease. It is characterized by pruritus, abnormal liver function and elevated total bile acid (TBA) levels, increasing the risk of maternal and fetal adverse outcomes. Its etiology remains poorly elucidated. Over the years, various omics techniques, including metabolomics, microbiome, genomics, etc., have emerged with the advancement of bioinformatics, providing a new direction for exploring the pathogenesis, diagnosis and treatment of ICP. In this review, we first summarize the role of bile acids and related components in the pathogenesis of ICP and then further illustrate the results of omics studies.
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Affiliation(s)
- Mi Tang
- GCP Institution, School of Medicine, Chengdu Women's and Children's Central Hospital, University of Electronic Science and Technology of China, Chengdu, 611731, China
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Liling Xiong
- Obstetrics Department, School of Medicine, Chengdu Women's and Children's Central Hospital, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Jianghui Cai
- Department of Pharmacy, School of Medicine, Chengdu Women's and Children's Central Hospital, University of Electronic Science and Technology of China, Chengdu, 611731, China
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Jinzhu Fu
- Obstetrics Department, School of Medicine, Chengdu Women's and Children's Central Hospital, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Hong Liu
- Operating Theater, School of Medicine, Chengdu Women's and Children's Central Hospital, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Ying Ye
- Operating Theater, School of Medicine, Chengdu Women's and Children's Central Hospital, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Li Yang
- Obstetrics Department, School of Medicine, Chengdu Women's and Children's Central Hospital, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - ShaSha Xing
- GCP Institution, School of Medicine, Chengdu Women's and Children's Central Hospital, University of Electronic Science and Technology of China, Chengdu, 611731, China.
| | - Xiao Yang
- Obstetrics Department, School of Medicine, Chengdu Women's and Children's Central Hospital, University of Electronic Science and Technology of China, Chengdu, 611731, China.
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Ni MM, Yang JF, Miao J, Xu J. Association between genetic variants of transmembrane transporters and susceptibility to anthracycline-induced cardiotoxicity: Current understanding and existing evidence. Clin Genet 2024; 105:115-129. [PMID: 37961936 DOI: 10.1111/cge.14452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 10/31/2023] [Accepted: 11/02/2023] [Indexed: 11/15/2023]
Abstract
Anthracyclines remain the cornerstone of numerous chemotherapeutic protocols, with beneficial effects against haematological malignancies and solid tumours. Unfortunately, the clinical usefulness of anthracyclines is compromised by the development of cardiotoxic side effects, leading to dose limitations or treatment discontinuation. There is no absolute linear correlation between the incidence of cardiotoxicity and the threshold dose, suggesting that genetic factors may modify the association between anthracyclines and cardiotoxicity risk. And the majority of single nucleotide polymorphisms (SNPs) associated with anthracycline pharmacogenomics were identified in the ATP-binding cassette (ABC) and solute carrier (SLC) transporters, generating increasing interest in the pharmacogenetic implications of their genetic variations for anthracycline-induced cardiotoxicity (AIC). This review focuses on the influence of SLC and ABC polymorphisms on AIC and highlights the prospects and clinical significance of pharmacogenetics for individualised preventive approaches.
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Affiliation(s)
- Ming-Ming Ni
- Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Ju-Fei Yang
- Department of Pharmacy, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Jing Miao
- Department of Pharmacy, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
- Research Center for Clinical Pharmacy, Zhejiang University, Hangzhou, China
| | - Jin Xu
- Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, China
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10
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Yin N, Jiang X, Yu M, Yang Y, Ge H, Han TL, Qi H. The maternal hair metabolome is capable of discriminating intrahepatic cholestasis of pregnancy from uncomplicated pregnancy. Front Endocrinol (Lausanne) 2024; 14:1280833. [PMID: 38260149 PMCID: PMC10801165 DOI: 10.3389/fendo.2023.1280833] [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: 08/21/2023] [Accepted: 12/18/2023] [Indexed: 01/24/2024] Open
Abstract
Introduction Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disease associated with elevated bile acids in the blood. Diagnosis typically only occurs after the manifestation of clinical symptoms and the metabolic mechanisms underlying its development remain unclear. The aim of this study was to investigate potential specific metabolites and the underlying metabolic changes occurring during the development of ICP in the maternal plasma and hair metabolomes of women diagnosed with either ICP or having a healthy pregnancy. Methods A total of 35 Chinese women with ICP and 42 healthy pregnancies were enrolled in our study. Plasma and hair samples, total bile acid levels (TBA), alanine transaminase levels (ALT), aspartate aminotransferase levels (AST), and additional clinical information were collected during the third trimester. Metabolites from maternal plasma and hair segments collected pre-conception and analyzed using gas chromatography-mass spectrometry (GC-MS). Results Three plasma metabolites (p < 0.05, q < 0.38) and 21 hair metabolites (p < 0.05, q < 0.05) were significantly different between ICP and healthy pregnancies. A combination of the eight most significant hair metabolites in a multivariate receiver operating characteristic curve model showed the best area under the curve (AUC) was 0.885, whereas the highest AUC using metabolites from plasma samples was only 0.74. Metabolic pathway analysis revealed 32 pathways were significantly (p and q values < 0.05) affected in the hair samples of patients with ICP. Pathways associated with glutathione metabolism and ABC transporters were affected. No metabolic pathways were significantly affected in plasma. Discussion Overall, this study showed that the hair metabolome could be more useful than the plasma metabolome for distinguishing ICP from normal pregnancy.
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Affiliation(s)
- Nanlin Yin
- Department of Obstetrics and Gynecology, Women and Children’s Hospital of Chongqing Medical University, Chongqing, China
- Center for Reproductive Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiuping Jiang
- Center for Reproductive Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Muhua Yu
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yang Yang
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Huisheng Ge
- Department of Obstetrics and Gynecology, Women and Children’s Hospital of Chongqing Medical University, Chongqing, China
| | - Ting-Li Han
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Joint International Research Laboratory of Reproduction and Development of Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Hongbo Qi
- Department of Obstetrics and Gynecology, Women and Children’s Hospital of Chongqing Medical University, Chongqing, China
- Joint International Research Laboratory of Reproduction and Development of Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, China
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11
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Quaglia A, Roberts EA, Torbenson M. Developmental and Inherited Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:122-294. [DOI: 10.1016/b978-0-7020-8228-3.00003-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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12
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Ontsouka E, Schroeder M, Albrecht C. Revisited role of the placenta in bile acid homeostasis. Front Physiol 2023; 14:1213757. [PMID: 37546542 PMCID: PMC10402276 DOI: 10.3389/fphys.2023.1213757] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 07/03/2023] [Indexed: 08/08/2023] Open
Abstract
To date, the discussion concerning bile acids (BAs) during gestation is almost exclusively linked to pregnancy complications such as intrahepatic cholestasis of pregnancy (ICP) when maternal serum BA levels reach very high concentrations (>100 μM). Generally, the placenta is believed to serve as a protective barrier avoiding exposure of the growing fetus to excessive amounts of maternal BAs that might cause detrimental effects (e.g., intrauterine growth restriction and/or increased vulnerability to metabolic diseases). However, little is known about the precise role of the placenta in BA biosynthesis, transport, and metabolism in healthy pregnancies when serum BAs are at physiological levels (i.e., low maternal and high fetal BA concentrations). It is well known that primary BAs are synthesized from cholesterol in the liver and are later modified to secondary BA species by colonic bacteria. Besides the liver, BA synthesis in extrahepatic sites such as the brain elicits neuroprotective actions through inhibition of apoptosis as well as oxidative and endoplasmic reticulum stress. Even though historically BAs were thought to be only "detergent molecules" required for intestinal absorption of dietary fats, they are nowadays acknowledged as full signaling molecules. They modulate a myriad of signaling pathways with functional consequences on essential processes such as gluconeogenesis -one of the principal energy sources of the fetus- and cellular proliferation. The current manuscript discusses the potential multipotent roles of physiologically circulating BAs on developmental processes during gestation and provides a novel perspective in terms of the importance of the placenta as a previously unknown source of BAs. Since the principle "not too much, not too little" applicable to other signaling molecules may be also true for BAs, the risks associated with fetal exposure to excessive levels of BAs are discussed.
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13
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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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14
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Zöllner J, Finer S, Linton KJ, van Heel DA, Williamson C, Dixon PH. Rare variant contribution to cholestatic liver disease in a South Asian population in the United Kingdom. Sci Rep 2023; 13:8120. [PMID: 37208429 PMCID: PMC10199085 DOI: 10.1038/s41598-023-33391-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 04/12/2023] [Indexed: 05/21/2023] Open
Abstract
This study assessed the contribution of five genes previously known to be involved in cholestatic liver disease in British Bangladeshi and Pakistani people. Five genes (ABCB4, ABCB11, ATP8B1, NR1H4, TJP2) were interrogated by exome sequencing data of 5236 volunteers. Included were non-synonymous or loss of function (LoF) variants with a minor allele frequency < 5%. Variants were filtered, and annotated to perform rare variant burden analysis, protein structure, and modelling analysis in-silico. Out of 314 non-synonymous variants, 180 fulfilled the inclusion criteria and were mostly heterozygous unless specified. 90 were novel and of those variants, 22 were considered likely pathogenic and 9 pathogenic. We identified variants in volunteers with gallstone disease (n = 31), intrahepatic cholestasis of pregnancy (ICP, n = 16), cholangiocarcinoma and cirrhosis (n = 2). Fourteen novel LoF variants were identified: 7 frameshift, 5 introduction of premature stop codon and 2 splice acceptor variants. The rare variant burden was significantly increased in ABCB11. Protein modelling demonstrated variants that appeared to likely cause significant structural alterations. This study highlights the significant genetic burden contributing to cholestatic liver disease. Novel likely pathogenic and pathogenic variants were identified addressing the underrepresentation of diverse ancestry groups in genomic research.
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Affiliation(s)
| | - Sarah Finer
- Institute for Population Health Sciences, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Kenneth J Linton
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - David A van Heel
- Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Catherine Williamson
- Department of Women and Children's Health, School of Life Course Sciences, FOLSM, King's College London, 2.30W Hodgkin Building, Guy's Campus, London, SE1 1UL, UK.
| | - Peter H Dixon
- Department of Women and Children's Health, School of Life Course Sciences, FOLSM, King's College London, 2.30W Hodgkin Building, Guy's Campus, London, SE1 1UL, UK
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15
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Abdelhafez MMA, Ahmed KAM, Than WW, Baharuddin DMP, Kadir F, Jeffree S, Hayati MF, Daud MNBM, Eldiastey AM, Tay KX. Intrahepatic cholestasis of pregnancy: from an obstetrician point of view. J OBSTET GYNAECOL 2022; 42:2550-2557. [PMID: 35666947 DOI: 10.1080/01443615.2022.2081801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Intrahepatic cholestasis of pregnancy (ICP) is the commonest among the specific dermatoses of pregnancy. The disease is characterised by intense pruritus and specifically by elevated bile acid levels and owing to the rarity of data published in this context, the disease carries a great challenge in both diagnosis and management. The disease is associated with significant maternal as well as perinatal adverse effects, hence, this article aims at improving the knowledge of the women's health carers with the up-to-date and evidence-based, whenever possible, recommendations while managing patients with ICP.
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Affiliation(s)
- Mohsen M A Abdelhafez
- Department of Obstetrics and Gynaecology, Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah, Kota Kinabalu, Malaysia
| | - Karim A M Ahmed
- Department of Dermatology, Helios Saint Johannes Klinikum, Duisburg, Germany
| | - Win Win Than
- Department of Obstetrics and Gynaecology, Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah, Kota Kinabalu, Malaysia
| | - Dg Marshitah Pg Baharuddin
- Department of Obstetrics and Gynaecology, Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah, Kota Kinabalu, Malaysia
| | - Fairrul Kadir
- Department of Emergency Medicine, Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah, Kota Kinabalu, Malaysia
| | - Saffree Jeffree
- Department of Public Health Medicine, Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah, Kota Kinabalu, Malaysia
| | - Mohammad Firdaus Hayati
- Department of Surgery, Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah, Kota Kinabalu, Malaysia
| | - Mohd Nazri Bin Mohd Daud
- Department of Public Health Medicine, Faculty of Medicine and Health Sciences, Family Medicine Unit, Universiti Malaysia Sabah, Kota Kinabalu, Malaysia
| | | | - Kai Xin Tay
- Faculty of Business, Economic, and Accountancy, Universiti Malaysia Sabah, Kota Kinabalu, Malaysia
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16
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Dixon PH, Levine AP, Cebola I, Chan MMY, Amin AS, Aich A, Mozere M, Maude H, Mitchell AL, Zhang J, Chambers J, Syngelaki A, Donnelly J, Cooley S, Geary M, Nicolaides K, Thorsell M, Hague WM, Estiu MC, Marschall HU, Gale DP, Williamson C. GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements. Nat Commun 2022; 13:4840. [PMID: 35977952 PMCID: PMC9385867 DOI: 10.1038/s41467-022-29931-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 04/08/2022] [Indexed: 12/15/2022] Open
Abstract
Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder affecting 0.5-2% of pregnancies. The majority of cases present in the third trimester with pruritus, elevated serum bile acids and abnormal serum liver tests. ICP is associated with an increased risk of adverse outcomes, including spontaneous preterm birth and stillbirth. Whilst rare mutations affecting hepatobiliary transporters contribute to the aetiology of ICP, the role of common genetic variation in ICP has not been systematically characterised to date. Here, we perform genome-wide association studies (GWAS) and meta-analyses for ICP across three studies including 1138 cases and 153,642 controls. Eleven loci achieve genome-wide significance and have been further investigated and fine-mapped using functional genomics approaches. Our results pinpoint common sequence variation in liver-enriched genes and liver-specific cis-regulatory elements as contributing mechanisms to ICP susceptibility.
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Affiliation(s)
- Peter H Dixon
- Department of Women and Children's Health, School of Life Course Sciences, King's College London, London, UK
| | - Adam P Levine
- Department of Renal Medicine, University College London, London, UK
- Research Department of Pathology, University College London, London, UK
| | - Inês Cebola
- Section of Genetics and Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Melanie M Y Chan
- Department of Renal Medicine, University College London, London, UK
| | - Aliya S Amin
- Department of Women and Children's Health, School of Life Course Sciences, King's College London, London, UK
| | - Anshul Aich
- Department of Renal Medicine, University College London, London, UK
| | - Monika Mozere
- Department of Renal Medicine, University College London, London, UK
| | - Hannah Maude
- Section of Genetics and Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Alice L Mitchell
- Department of Women and Children's Health, School of Life Course Sciences, King's College London, London, UK
| | - Jun Zhang
- Department of Renal Medicine, University College London, London, UK
- Division of Nephrology, Department of Medicine, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Jenny Chambers
- ICP Support, 69 Mere Green Road, Sutton Coldfield, UK
- Women's Health Research Centre, Imperial College London, London, UK
| | - Argyro Syngelaki
- Harris Birthright Research Centre for Fetal Medicine, King's College Hospital, London, UK
| | | | | | | | - Kypros Nicolaides
- Harris Birthright Research Centre for Fetal Medicine, King's College Hospital, London, UK
| | | | - William M Hague
- Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia
| | | | - Hanns-Ulrich Marschall
- Department of Molecular and Clinical Medicine/Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden
| | - Daniel P Gale
- Department of Renal Medicine, University College London, London, UK
| | - Catherine Williamson
- Department of Women and Children's Health, School of Life Course Sciences, King's College London, London, UK.
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17
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Liu X, Zheng J, Xin S, Zeng Y, Wu X, Zeng X, Lai H, Zou Y. Whole-exome sequencing expands the roles of novel mutations of organic anion transporting polypeptide, ATP-binding cassette transporter, and receptor genes in intrahepatic cholestasis of pregnancy. Front Genet 2022; 13:941027. [PMID: 36046230 PMCID: PMC9421141 DOI: 10.3389/fgene.2022.941027] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 07/01/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Intrahepatic cholestasis of pregnancy (ICP) is associated with a high incidence of fetal morbidity and mortality. Therefore, revealing the mechanisms involved in ICP and its association with fetal complications is very important. Methods: Here, we used a whole-exome sequencing (WES) approach to detect novel mutations of organic anion transporting polypeptide (OTAP) genes, ATP-binding cassette transporter (ABC) genes, and receptor genes associated with ICP in 249 individuals and 1,029 local control individuals. Two available tools, SIFT and PolyPhen-2, were used to predict protein damage. Protein structuremodeling and comparison between the reference and modified protein structures were conducted by SWISS-MODEL and Chimera 1.14rc software, respectively. Results: A total of 5,583 mutations were identified in 82 genes related to bile acid transporters and receptors, of which 62 were novel mutations. These novel mutations were absent in the 1,029 control individuals and three databases, including the 1,000 Genome Project (1000G_ALL), Exome Aggregation Consortium (ExAC), and Single-Nucleotide Polymorphism Database (dbSNP). We classified the 62 novel loci into two groups (damaging and probably damaging) according to the results of SIFT and PolyPhen-2. Out of the 62 novel mutations, 24 were detected in the damaging group. Of these, five novel possibly pathogenic variants were identified that were located in known functional genes, including ABCB4 (Ile377Asn), ABCB11 (Ala588Pro), ABCC2 (Ile681Lys and Met688Thr), and NR1H4 (Tyr149Ter). Moreover, compared to the wild-type protein structure, ABCC2 Ile681Lys and Met688Thr protein structures showed a slight change in the chemical bond lengths of ATP-ligand binding amino acid side chains. The combined 32 clinical data points indicate that the mutation group had a significantly (p = 0.04) lower level of Cl ions than the wild-type group. Particularly, patients with the 24 novel mutations had higher average values of alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), total bile acids (TBA), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) than patients with the 38 novel mutations in the probably damaging group and the local control individuals. Conclusion: The present study provides new insights into the genetic architecture of ICP involving these novel mutations.
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Affiliation(s)
| | | | | | | | | | - Xiaoming Zeng
- *Correspondence: Xiaoming Zeng, ; Hua Lai, ; Yang Zou,
| | - Hua Lai
- *Correspondence: Xiaoming Zeng, ; Hua Lai, ; Yang Zou,
| | - Yang Zou
- *Correspondence: Xiaoming Zeng, ; Hua Lai, ; Yang Zou,
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18
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Pfister ED, Dröge C, Liebe R, Stalke A, Buhl N, Ballauff A, Cantz T, Bueltmann E, Stindt J, Luedde T, Baumann U, Keitel V. Extrahepatic manifestations of progressive familial intrahepatic cholestasis syndromes: Presentation of a case series and literature review. Liver Int 2022; 42:1084-1096. [PMID: 35184362 DOI: 10.1111/liv.15200] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 02/02/2022] [Accepted: 02/11/2022] [Indexed: 02/13/2023]
Abstract
BACKGROUND AND AIMS Progressive familial intrahepatic cholestasis (PFIC) is a collective term for a heterogenous group of rare, inherited cholestasis syndromes. The number of genes underlying the clinical PFIC phenotype is still increasing. While progressive liver disease and its sequelae such as portal hypertension, pruritus and hepatocellular carcinoma determine transplant-free survival, extrahepatic manifestations may cause relevant morbidity. METHODS We performed a literature search for extrahepatic manifestations of PFIC associated with pathogenic gene variants in ATP8B1, ABCB11, ABCB4, TJP2, NR1H4 and MYO5B. To illustrate the extrahepatic symptoms described in the literature, PFIC cases from our centres were revisited. RESULTS Extrahepatic symptoms are common in PFIC subtypes, where the affected gene is expressed at high levels in other tissues. While most liver-associated complications resolve after successful orthotopic liver transplantation (OLT), some extrahepatic symptoms show no response or even worsen after OLT. CONCLUSION The spectrum of extrahepatic manifestations in PFIC highlights essential, non-redundant roles of the affected genes in other organs. Extrahepatic features contribute towards low health-related quality of life (HRQOL) and morbidity in PFIC. While OLT is often the only remaining, curative treatment, potential extrahepatic manifestations need to be carefully monitored and addressed.
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Affiliation(s)
- Eva-Doreen Pfister
- Division of Paediatric Gastroenterology and Hepatology, Department of Paediatric Liver, Kidney and Metabolic Diseases, Hannover Medical School, Hannover, Germany
| | - Carola Dröge
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany.,Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Magdeburg, Medical Faculty of Otto von Guericke University, Magdeburg, Germany
| | - Roman Liebe
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Amelie Stalke
- Division of Paediatric Gastroenterology and Hepatology, Department of Paediatric Liver, Kidney and Metabolic Diseases, Hannover Medical School, Hannover, Germany.,Department of Human Genetics, Hannover Medical School, Hannover, Germany
| | - Nicole Buhl
- Division of Paediatric Gastroenterology and Hepatology, Department of Paediatric Liver, Kidney and Metabolic Diseases, Hannover Medical School, Hannover, Germany.,Department of Human Genetics, Hannover Medical School, Hannover, Germany
| | - Antje Ballauff
- Department of Paediatrics, Helios Hospital, Krefeld, Germany
| | - Tobias Cantz
- Translational Hepatology and Stem Cell Biology, Department of Gastroenterology, Hepatology and Endocrinology, REBIRTH-Center for Translational Regenerative Medicine, Hannover Medical School, Hannover, Germany
| | - Eva Bueltmann
- Institute of Diagnostic and Interventional Neuroradiology, Hannover Medical School, Hannover, Germany
| | - Jan Stindt
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Tom Luedde
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Ulrich Baumann
- Division of Paediatric Gastroenterology and Hepatology, Department of Paediatric Liver, Kidney and Metabolic Diseases, Hannover Medical School, Hannover, Germany.,Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Verena Keitel
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany.,Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Magdeburg, Medical Faculty of Otto von Guericke University, Magdeburg, Germany
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19
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Celik S, Golbasi H, Gulucu S, Guclu M, Caliskan CS, Celik S, Akpak YK, Golbasi C. Role of Vitamin B12 and Vitamin D levels in intrahepatic cholestasis of pregnancy and correlation with total bile acid. J OBSTET GYNAECOL 2022; 42:1847-1852. [PMID: 35482784 DOI: 10.1080/01443615.2022.2042797] [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: 10/18/2022]
Abstract
This study aimed to evaluate the relationship between intrahepatic cholestasis of pregnancy (ICP) and Vitamin D and B12 levels. The study was a retrospective, cross-sectional, case-control study that evaluated 92 ICP cases and 102 pregnant women without any additional disease. ICP cases were grouped as mild and severe according to their total bile acid (TBA) levels, and their relationship with Vitamin D and B12 levels and perinatal outcomes was evaluated. Vitamin D and B12 levels of the ICP group were significantly lower than those of the control group. There was a moderate negative correlation between TBA and Vitamin D levels and a low negative correlation between TBA and Vitamin B12 levels. Adverse neonatal outcomes were significantly higher in the severe ICP group than in the mild ICP group. IMPACT STATEMENTWhat is already known on this subject? The pathophysiology of ICP, which can lead to adverse perinatal outcomes, is not yet fully understood, and there is no preventive treatment.What do the results of this study add? This study showed that Vitamins B12 and D levels were low in women with ICP and that TBA levels were negatively correlated with Vitamin D and B12 levels.What are the implications of these findings for clinical practice and/or further research? This study may guide future studies in terms of explaining the etiopathogenesis of ICP and developing treatment options.
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Affiliation(s)
- Sebahattin Celik
- Department of Obstetrics and Gynecology, Balikesir State Hospital, Balikesir, Turkey
| | - Hakan Golbasi
- Department of Obstetrics and Gynecology, Division of Perinatology, University of Health Sciences, Tepecik Training and Research Hospital, Izmir, Turkey
| | - Selim Gulucu
- Department of Obstetrics and Gynecology, Gaziosmanpasa University, Tokat, Turkey
| | - Mehmet Guclu
- Department of Obstetrics and Gynecology, Marmara University, Pendik Training and Research Hospital, Istanbul, Turkey
| | - Canan Soyer Caliskan
- Department of Obstetrics and Gynecology, Samsun Training and Research Hospital, Samsun, Turkey
| | - Samettin Celik
- Department of Obstetrics and Gynecology, Samsun Training and Research Hospital, Samsun, Turkey
| | - Yasam Kemal Akpak
- Department of Obstetrics and Gynecology, University of Health Sciences, Tepecik Training and Research Hospital, Izmir, Turkey
| | - Ceren Golbasi
- Department of Obstetrics and Gynecology, Tinaztepe University, Izmir, Turkey
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Mareux E, Lapalus M, Ben-Saad A, Callebaut I, Falguières T, Gonzales E, Jacquemin E. In vitro functional rescue by ivacaftor of an ABCB11 variant involved in PFIC2 and intrahepatic cholestasis of pregnancy. Orphanet J Rare Dis 2021; 16:484. [PMID: 34794484 PMCID: PMC8600881 DOI: 10.1186/s13023-021-02125-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 11/06/2021] [Indexed: 01/16/2023] Open
Abstract
Background ABCB11 variations are responsible for a spectrum of rare liver diseases, including progressive familial intrahepatic cholestasis type 2 (PFIC2) and intrahepatic cholestasis of pregnancy (ICP). Current medical treatment of these conditions mostly relies on ursodeoxycholic acid with limited efficacy. We report on the in vitro study of the p.A257V missense variant of ABCB11 identified in a PFIC2 patient and in her mother who experienced ICP. Results The Ala257 residue is located outside the ATP-binding site of ABCB11. We show that the p.A257V variant of ABCB11 is correctly expressed at the canalicular membrane of HepG2 cells but that its function significantly decreased when studied in MDCK cells. This functional defect can be fully rescued by Ivacaftor. Conclusion Ivacaftor could be considered as a new pharmacological tool able to respond to an unmet medical need for patients with ICP and PFIC2 due to ABCB11 variations affecting ABCB11 function, even when the residue involved is not located in an ATP-binding site of ABCB11. Supplementary Information The online version contains supplementary material available at 10.1186/s13023-021-02125-4.
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Affiliation(s)
- Elodie Mareux
- Inserm, Physiopathogénèse et traitement des maladies du foie, UMR_S 1193, Université Paris-Saclay, Hepatinov, 91400, Orsay, France
| | - Martine Lapalus
- Inserm, Physiopathogénèse et traitement des maladies du foie, UMR_S 1193, Université Paris-Saclay, Hepatinov, 91400, Orsay, France
| | - Amel Ben-Saad
- Inserm, Physiopathogénèse et traitement des maladies du foie, UMR_S 1193, Université Paris-Saclay, Hepatinov, 91400, Orsay, France
| | - Isabelle Callebaut
- Muséum National d'Histoire Naturelle, UMR CNRS 7590, Institut de Minéralogie, de Physique des Matériaux et de Cosmochimie, IMPMC, Sorbonne Université, 75005, Paris, France
| | - Thomas Falguières
- Inserm, Physiopathogénèse et traitement des maladies du foie, UMR_S 1193, Université Paris-Saclay, Hepatinov, 91400, Orsay, France
| | - Emmanuel Gonzales
- Inserm, Physiopathogénèse et traitement des maladies du foie, UMR_S 1193, Université Paris-Saclay, Hepatinov, 91400, Orsay, France.,Paediatric Hepatology and Paediatric Liver Transplant Department, National Reference Center for Rare Paediatric Liver Diseases, FILFOIE, ERN RARE LIVER, Assistance Publique-Hôpitaux de Paris, Faculté de Médecine Paris-Saclay, CHU Bicêtre, 94270, Le Kremlin-Bicêtre, France
| | - Emmanuel Jacquemin
- Inserm, Physiopathogénèse et traitement des maladies du foie, UMR_S 1193, Université Paris-Saclay, Hepatinov, 91400, Orsay, France. .,Paediatric Hepatology and Paediatric Liver Transplant Department, National Reference Center for Rare Paediatric Liver Diseases, FILFOIE, ERN RARE LIVER, Assistance Publique-Hôpitaux de Paris, Faculté de Médecine Paris-Saclay, CHU Bicêtre, 94270, Le Kremlin-Bicêtre, France.
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Lifshitz I, Kleinstern G, Rottenstreich O, Porat S, Rosenbloom JI, Kabiri D, Rottenstreich M, Ezra Y, Shibolet O, Safadi R, Rottenstreich A. A model based on routine liver tests can reliably exclude intrahepatic cholestasis of pregnancy. Eur J Intern Med 2021; 90:66-70. [PMID: 33985887 DOI: 10.1016/j.ejim.2021.04.022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 04/16/2021] [Accepted: 04/20/2021] [Indexed: 01/17/2023]
Abstract
OBJECTIVES Serum bile acid (BA) levels testing is used for the diagnosis of intrahepatic cholestasis of pregnancy (ICP). We aimed to determine the performance of routine liver tests in the evaluation of ICP. METHODS A retrospective cohort study conducted at a university hospital, including all pregnant women who underwent serum BA levels testing due to suspected ICP during 2007-2019. Liver tests were performed in all women including: aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase (ALK), gamma-glutamyl transferase (GGT), and total bilirubin (TB). The optimal combination of laboratory values was determined by an algorithm developed in the Python programming language. RESULTS Of 640 women who met the inclusion criteria, 22% (n = 142) were diagnosed with ICP (serum BA>10 μmol/L). A combined laboratory score of: (TB>11 μmol/L) or (ALK>255 U/L) or (GGT>32 U/L) or (AST>31 U/L), had a sensitivity of 94%, negative predictive value (NPV) of 97%, specificity of 50%, positive predictive value of 35%, and a negative likelihood ratio of 0.11 for the diagnosis of ICP. The AUC of the laboratory model alone was 0.72 (95% CI: 0.69-0.75). The addition of history of ICP to the suggested laboratory score resulted in a sensitivity of 97%, NPV of 98% and a negative likelihood ratio of 0.06. The AUC of the final model was 0.76 (95% CI: 0.72-0.79). CONCLUSIONS A combined laboratory score incorporating AST, GGT, ALK and TB was shown to reliably exclude the diagnosis of ICP. This may be particularly useful in settings with limited access to BA levels testing.
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Affiliation(s)
- Inbar Lifshitz
- Faculty of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Geffen Kleinstern
- Department Health Sciences Research, Mayo Clinic, Rochester, MN, United States
| | - Ori Rottenstreich
- Departments of Computer Science and Electrical Engineering, Technion- Israeli Institute of Technology, Haifa, Israel
| | - Shay Porat
- Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, POB 12000, Jerusalem 91120, Israel
| | - Joshua I Rosenbloom
- Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, POB 12000, Jerusalem 91120, Israel
| | - Doron Kabiri
- Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, POB 12000, Jerusalem 91120, Israel
| | - Moshe Rottenstreich
- Department of Gastroenterology and Liver Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Yosef Ezra
- Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, POB 12000, Jerusalem 91120, Israel
| | - Oren Shibolet
- Department of Gastroenterology and Hepatology, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Rifaat Safadi
- Department of Gastroenterology and Liver Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Amihai Rottenstreich
- Faculty of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, POB 12000, Jerusalem 91120, Israel.
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Hagenbeck C, Pecks U, Lammert F, Hütten MC, Borgmeier F, Fehm T, Schleußner E, Maul H, Kehl S, Hamza A, Keitel V. [Intrahepatic cholestasis of pregnancy]. DER GYNAKOLOGE 2021; 54:341-356. [PMID: 33896963 PMCID: PMC8056200 DOI: 10.1007/s00129-021-04787-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Accepted: 03/08/2021] [Indexed: 12/19/2022]
Abstract
Intrahepatic cholestasis of pregnancy (ICP) is the most frequent pregnancy-specific liver disease. It is characterized by pruritus and an accompanying elevation of serum bile acid concentrations and/or alanine aminotransferase (ALT), which are the key parameters in the diagnosis. Despite good maternal prognosis, elevated bile acid concentration in maternal blood is an influencing factor to advers fetal outcome. The ICP is associated with increased rates of preterm birth, neonatal unit admission and stillbirth. This is the result of acute fetal asphyxia as opposed to a chronic uteroplacental insufficiency. Reliable monitoring or predictive tools (e.g. cardiotocography (CTG) or ultrasound) that help to prevent advers events are yet to be explored. Medicinal treatment with ursodeoxycholic acid (UDCA) does not demonstrably reduce adverse perinatal outcomes but does improve pruritus and liver function test results. Bile acid concentrations and gestational age should be used as indications to determine delivery. There is a high risk of recurrence in subsequent pregnancies.
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Affiliation(s)
- Carsten Hagenbeck
- Klinik für Frauenheilkunde und Geburtshilfe, Universität Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, Deutschland
| | - Ulrich Pecks
- Klinik für Gynäkologie und Geburtshilfe, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel, Deutschland
| | - Frank Lammert
- Klinik für Innere Medizin II, Universitätsklinikum des Saarlandes, Universität des Saarlandes, Homburg, Deutschland
| | - Matthias C. Hütten
- Neonatologie, Maastricht Universitair Medisch Centrum+, Maastricht, Niederlande
| | - Felix Borgmeier
- Klinik für Frauenheilkunde und Geburtshilfe, Universität Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, Deutschland
| | - Tanja Fehm
- Klinik für Frauenheilkunde und Geburtshilfe, Universität Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, Deutschland
| | | | - Holger Maul
- Frauenklinik, Asklepios Kliniken Barmbek, Wandsbek und Nord-Heidberg, Hamburg, Deutschland
| | - Sven Kehl
- Frauenklinik, Universitätsklinikum Erlangen, Erlangen, Deutschland
| | - Amr Hamza
- Kantonsspital Baden, Baden, Schweiz
- Klinikum für Frauenheilkunde, Geburtshilfe und Reproduktionsmedizin, Universität des Saarlandes, Homburg, Deutschland
| | - Verena Keitel
- Klinik für Gastroenterologie, Hepatologie und Infektiologie, Universität Düsseldorf, Düsseldorf, Deutschland
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23
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Gijbels E, Pieters A, De Muynck K, Vinken M, Devisscher L. Rodent models of cholestatic liver disease: A practical guide for translational research. Liver Int 2021; 41:656-682. [PMID: 33486884 PMCID: PMC8048655 DOI: 10.1111/liv.14800] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 01/08/2021] [Accepted: 01/15/2021] [Indexed: 12/12/2022]
Abstract
Cholestatic liver disease denotes any situation associated with impaired bile flow concomitant with a noxious bile acid accumulation in the liver and/or systemic circulation. Cholestatic liver disease can be subdivided into different types according to its clinical phenotype, such as biliary atresia, drug-induced cholestasis, gallstone liver disease, intrahepatic cholestasis of pregnancy, primary biliary cholangitis and primary sclerosing cholangitis. Considerable effort has been devoted to elucidating underlying mechanisms of cholestatic liver injuries and explore novel therapeutic and diagnostic strategies using animal models. Animal models employed according to their appropriate applicability domain herein play a crucial role. This review provides an overview of currently available in vivo animal models, fit-for-purpose in modelling different types of cholestatic liver diseases. Moreover, a practical guide and workflow is provided which can be used for translational research purposes, including all advantages and disadvantages of currently available in vivo animal models.
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Affiliation(s)
- Eva Gijbels
- Department of In Vitro Toxicology and Dermato‐CosmetologyVrije Universiteit BrusselBrusselsBelgium,Gut‐Liver Immunopharmacology Unit, Basic and Applied Medical SciencesLiver Research Center GhentFaculty of Medicine and Health SciencesGhent UniversityGhentBelgium
| | - Alanah Pieters
- Department of In Vitro Toxicology and Dermato‐CosmetologyVrije Universiteit BrusselBrusselsBelgium
| | - Kevin De Muynck
- Gut‐Liver Immunopharmacology Unit, Basic and Applied Medical SciencesLiver Research Center GhentFaculty of Medicine and Health SciencesGhent UniversityGhentBelgium,Hepatology Research UnitInternal Medicine and PaediatricsLiver Research Center GhentFaculty of Medicine and Health SciencesGhent UniversityGhentBelgium
| | - Mathieu Vinken
- Department of In Vitro Toxicology and Dermato‐CosmetologyVrije Universiteit BrusselBrusselsBelgium
| | - Lindsey Devisscher
- Gut‐Liver Immunopharmacology Unit, Basic and Applied Medical SciencesLiver Research Center GhentFaculty of Medicine and Health SciencesGhent UniversityGhentBelgium
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Burden of Future Liver Abnormalities in Patients With Intrahepatic Cholestasis of Pregnancy. Am J Gastroenterol 2021; 116:568-575. [PMID: 33657042 PMCID: PMC8451947 DOI: 10.14309/ajg.0000000000001132] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 12/14/2020] [Indexed: 12/11/2022]
Abstract
INTRODUCTION There are limited data on the incidence, predictors, and time to future liver abnormalities in patients with intrahepatic cholestasis of pregnancy (ICP). METHODS Single-center retrospective study of pregnant women with and without ICP who delivered from 2005 to 2009 evaluating incidence and time to future liver abnormalities. Women returning for care with liver function tests at a minimum of 6 months postpartum were included. Liver disease diagnoses and liver functions test abnormalities were compared. Time to development of alanine aminotransferase (ALT) >25 U/L, alkaline phosphatase (ALP) >140 U/L, and diagnosis of liver disease (through imaging or clinical evaluation) were compared between women with and without ICP using Kaplan-Meier methods and Cox regression models. RESULTS A total of 255 women with ICP and 131 age-matched control subjects with delivery during the same period were identified. Subjects in both groups were similar in follow-up time, age at pregnancy, prepregnancy body mass index, and ethnicity (≥75% were Hispanic in both groups). On univariate analyses, ICP was associated with increased incidence of ALT >25 U/L P < 0.01 ALP >140 U/L (P < 0.01) and liver disease (P = 0.03). Adjusting for metabolic factors, ICP diagnosis was associated with risk of future liver abnormalities: postpartum ALT >25 U/L (hazard ratio [HR] 1.9, P < 0.01), ALP >140 U/L (HR 3.4, P < 0.01), and liver disease (HR 1.5, P = 0.05). DISCUSSION In our cohort of urban women, ICP diagnosis predicted risk of future liver disease and abnormal liver tests. Women with pregnancies complicated by ICP may benefit from surveillance for postpartum liver abnormalities.
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25
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ABCB4 variants in adult patients with cholestatic disease are frequent and underdiagnosed. Dig Liver Dis 2021; 53:329-344. [PMID: 33390354 DOI: 10.1016/j.dld.2020.12.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 12/01/2020] [Accepted: 12/05/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Heterozygous ABCB4 variants are not routinely tested in adults with cholestasis because of their supposed rarity and high costs. METHODS Nineteen adult patients presenting with unexplained cholestasis, and/or recurrent gallstones were included; genotyping was not done in five due to lack of health insurance approval. RESULTS heterozygous ABCB4 variants were identified in seven patients, followed by cascade testing of 12 family members: one patient underwent liver transplantation at age 40 for end-stage liver disease; one had compensated cirrhosis; all symptomatic adults had gallstones, including four with low phospholipid-associated cholelithiasis; four had intrahepatic cholestasis of pregnancy; all children and one 54-year old female were asymptomatic. Genotype: Families A and C: c.2211G>A (p.Ala737=) combined with c.959C>T (p.Ser320Phe) in one subject; Family B: c.1130T>C (p.Ile377Thr); Family D: large deletion removing ABCB4 exons 1-4 plus ABCB1, RUNDC3B, SLC25A40, DBF4, ADAM22 exons 1-3; Family E: c.1565T>C (p.Phe522Ser) ; Family F: c.1356+2T>C combined with c.217C>G (p.Leu73Val). All patients responded to ursodeoxycholic acid. CONCLUSIONS We found ABCB4 variants in half of the adults with unexplained cholestasis and/or recurrent gallstones presenting at our center, suggesting that this condition is underdiagnosed and undertreated, with serious consequences not only for the patients and their families, but also in terms of healthcare costs.
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26
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A Link between Intrahepatic Cholestasis and Genetic Variations in Intracellular Trafficking Regulators. BIOLOGY 2021; 10:biology10020119. [PMID: 33557414 PMCID: PMC7914782 DOI: 10.3390/biology10020119] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/27/2021] [Accepted: 02/01/2021] [Indexed: 12/20/2022]
Abstract
Simple Summary Cholestasis refers to a medical condition in which the liver is not capable of secreting bile. The consequent accumulation of toxic bile components in the liver leads to liver failure. Cholestasis can be caused by mutations in genes that code for proteins involved in bile secretion. Recently mutations in other genes have been discovered in patients with cholestasis of unknown origin. Interestingly, many of these newly discovered genes code for proteins that regulate the intracellular distribution of other proteins, including those involved in bile secretion. This group of genes thus suggests the deregulated intracellular distribution of bile-secreting proteins as an important but still poorly understood mechanism that underlies cholestasis. To expedite a better understanding of this mechanism, we have reviewed these genes and their mutations and we discuss these in the context of cholestasis. Abstract Intrahepatic cholestasis is characterized by the accumulation of compounds in the serum that are normally secreted by hepatocytes into the bile. Genes associated with familial intrahepatic cholestasis (FIC) include ATP8B1 (FIC1), ABCB11 (FIC2), ABCB4 (FIC3), TJP2 (FIC4), NR1H4 (FIC5) and MYO5B (FIC6). With advanced genome sequencing methodologies, additional mutated genes are rapidly identified in patients presenting with idiopathic FIC. Notably, several of these genes, VPS33B, VIPAS39, SCYL1, and AP1S1, together with MYO5B, are functionally associated with recycling endosomes and/or the Golgi apparatus. These are components of a complex process that controls the sorting and trafficking of proteins, including those involved in bile secretion. These gene variants therefore suggest that defects in intracellular trafficking take a prominent place in FIC. Here we review these FIC-associated trafficking genes and their variants, their contribution to biliary transporter and canalicular protein trafficking, and, when perturbed, to cholestatic liver disease. Published variants for each of these genes have been summarized in table format, providing a convenient reference for those who work in the intrahepatic cholestasis field.
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27
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Li R, Chen X, Liu Z, Chen Y, Liu C, Ye L, Xiao L, Yang Z, He J, Wang WJ, Qi H. Characterization of gut microbiota associated with clinical parameters in intrahepatic cholestasis of pregnancy. BMC Gastroenterol 2020; 20:395. [PMID: 33225888 PMCID: PMC7682054 DOI: 10.1186/s12876-020-01510-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Accepted: 10/21/2020] [Indexed: 12/20/2022] Open
Abstract
Background Intrahepatic cholestasis of pregnancy (ICP) is a liver disorder that specifically occurs in pregnancy. Elevated levels of liver transaminases aspartate aminotransferase, alanine aminotransferase and serum bilirubin levels are common biochemical characteristics in ICP. The disorder is associated with an increased risk of premature delivery and stillbirth. The characterization of the potential microbiota in ICP could go a long way in the prevention and treatment of this pregnancy disease. Methods A total of 58 patients were recruited for our study: 27 ICP patients and 31 healthy pregnant subjects with no ICP. The V3 and V4 regions of the 16S rDNA collected from fecal samples of both diseased and control groups were amplified. 16S rRNA gene amplicon sequencing was then performed on gut microbiota. Sequencing data were analyzed and the correlation between components of microbiota and patient ICP status was found. Related metabolic pathways, relative abundance and significantly different operational taxonomic units (OTUs) between ICP and controls were also identified. Results Elevated levels of total bile acid, ALT, AST, Dbil and Tbil were recorded or observed in ICP subjects as compared to the control. Gut microbiota in pregnant women was dominated by four major phyla and 27 core genera. PCoA analysis results indicated that there was no significant clustering in Bray–Curtis distance matrices. Our results showed that there was a correlation between specific OTUs and measured clinical parameters of pregnant women. Comparison at the different taxonomy levels revealed high levels of abundance of Blautia and Citrobacter in ICP patients. At the family level, Enterobacteriaceae and Leuconostocaceae were higher in ICP patients. 638 KEGG Orthologs and 138 pathways significantly differed in the two groups. PLS-DA model with VIP plots indicated a total of eight genera and seven species were key taxa in ICP and control groups. Conclusions Our research indicated that although there was no significant clustering by PCoA analysis, patients with ICP have increased rare bacteria at different phylogenetic levels. Our results also illustrated that all 638 KEGG Orthologs and 136 in 138 KEGG pathways were less abundant in ICP patients compared to the controls.
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Affiliation(s)
- Rong Li
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing, 400016, People's Republic of China.,State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, Chongqing Medical University, Chongqing, 400016, People's Republic of China.,International Collaborative Laboratory of Reproduction and Development of Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, People's Republic of China
| | - Xuehai Chen
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing, 400016, People's Republic of China.,State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, Chongqing Medical University, Chongqing, 400016, People's Republic of China.,International Collaborative Laboratory of Reproduction and Development of Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, People's Republic of China
| | - Zhongzhen Liu
- BGI-Shenzhen, Build 11, Beishan Industrial Zone, Yantian District, Shenzhen, 518000, People's Republic of China.,China National GeneBank, BGI-Shenzhen, Shenzhen, 518000, People's Republic of China
| | - Yan Chen
- BGI-Shenzhen, Build 11, Beishan Industrial Zone, Yantian District, Shenzhen, 518000, People's Republic of China.,China National GeneBank, BGI-Shenzhen, Shenzhen, 518000, People's Republic of China
| | - Chuan Liu
- BGI-Shenzhen, Build 11, Beishan Industrial Zone, Yantian District, Shenzhen, 518000, People's Republic of China.,China National GeneBank, BGI-Shenzhen, Shenzhen, 518000, People's Republic of China
| | - Lingfei Ye
- BGI-Shenzhen, Build 11, Beishan Industrial Zone, Yantian District, Shenzhen, 518000, People's Republic of China.,China National GeneBank, BGI-Shenzhen, Shenzhen, 518000, People's Republic of China
| | - Liang Xiao
- BGI-Shenzhen, Build 11, Beishan Industrial Zone, Yantian District, Shenzhen, 518000, People's Republic of China.,China National GeneBank, BGI-Shenzhen, Shenzhen, 518000, People's Republic of China
| | - Zhenjun Yang
- BGI-Shenzhen, Build 11, Beishan Industrial Zone, Yantian District, Shenzhen, 518000, People's Republic of China.,China National GeneBank, BGI-Shenzhen, Shenzhen, 518000, People's Republic of China
| | - Jian He
- BGI-Chongqing Clinical Laboratory, BGI-Shenzhen, Chongqing, 401120, People's Republic of China
| | - Wen-Jing Wang
- BGI-Shenzhen, Build 11, Beishan Industrial Zone, Yantian District, Shenzhen, 518000, People's Republic of China. .,China National GeneBank, BGI-Shenzhen, Shenzhen, 518000, People's Republic of China.
| | - Hongbo Qi
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing, 400016, People's Republic of China. .,State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, Chongqing Medical University, Chongqing, 400016, People's Republic of China. .,International Collaborative Laboratory of Reproduction and Development of Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, People's Republic of China.
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Mirza N, Malhotra S, Sibal A. A Novel Compound Heterozygous Mutation in ABCB4 Gene Leading to Cholelithiasis, Progressive Familial Intrahepatic Cholestasis (Type 3), and Cirrhosis in a Child. JOURNAL OF CHILD SCIENCE 2020. [DOI: 10.1055/s-0040-1717106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
AbstractProgressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of autosomal recessive disorders of childhood which presents with intermittent or progressive episodes of cholestasis, with jaundice and pruritus as most common presenting symptoms. PFIC type 3 occurs due to mutations in the ABCB4 gene, mutation in this gene has wide spectrum of features which include intrahepatic stones, cholelithiasis, PFIC type 3, and intrahepatic cholestasis of pregnancy. Here, we are reporting a peculiar case of young male adolescent with novel variant compound heterozygote missense mutation in ABCB4 gene who had gall stone as initial symptom, followed by symptoms of PFIC and eventually decompensated chronic liver disease.
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Affiliation(s)
- Nida Mirza
- Indraprastha Apollo Hospital, New Delhi, India
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Whole-exome sequencing reveals ANO8 as a genetic risk factor for intrahepatic cholestasis of pregnancy. BMC Pregnancy Childbirth 2020; 20:544. [PMID: 32942997 PMCID: PMC7499841 DOI: 10.1186/s12884-020-03240-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 09/08/2020] [Indexed: 12/13/2022] Open
Abstract
Background Intrahepatic cholestasis of pregnancy (ICP) is characterized by pruritus and cholestasis in late pregnancy and results in adverse pregnancy outcomes, including preterm delivery and birth weight, which are affected by the genetic and environmental background. However, until now, the genetic architecture of ICP has remained largely unclear. Methods Twenty-six clinical data points were recorded for 151 Chinese ICP patients. The data generated from whole-exome sequencing (WES) using the BGISEQ-500 platform were further analyzed by Burrows-Wheeler Aligner (BWA) software, Genome Analysis Toolkit (GATK), ANNOVAR tool, etc. R packages were used to conduct t-test, Fisher’s test and receiver operating characteristic (ROC) curve analyses. Results We identified eighteen possible pathogenic loci associated with ICP disease in known genes, covering ABCB4, ABCB11, ATP8B1 and TJP2. The loci Lys386Gln, Gly527Gln and Trp708Ter in ABCB4, Leu589Met, Gln605Pro and Gln1194Ter in ABCB11, and Arg189Ser in TJP2 were novel discoveries. In addition, WES analysis indicated that the gene ANO8 involved in the transport of bile salts is newly identified as associated with ICP. The functional network of the ANO8 gene confirmed this finding. ANO8 contained 8 rare missense mutations that were found in eight patients among the 151 cases and were absent from 1029 controls. Out of the eight SNPs, 3 were known, and the remaining five are newly identified. These variants have a low frequency, ranging from 0.000008 to 0.00001 in the ExAC, gnomAD – Genomes and TOPMED databases. Bioinformatics analysis showed that the sites and their corresponding amino acids were both highly conserved among vertebrates. Moreover, the influences of all the mutations on protein function were predicted to be damaging by the SIFT tool. Combining clinical data, it was found that the mutation group (93.36 µmol/L) had significantly (P = 0.038) higher total bile acid (TBA) levels than the wild-type group (40.81 µmol/L). Conclusions To the best of our knowledge, this is the first study to employ WES technology to detect genetic loci for ICP. Our results provide new insights into the genetic basis of ICP and will benefit the final identification of the underlying mutations.
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Stättermayer AF, Halilbasic E, Wrba F, Ferenci P, Trauner M. Variants in ABCB4 (MDR3) across the spectrum of cholestatic liver diseases in adults. J Hepatol 2020; 73:651-663. [PMID: 32376413 DOI: 10.1016/j.jhep.2020.04.036] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 04/18/2020] [Accepted: 04/22/2020] [Indexed: 12/14/2022]
Abstract
The ATP binding cassette subfamily B member 4 (ABCB4) gene on chromosome 7 encodes the ABCB4 protein (alias multidrug resistance protein 3 [MDR3]), a P-glycoprotein in the canalicular membrane of the hepatocytes that acts as a translocator of phospholipids into bile. Several variants in ABCB4 have been shown to cause ABCB4 deficiency, accounting for a disease spectrum ranging from progressive familial cholestasis type 3 to less severe conditions like low phospholipid-associated cholelithiasis, intrahepatic cholestasis of pregnancy or drug-induced liver injury. Furthermore, whole genome sequencing has shown that ABCB4 variants are associated with an increased incidence of gallstone disease, gallbladder and bile duct carcinoma, liver cirrhosis or elevated liver function tests. Diagnosis of ABCB4 deficiency-related diseases is based on clinical presentation, serum biomarkers, imaging techniques, liver histology and genetic testing. Nevertheless, the clinical presentation can vary widely and clear genotype-phenotype correlations are currently lacking. Ursodeoxycholic acid is the most commonly used medical treatment, but its efficacy has yet to be proven in large controlled clinical studies. Future pharmacological options may include stimulation/restoration of residual function by chaperones (e.g. 4-phenyl butyric acid, curcumin) or induction of ABCB4 transcription by FXR (farnesoid X receptor) agonists or PPARα (peroxisome proliferator-activated receptor-α)-ligands/fibrates. Orthotopic liver transplantation remains the last and often only therapeutic option in cirrhotic patients with end-stage liver disease or patients with intractable pruritus.
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Affiliation(s)
- Albert Friedrich Stättermayer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Emina Halilbasic
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Fritz Wrba
- Institute of Clinical Pathology, Medical University of Vienna, Vienna, Austria
| | - Peter Ferenci
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
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Intrahepatic Cholestasis in Pregnancy: Review of the Literature. J Clin Med 2020; 9:jcm9051361. [PMID: 32384779 PMCID: PMC7290322 DOI: 10.3390/jcm9051361] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 04/27/2020] [Accepted: 05/04/2020] [Indexed: 12/14/2022] Open
Abstract
Intrahepatic cholestasis of pregnancy (ICP) is the most common hepatic disorder related to pregnancy in women. It usually develops within the third trimester of pregnancy and presents with pruritus as well as elevated levels of bile acid and/or alanine aminotransferase. Clinical signs quickly resolve after delivery; however, there is a high risk of the disorder recurring in subsequent pregnancies. ICP is associated with an increased risk of perinatal complications (premature birth, respiratory disorders, even stillbirth). Elevated levels of gestational hormones and genetic predispositions are important factors for the development of ICP; among the latter, mutations in hepatobiliary transport proteins (multidrug resistance protein 3-MDR3, bile salt export pump- BSEP) play a major role. Clinical and biochemical symptoms of ICP include pruritus and increased levels of total bile acids (TBA). Serum levels of TBA should be monitored in ICP patients throughout the pregnancy as concentrations above 40 μmol/L, which define that severe ICP isassociated with an increased risk of fetal complications. Therapeutic management is aimed at reducing the clinical symptoms, normalizing maternal biochemistry and preventing complications to the fetus. Pharmacological treatment of intrahepatic cholestasis of pregnancy consists of the administration of ursodeoxycholic acid to lower the levels of TBA and possibly reduce pruritus. If the treatment fails, premature delivery should be considered.
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Hämäläinen S, Turunen K, Mattila KJ, Kosunen E, Sumanen M. Intrahepatic cholestasis of pregnancy and comorbidity: A 44‐year follow‐up study. Acta Obstet Gynecol Scand 2019; 98:1534-1539. [DOI: 10.1111/aogs.13695] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Accepted: 07/11/2019] [Indexed: 12/11/2022]
Affiliation(s)
- Suvi‐Tuulia Hämäläinen
- Department of General Practice Faculty of Medicine and Health Technology Tampere University Tampere Finland
- Janakkala Health Center Turenki Finland
- Science Center Tampere University Hospital Tampere Finland
| | - Kaisa Turunen
- Department of General Practice Faculty of Medicine and Health Technology Tampere University Tampere Finland
| | - Kari J. Mattila
- Department of General Practice Faculty of Medicine and Health Technology Tampere University Tampere Finland
| | - Elise Kosunen
- Department of General Practice Faculty of Medicine and Health Technology Tampere University Tampere Finland
- Center for General Practice Pirkanmaa Hospital District Tampere Finland
| | - Markku Sumanen
- Department of General Practice Faculty of Medicine and Health Technology Tampere University Tampere Finland
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Abstract
The farnesoid X receptor (FXR, NR1H4) is a bile acid (BA)-activated transcription factor, which is essential for BA homeostasis. FXR and its hepatic and intestinal target genes, small heterodimer partner (SHP, NR0B2) and fibroblast growth factor 15/19 (Fgf15 in mice, FGF19 in humans), transcriptionally regulate BA synthesis, detoxification, secretion, and absorption in the enterohepatic circulation. Furthermore, FXR modulates a large variety of physiological processes, such as lipid and glucose homeostasis as well as the inflammatory response. Targeted deletion of FXR renders mice highly susceptible to cholic acid feeding resulting in cholestatic liver injury, weight loss, and increased mortality. Combined deletion of FXR and SHP spontaneously triggers early-onset intrahepatic cholestasis in mice resembling human progressive familial intrahepatic cholestasis (PFIC). Reduced expression levels and activity of FXR have been reported in human cholestatic conditions, such as PFIC type 1 and intrahepatic cholestasis of pregnancy. Recently, two pairs of siblings with homozygous FXR truncation or deletion variants were identified. All four children suffered from severe, early-onset PFIC and liver failure leading to death or need for liver transplantation before the age of 2. These findings underscore the central role of FXR as regulator of systemic and hepatic BA levels. Therefore, targeting FXR has been exploited in different animal models of both intrahepatic and obstructive cholestasis, and the first FXR agonist obeticholic acid (OCA) has been approved for the treatment of primary biliary cholangitis (PBC). Further FXR agonists as well as a FGF19 analogue are currently tested in clinical trials for different cholestatic liver diseases. This chapter will summarize the current knowledge on the role of FXR in cholestasis both in rodent models and in human diseases.
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Manzotti C, Casazza G, Stimac T, Nikolova D, Gluud C. Total serum bile acids or serum bile acid profile, or both, for the diagnosis of intrahepatic cholestasis of pregnancy. Cochrane Database Syst Rev 2019; 7:CD012546. [PMID: 31283001 PMCID: PMC6613619 DOI: 10.1002/14651858.cd012546.pub2] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Intrahepatic cholestasis of pregnancy is a pregnancy-specific liver disorder, possibly associated with an increased risk of severe fetal adverse events. Total serum bile acids (TSBA) concentration, alone or in combination with serum aminotransferases, have been the most often used biomarkers for the diagnosis of intrahepatic cholestasis of pregnancy in clinical practice. Serum bile acid profile, composed of primary or secondary, conjugated or non-conjugated bile acids, may provide more specific disease information. OBJECTIVES To assess and compare, independently or in combination, the diagnostic accuracy of total serum bile acids or serum bile acids profile, or both, for the diagnosis of intrahepatic cholestasis of pregnancy in pregnant women, presenting with pruritus. To define the optimal cut-off values for components of serum bile acid profile; to investigate possible sources of heterogeneity. SEARCH METHODS We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Hepato-Biliary Group Diagnostic Test Accuracy Studies Register, the Cochrane Library, MEDLINE Ovid, Embase Ovid, Science Citation Index Expanded, Conference Proceedings Citation Index - Science, BIOSIS, CINAHL, two Chinese databases (CKNI, VIP), Latin American and Caribbean Health Sciences Literature (LILACS), Scientific Electronic Library Online (SciELO), Evidence Search: Health and Social Care by the National Institute for Health and Care Excellence (NICE), the World Health Organization (WHO) Reproductive Health Library (RHL), and the Turning Research into Practice database (TRIP). The most recent date of search was 6 May 2019. We identified additional references by handsearching the references of articles, meta-analyses, and evidence-based guidelines retrieved from the computerised databases, on-line trial registries, and grey literature through OpenSIGLE, National Technical Information Service (NTIS), ProQuest Dissertations & Thesis Database, and Index to Theses in Great Britain and Ireland. SELECTION CRITERIA Prospective or retrospective diagnostic case-control or cross-sectional studies, irrespective of publication date, format, and language, which evaluated the diagnostic accuracy of total serum bile acids (TSBA) or components of serum bile acid profile for the diagnosis of intrahepatic cholestasis of pregnancy in pregnant women of any age or ethnicity, in any clinical setting, symptomatic for pruritus. DATA COLLECTION AND ANALYSIS We selected studies by reading titles, abstracts, or full texts, and assessing their fulfilment of our inclusion criteria. We emailed primary authors to request missing data or individual participant data. Having extracted data from each included study, we built the two-by-two tables for each primary study and for all the index tests considered. We estimated sensitivity and specificity with their 95% confidence intervals (CI). We presented data in coupled forest plots, showing sensitivities and specificities of each study, and we plotted the studies in the Receiver Operating Characteristic (ROC) space. We performed meta-analyses adopting the hierarchical summary ROC model (HSROC) or the bivariate model to meta-analyse the data. We made indirect comparisons of the considered index tests by adding the index tests as covariates to the bivariate or HSROC models. We performed heterogeneity analysis and sensitivity analysis on studies assessing TSBA accuracy. We used Review Manager 5 (RevMan 5) and SAS statistical software, release 9.4 (SAS Institute Inc., Cary, NC, USA), to perform all statistical analyses. We used QUADAS-2 domains to assess the risk of bias of the included studies. MAIN RESULTS Our search yielded 5073 references, but at the end of our selection process, only 16 studies fulfilled the review inclusion criteria. Nine of these provided individual participant data. We analysed only data concerning TSBA, cholic acid (CA), glycocholic acid (GCA), chenodeoxycholic acid (CDCA), and CA/CDCA because the remaining planned index tests were assessed in few studies. Only one study had low risk of bias in all four QUADAS-2 domains. The most biased domains were the patient sampling and the reference standard domains. When considering all studies with a cut-off of 10 μmol/L, TSBA overall sensitivity ranged from 0.72 to 0.98 and specificity ranged from 0.81 to 0.97. After a sensitivity analysis excluding case-control studies, TSBA sensitivity ranged from 0.48 to 0.66 and specificity from 0.52 to 0.99. After a sensitivity analysis excluding studies in which TSBA was part of the reference standard, TSBA sensitivity ranged from 0.49 to 0.65 and specificity from 0.53 to 0.99. We found the estimates of the overall accuracy for some serum bile acid components (CA, GCA, CDCA, and CA/CDCA) to be imprecise, with the CI for sensitivity and specificity very wide or impossible to calculate. Indirect comparisons between serum bile acid profile components and TSBA were not statistically significant. None of the heterogeneity analysis performed was statistically significant, except for the timing of assessment of TSBA (onset of symptoms, peak value among multiple assessments, delivery) but without clinically relevant results. We could not analyse the diagnostic accuracy of combinations of index tests because none of the included studies carried them out, and because of the small number of included studies. AUTHORS' CONCLUSIONS The overall high risk of bias, the existing concern regarding applicability of the results in clinical practice, and the great heterogeneity of the results in the included studies prevents us from making recommendations and reaching definitive conclusions at the present time. Thus, we do not find any compelling evidence to recommend or refute the routine use of any of these tests in clinical practice. So far, the diagnostic accuracy of TSBA for intrahepatic cholestasis of pregnancy might have been overestimated. There were too few studies to permit a precise estimate of the accuracy of serum bile acid profile components. Further primary clinical research is mandatory. We need both further phase II and phase III diagnostic studies.
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Affiliation(s)
- Cristina Manzotti
- Fondazione IRCCS Ca' Granda ‐ Ospedale Maggiore Policlinico, Università degli Studi di MilanoObstetrics and Gynecology DepartmentVia Commenda 12 ‐ Clinica Mangiagalli, piano terraMilanMilanItaly20122
- Department 7812, Rigshospitalet, Copenhagen University HospitalCochrane Hepato‐Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention ResearchCopenhagenDenmark
- Fondazione IRCCS Ca' Granda ‐ Ospedale Maggiore Policlinico, Università degli Studi di MilanoGastro‐Intestinal UnitVia Commenda 12 ‐ Clinica Mangiagalli, 1° piano, scala AMilanMilanItaly20122
| | - Giovanni Casazza
- Università degli Studi di MilanoDipartimento di Scienze Biomediche e Cliniche "L. Sacco"via GB Grassi 74MilanItaly20157
| | - Tea Stimac
- Clinical Hospital Centre RijekaObstetrics and GynecologyCambierieva 17RijekaCroatia51000
| | - Dimitrinka Nikolova
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalCochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
| | - Christian Gluud
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalCochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
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Hämäläinen ST, Turunen K, Mattila KJ, Kosunen E, Sumanen M. Long-term survival after intrahepatic cholestasis of pregnancy: A follow-up of 571 mothers. Eur J Obstet Gynecol Reprod Biol 2019; 240:109-112. [PMID: 31247486 DOI: 10.1016/j.ejogrb.2019.06.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2019] [Accepted: 06/11/2019] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disorder during pregnancy. ICP has been associated with morbidity but little is known about women's long-term survival. Our aim was to determine whether ICP is associated with mothers' long-term survival. STUDY DESIGN The study population comprised 571 women with ICP in at least one pregnancy seen at Tampere University Hospital in Finland between 1969‒1988. The reference group comprised 1333 women: the previous and the following participant in the maternity ward diary. The data were obtained from Statistics Finland in March 2017 containing deaths among the study participants between 1971‒2015. The follow-up time of the cohort was 27-46 years. The Kaplan-Meier method was used. RESULTS Totally, 39 of the mothers with ICP (6.8%) and 111 of the reference group (8.3%) had died by the end of 2015 (p = 0.267). The mean survival time of ICP women was 77.4 years and of the reference group 79.2 years (p = 0.288). The mean survival time from labour in the ICP group was 45.0 years and in the reference group 44.8 years (p = 0.259). CONCLUSIONS Based on this study ICP does not seem to be associated with women's survival. There is no need to follow-up ICP mothers' health because of the nonexistent risk of premature death.
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Affiliation(s)
- Suvi-Tuulia Hämäläinen
- Department of General Practice, Faculty of Medicine and Health Technology, Tampere University, Arvo Ylpön katu 34, 33520 Tampere, Finland; Janakkala Health Centre, Tapailanpiha 13 B, 14200 Turenki, Finland; Science Center, Tampere University Hospital, 33521 Tampere, Finland; Centre for General Practice, Pirkanmaa Hospital District, 33521 Tampere, Finland.
| | - Kaisa Turunen
- Department of General Practice, Faculty of Medicine and Health Technology, Tampere University, Arvo Ylpön katu 34, 33520 Tampere, Finland
| | - Kari J Mattila
- Department of General Practice, Faculty of Medicine and Health Technology, Tampere University, Arvo Ylpön katu 34, 33520 Tampere, Finland
| | - Elise Kosunen
- Department of General Practice, Faculty of Medicine and Health Technology, Tampere University, Arvo Ylpön katu 34, 33520 Tampere, Finland; Science Center, Tampere University Hospital, 33521 Tampere, Finland; Centre for General Practice, Pirkanmaa Hospital District, 33521 Tampere, Finland
| | - Markku Sumanen
- Department of General Practice, Faculty of Medicine and Health Technology, Tampere University, Arvo Ylpön katu 34, 33520 Tampere, Finland
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Chen R, Deng M, Rauf YM, Lin GZ, Qiu JW, Zhu SY, Xiao XM, Song YZ. Intrahepatic Cholestasis of Pregnancy as a Clinical Manifestation of Sodium-Taurocholate Cotransporting Polypeptide Deficiency. TOHOKU J EXP MED 2019; 248:57-61. [DOI: 10.1620/tjem.248.57] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Affiliation(s)
- Rong Chen
- Department of Pediatrics, The First Affiliated Hospital, Jinan University
| | - Mei Deng
- Department of Pediatrics, The First Affiliated Hospital, Jinan University
| | | | - Gui-Zhi Lin
- Department of Pediatrics, The First Affiliated Hospital, Jinan University
| | - Jian-Wu Qiu
- Department of Pediatrics, The First Affiliated Hospital, Jinan University
| | - Shun-Ye Zhu
- Department of Pediatrics, The Third Affiliated Hospital of Sun Yat-Sen University
| | - Xiao-Min Xiao
- Department of Gynecology and Obstetrics, The First Affiliated Hospital, Jinan University
| | - Yuan-Zong Song
- Department of Pediatrics, The First Affiliated Hospital, Jinan University
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Bicocca MJ, Sperling JD, Chauhan SP. Intrahepatic cholestasis of pregnancy: Review of six national and regional guidelines. Eur J Obstet Gynecol Reprod Biol 2018; 231:180-187. [DOI: 10.1016/j.ejogrb.2018.10.041] [Citation(s) in RCA: 95] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Revised: 10/11/2018] [Accepted: 10/22/2018] [Indexed: 12/27/2022]
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Wang HH, Portincasa P, Liu M, Tso P, Wang DQH. Similarities and differences between biliary sludge and microlithiasis: Their clinical and pathophysiological significances. LIVER RESEARCH 2018; 2:186-199. [PMID: 34367716 PMCID: PMC8341470 DOI: 10.1016/j.livres.2018.10.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The terms biliary sludge and cholesterol microlithiasis (hereafter referred to as microlithiasis) were originated from different diagnostic techniques and may represent different stages of cholesterol gallstone disease. Although the pathogenesis of biliary sludge and microlithiasis may be similar, microlithiasis could be preceded by biliary sludge, followed by persistent precipitation and aggregation of solid cholesterol crystals, and eventually, gallstone formation. Many clinical conditions are clearly associated with the formation of biliary sludge and microlithiasis, including total parenteral nutrition, rapid weight loss, pregnancy, organ transplantation, administration of certain medications, and a variety of acute and chronic illnesses. Numerous studies have demonstrated complete resolution of biliary sludge in approximately 40% of patients, a cyclic pattern of disappearing and reappearing in about 40%, and progression to gallstones in nearly 20%. Although only a minority of patients with ultrasonographic demonstration of biliary sludge develop gallstones, it is still a matter of controversy whether microlithiasis could eventually evolve to cholesterol gallstones. Biliary sludge and microlithiasis are asymptomatic in the vast majority of patients; however, they can cause biliary colic, acute cholecystitis, and acute pancreatitis. Biliary sludge and microlithiasis are most often diagnosed ultrasonographically and bile microscopy is considered the gold standard for their diagnosis. Specific measures to prevent the development of biliary sludge are not practical or cost-effective in the general population. Laparoscopic cholecystectomy offers the most definitive therapy on biliary sludge. Endoscopic sphincterotomy or surgical intervention is effective for microlithiasis-induced pancreatitis. Ursodeoxycholic acid can effectively prevent the recurrence of solid cholesterol crystals and significantly reduce the risk of recurrent pancreatitis.
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Affiliation(s)
- Helen H. Wang
- Department of Medicine, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Piero Portincasa
- Department of Biomedical Sciences and Human Oncology, Clinica Medica “A. Murri”, University of Bari “Aldo Moro” Medical School, Bari, Italy
| | - Min Liu
- Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Patrick Tso
- Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - David Q.-H. Wang
- Department of Medicine, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA,Corresponding author. Department of Medicine, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA., (D.Q.-H. Wang)
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Hämäläinen ST, Turunen K, Mattila KJ, Sumanen M. Intrahepatic cholestasis of pregnancy and associated causes of death: a cohort study with follow-up of 27-46 years. BMC Womens Health 2018; 18:98. [PMID: 29914448 PMCID: PMC6006795 DOI: 10.1186/s12905-018-0606-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Accepted: 06/08/2018] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND The aim of this study was to determine whether intrahepatic cholestasis of pregnancy (ICP) is associated with causes of death during on average 35 years follow-up after the delivery. METHODS The study population comprised 571 women with ICP in at least one pregnancy seen at Tampere University Hospital, Finland, between 1969 and 1988. ICP was verified from patient records. The previous and following subjects in the maternity ward diary were taken as controls for each ICP case. In total, there were 1333 controls. All underlying causes of death were obtained from Statistics Finland in March 2017. The deaths occurred during 1971-2015 and the causes of death were classified according to ICD-10. RESULTS Altogether, 39 of the mothers with ICP (6.8%) and 111 of the controls (8.3%) had died by the end of 2015 (p = 0.267). There were more underlying causes of death from gastrointestinal diseases (15%) in the ICP group than in the control group (4%) (p = 0.011). The number of underlying causes of death due to diseases of the circulatory system were lower in the ICP group (13%) than in the control group (26%), although the finding was not statistically significant (p = 0.088). Moreover, neoplasms were the underlying cause of death in 46% of cases among mothers with ICP and in 41% of cases among the controls (p = 0.609). Diseases of the other organ systems were rare in both groups. CONCLUSION Women with a history of ICP do not have an increased overall mortality. However, deaths from gastrointestinal diseases are overrepresented among women with a history of ICP.
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Affiliation(s)
- Suvi-Tuulia Hämäläinen
- Department of General Practice, Faculty of Medicine and Life Sciences, University of Tampere, 33100 Tampere, Finland
- Janakkala Health Centre, Tapailanpiha 13 B, 14200 Turenki, Finland
- Science Center, Tampere University Hospital, 33521 Tampere, Finland
| | - Kaisa Turunen
- Department of General Practice, Faculty of Medicine and Life Sciences, University of Tampere, 33100 Tampere, Finland
| | - Kari J. Mattila
- Department of General Practice, Faculty of Medicine and Life Sciences, University of Tampere, 33100 Tampere, Finland
| | - Markku Sumanen
- Department of General Practice, Faculty of Medicine and Life Sciences, University of Tampere, 33100 Tampere, Finland
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Schatz SB, Jüngst C, Keitel‐Anselmo V, Kubitz R, Becker C, Gerner P, Pfister E, Goldschmidt I, Junge N, Wenning D, Gehring S, Arens S, Bretschneider D, Grothues D, Engelmann G, Lammert F, Baumann U. Phenotypic spectrum and diagnostic pitfalls of ABCB4 deficiency depending on age of onset. Hepatol Commun 2018; 2:504-514. [PMID: 29761167 PMCID: PMC5944585 DOI: 10.1002/hep4.1149] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Revised: 11/09/2017] [Accepted: 11/27/2017] [Indexed: 12/27/2022] Open
Abstract
Genetic variants in the adenosine triphosphate-binding cassette subfamily B member 4 (ABCB4) gene, which encodes hepatocanalicular phosphatidylcholine floppase, can lead to different phenotypes, such as progressive familial intrahepatic cholestasis (PFIC) type 3, low phospholipid-associated cholelithiasis, and intrahepatic cholestasis of pregnancy. The aim of this multicenter project was to collect information on onset and progression of this entity in different age groups and to assess the relevance of this disease for the differential diagnosis of chronic liver disease. Clinical and laboratory data of 38 patients (17 males, 21 females, from 29 families) with homozygous or (compound) heterozygous ABCB4 mutations were retrospectively collected. For further analysis, patients were grouped according to the age at clinical diagnosis of ABCB4-associated liver disease into younger age (<18 years) or adult age (≥18 years). All 26 patients diagnosed in childhood presented with pruritus (median age 1 year). Hepatomegaly and splenomegaly were present in 85% and 96% of these patients, respectively, followed by jaundice (62%) and portal hypertension (69%). Initial symptoms preceded diagnosis by 1 year, and 13 patients received a liver transplant (median age 6.9 years). Of note, 9 patients were misdiagnosed as biliary atresia, Alagille syndrome, or PFIC type 1. In the 12 patients with diagnosis in adulthood, the clinical phenotype was generally less severe, including intrahepatic cholestasis of pregnancy, low phospholipid-associated cholelithiasis, or (non)cirrhotic PFIC3. Conclusion: ABCB4 deficiency with onset in younger patients caused a more severe PFIC type 3 phenotype with the need for liver transplantation in half the children. Patients with milder phenotypes are often not diagnosed before adulthood. One third of the children with PFIC type 3 were initially misdiagnosed, indicating the need for better diagnostic tools and medical education. (Hepatology Communications 2018;2:504-514).
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Affiliation(s)
- Stephanie Barbara Schatz
- Hannover Medical School, Division of Pediatric Gastroenterology and Hepatology, Department of Pediatric Kidney, Liver, and Metabolic DiseasesHannoverGermany
| | - Christoph Jüngst
- Department of Medicine IISaarland University Medical CenterHomburgGermany
| | - Verena Keitel‐Anselmo
- University Hospital, Heinrich Heine University Düsseldorf, Department of Gastroenterology, Hepatology and Infectious DiseasesDüsseldorfGermany
| | - Ralf Kubitz
- University Hospital, Heinrich Heine University Düsseldorf, Department of Gastroenterology, Hepatology and Infectious DiseasesDüsseldorfGermany
| | - Christina Becker
- Department of Medicine IISaarland University Medical CenterHomburgGermany
| | - Patrick Gerner
- Division of Pediatric Gastroenterology, Clinic for Pediatrics IIUniversity Hospital, University EssenEssenGermany
| | - Eva‐Doreen Pfister
- Hannover Medical School, Division of Pediatric Gastroenterology and Hepatology, Department of Pediatric Kidney, Liver, and Metabolic DiseasesHannoverGermany
| | - Imeke Goldschmidt
- Hannover Medical School, Division of Pediatric Gastroenterology and Hepatology, Department of Pediatric Kidney, Liver, and Metabolic DiseasesHannoverGermany
| | - Norman Junge
- Hannover Medical School, Division of Pediatric Gastroenterology and Hepatology, Department of Pediatric Kidney, Liver, and Metabolic DiseasesHannoverGermany
| | - Daniel Wenning
- Department of General PediatricsUniversity HospitalHeidelbergGermany
| | - Stephan Gehring
- Department of PediatricsUniversity Medical Center of the Johannes Gutenberg University MainzMainzGermany
| | - Stefan Arens
- Klinikum KasselPediatric GastroenterologyKasselGermany
| | | | - Dirk Grothues
- KUNO University Children's HospitalRegensburgGermany
| | | | - Frank Lammert
- Department of Medicine IISaarland University Medical CenterHomburgGermany
| | - Ulrich Baumann
- Hannover Medical School, Division of Pediatric Gastroenterology and Hepatology, Department of Pediatric Kidney, Liver, and Metabolic DiseasesHannoverGermany
- Institute of Immunology and ImmunotherapyUniversity of BirminghamBirminghamUnited Kingdom
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Quaglia A, Roberts EA, Torbenson M. Developmental and Inherited Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2018:111-274. [DOI: 10.1016/b978-0-7020-6697-9.00003-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Petrescu AD, Grant S, Frampton G, Kain J, Hadidi K, Williams E, McMillin M, DeMorrow S. Glucocorticoids Cause Gender-Dependent Reversal of Hepatic Fibrosis in the MDR2-Knockout Mouse Model. Int J Mol Sci 2017; 18:E2389. [PMID: 29125588 PMCID: PMC5713358 DOI: 10.3390/ijms18112389] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 11/06/2017] [Accepted: 11/06/2017] [Indexed: 12/12/2022] Open
Abstract
Hepatic cholestasis is associated with a significant suppression of the hypothalamus-pituitary-adrenal axis (HPA). In the present study, we tested the hypothesis that activation of the HPA axis by corticosterone treatment can reverse liver inflammation and fibrosis in a multidrug resistance protein 2 knockout (MDR2KO) transgenic mouse model of hepatic cholestasis. Friend Virus B NIH-Jackson (FVBN) control and MDR2KO male and female mice were treated with vehicle or corticosterone for two weeks, then serum and liver analyses of hepatic cholestasis markers were performed. Indicators of inflammation, such as increased numbers of macrophages, were determined. MDR2KO mice had lower corticotropin releasing hormone and corticosterone levels than FVBN controls in the serum. There was a large accumulation of CD68 and F4/80 macrophages in MDR2KO mice livers, which indicated greater inflammation compared to FVBNs, an effect reversed by corticosterone treatment. Intrahepatic biliary duct mass, collagen deposition and alpha smooth muscle actin (αSMA) were found to be much higher in livers of MDR2KO mice than in controls; corticosterone treatment significantly decreased these fibrosis markers. When looking at the gender-specific response to corticosterone treatment, male MDR2KO mice tended to have a more pronounced reversal of liver fibrosis than females treated with corticosterone.
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Affiliation(s)
- Anca D Petrescu
- Department of Medical Physiology, Texas A & M Health Science Center College of Medicine, Temple, TX 76504, USA.
| | - Stephanie Grant
- Department of Medical Physiology, Texas A & M Health Science Center College of Medicine, Temple, TX 76504, USA.
| | - Gabriel Frampton
- Department of Medical Physiology, Texas A & M Health Science Center College of Medicine, Temple, TX 76504, USA.
| | - Jessica Kain
- Department of Medical Physiology, Texas A & M Health Science Center College of Medicine, Temple, TX 76504, USA.
| | - Karam Hadidi
- Department of Medical Physiology, Texas A & M Health Science Center College of Medicine, Temple, TX 76504, USA.
| | - Elaina Williams
- Department of Medical Physiology, Texas A & M Health Science Center College of Medicine, Temple, TX 76504, USA.
| | - Matthew McMillin
- Central Texas Veterans Health Care System, Temple, TX 76504, USA.
| | - Sharon DeMorrow
- Department of Medical Physiology, Texas A & M Health Science Center College of Medicine, Temple, TX 76504, USA.
- Central Texas Veterans Health Care System, Temple, TX 76504, USA.
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43
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Cariello M, Piccinin E, Garcia-Irigoyen O, Sabbà C, Moschetta A. Nuclear receptor FXR, bile acids and liver damage: Introducing the progressive familial intrahepatic cholestasis with FXR mutations. Biochim Biophys Acta Mol Basis Dis 2017; 1864:1308-1318. [PMID: 28965883 DOI: 10.1016/j.bbadis.2017.09.019] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Revised: 09/15/2017] [Accepted: 09/17/2017] [Indexed: 02/07/2023]
Abstract
The nuclear receptor farnesoid X receptor (FXR) is the master regulator of bile acids (BAs) homeostasis since it transcriptionally drives modulation of BA synthesis, influx, efflux, and detoxification along the enterohepatic axis. Due to its crucial role, FXR alterations are involved in the progression of a plethora of BAs associated inflammatory disorders in the liver and in the gut. The involvement of the FXR pathway in cholestasis development and management has been elucidated so far with a direct role of FXR activating therapy in this condition. However, the recent identification of a new type of genetic progressive familial intrahepatic cholestasis (PFIC) linked to FXR mutations has strengthen also the bona fide beneficial effects of target therapies that by-pass FXR activation, directly promoting the action of its target, namely the enterokine FGF19, in the repression of hepatic BAs synthesis with reduction of total BA levels in the liver and serum, accomplishing one of the major goals in cholestasis. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni and Peter Jansen.
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Affiliation(s)
- Marica Cariello
- Department of Interdisciplinary Medicine, "Aldo Moro" University of Bari, 70124 Bari, Italy
| | - Elena Piccinin
- INBB, National Institute for Biostructures and Biosystems, 00136 Rome, Italy
| | - Oihane Garcia-Irigoyen
- Department of Interdisciplinary Medicine, "Aldo Moro" University of Bari, 70124 Bari, Italy
| | - Carlo Sabbà
- Department of Interdisciplinary Medicine, "Aldo Moro" University of Bari, 70124 Bari, Italy
| | - Antonio Moschetta
- Department of Interdisciplinary Medicine, "Aldo Moro" University of Bari, 70124 Bari, Italy; National Cancer Center, IRCCS Istituto Oncologico "Giovanni Paolo II", 70124 Bari, Italy.
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An expanded role for heterozygous mutations of ABCB4, ABCB11, ATP8B1, ABCC2 and TJP2 in intrahepatic cholestasis of pregnancy. Sci Rep 2017; 7:11823. [PMID: 28924228 PMCID: PMC5603585 DOI: 10.1038/s41598-017-11626-x] [Citation(s) in RCA: 89] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Accepted: 08/24/2017] [Indexed: 12/12/2022] Open
Abstract
Intrahepatic cholestasis of pregnancy (ICP) affects 1/140 UK pregnancies; with pruritus, hepatic impairment and elevated serum bile acids. Severe disease is complicated by spontaneous preterm delivery and stillbirth. Previous studies have reported mutations in hepatocellular transporters (ABCB4, ABCB11). High throughput sequencing in 147 patients was performed in the transporters ABCB4, ABCB11, ATP8B1, ABCC2 and tight junction protein 2 (TJP2). Twenty-six potentially damaging variants were identified with the following predicted protein changes: Twelve ABCB4 mutations - Arg47Gln, Met113Val, Glu161Gly, Thr175Ala, Glu528Glyfs*6, Arg590Gln, Ala601Ser, Glu884Ter, Gly722Ala, Tyr775Met (x2), Trp854Ter. Four potential ABCB11 mutations - Glu297Gly (x3) and a donor splice site mutation (intron 19). Five potential ATP8B1 mutations - Asn45Thr (x3), and two others, Glu114Gln and Lys203Glu. Two ABCC2 mutations - Glu1352Ala and a duplication (exons 24 and 25). Three potential mutations were identified in TJP2; Thr62Met (x2) and Thr626Ser. No patient harboured more than one mutation. All were heterozygous. An additional 545 cases were screened for the potential recurrent mutations of ATP8B1 (Asn45Thr) and TJP2 (Thr62Met) identifying three further occurrences of Asn45Thr. This study has expanded known mutations in ABCB4 and ABCB11 and identified roles in ICP for mutations in ATP8B1 and ABCC2. Possible novel mutations in TJP2 were also discovered.
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45
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Walker N, Filis P, Soffientini U, Bellingham M, O’Shaughnessy PJ, Fowler PA. Placental transporter localization and expression in the Human: the importance of species, sex, and gestational age differences†. Biol Reprod 2017; 96:733-742. [PMID: 28339967 PMCID: PMC5441296 DOI: 10.1093/biolre/iox012] [Citation(s) in RCA: 89] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Revised: 02/22/2017] [Accepted: 03/03/2017] [Indexed: 12/11/2022] Open
Abstract
The placenta is a critical organ during pregnancy, essential for the provision of an optimal intrauterine environment, with fetal survival, growth, and development relying on correct placental function. It must allow nutritional compounds and relevant hormones to pass into the fetal bloodstream and metabolic waste products to be cleared. It also acts as a semipermeable barrier to potentially harmful chemicals, both endogenous and exogenous. Transporter proteins allow for bidirectional transport and are found in the syncytiotrophoblast of the placenta and endothelium of fetal capillaries. The major transporter families in the human placenta are ATP-binding cassette (ABC) and solute carrier (SLC), and insufficiency of these transporters may lead to deleterious effects on the fetus. Transporter expression levels are gestation-dependent and this is of considerable clinical interest as levels of drug resistance may be altered from one trimester to the next. This highlights the importance of these transporters in mediating correct and timely transplacental passage of essential compounds but also for efflux of potentially toxic drugs and xenobiotics. We review the current literature on placental molecular transporters with respect to their localization and ontogeny, the influence of fetal sex, and the relevance of animal models. We conclude that a paucity of information exists, and further studies are required to unlock the enigma of this dynamic organ.
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Affiliation(s)
- Natasha Walker
- Institute of Medical Sciences, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK
| | - Panagiotis Filis
- Institute of Medical Sciences, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK
| | - Ugo Soffientini
- Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Michelle Bellingham
- Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Peter J O’Shaughnessy
- Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Paul A Fowler
- Institute of Medical Sciences, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK
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Manzotti C, Casazza G, Stimac T, Nikolova D, Gluud C. Total serum bile acids or serum bile acid profile, or both, for the diagnosis of intrahepatic cholestasis of pregnancy. THE COCHRANE DATABASE OF SYSTEMATIC REVIEWS 2017. [DOI: 10.1002/14651858.cd012546] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Cristina Manzotti
- Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Università degli Studi di Milano; Obstetrics and Gynecology Department; Via Commenda 12 - Clinica Mangiagalli, piano terra Milan Milan Italy 20122
- Department 7812, Rigshospitalet, Copenhagen University Hospital; The Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research; Copenhagen Denmark
- Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Università degli Studi di Milano; Gastro-Intestinal Unit; Via Commenda 12 - Clinica Mangiagalli, 1° piano, scala A Milan Milan Italy 20122
| | - Giovanni Casazza
- Università degli Studi di Milano; Dipartimento di Scienze Biomediche e Cliniche "L. Sacco"; via GB Grassi 74 Milan Italy 20157
| | - Tea Stimac
- Clinical Hospital Centre Rijeka; Obstetrics and Gynecology; Cambierieva 17 Rijeka Croatia 51000
| | - Dimitrinka Nikolova
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital; The Cochrane Hepato-Biliary Group; Blegdamsvej 9 Copenhagen Denmark DK-2100
| | - Christian Gluud
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital; The Cochrane Hepato-Biliary Group; Blegdamsvej 9 Copenhagen Denmark DK-2100
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47
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Jansen PLM, Ghallab A, Vartak N, Reif R, Schaap FG, Hampe J, Hengstler JG. The ascending pathophysiology of cholestatic liver disease. Hepatology 2017; 65:722-738. [PMID: 27981592 DOI: 10.1002/hep.28965] [Citation(s) in RCA: 218] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Revised: 10/26/2016] [Accepted: 11/17/2016] [Indexed: 02/06/2023]
Abstract
In this review we develop the argument that cholestatic liver diseases, particularly primary biliary cholangitis and primary sclerosing cholangitis (PSC), evolve over time with anatomically an ascending course of the disease process. The first and early lesions are in "downstream" bile ducts. This eventually leads to cholestasis, and this causes bile salt (BS)-mediated toxic injury of the "upstream" liver parenchyma. BS are toxic in high concentration. These concentrations are present in the canalicular network, bile ducts, and gallbladder. Leakage of bile from this network and ducts could be an important driver of toxicity. The liver has a great capacity to adapt to cholestasis, and this may contribute to a variable symptom-poor interval that is often observed. Current trials with drugs that target BS toxicity are effective in only about 50%-60% of primary biliary cholangitis patients, with no effective therapy in PSC. This motivated us to develop and propose a new view on the pathophysiology of primary biliary cholangitis and PSC in the hope that these new drugs can be used more effectively. These views may lead to better stratification of these diseases and to recommendations on a more "tailored" use of the new therapeutic agents that are currently tested in clinical trials. Apical sodium-dependent BS transporter inhibitors that reduce intestinal BS absorption lower the BS load and are best used in cholestatic patients. The effectiveness of BS synthesis-suppressing drugs, such as farnesoid X receptor agonists, is greatest when optimal adaptation is not yet established. By the time cytochrome P450 7A1 expression is reduced these drugs may be less effective. Anti-inflammatory agents are probably most effective in early disease, while drugs that antagonize BS toxicity, such as ursodeoxycholic acid and nor-ursodeoxycholic acid, may be effective at all disease stages. Endoscopic stenting in PSC should be reserved for situations of intercurrent cholestasis and cholangitis, not for cholestasis in end-stage disease. These are arguments to consider a step-wise pathophysiology for these diseases, with therapy adjusted to disease stage. An obstacle in such an approach is that disease stage-defining biomarkers are still lacking. This review is meant to serve as a call to prioritize the development of biomarkers that help to obtain a better stratification of these diseases. (Hepatology 2017;65:722-738).
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Affiliation(s)
- Peter L M Jansen
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.,Department of Surgery, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands.,Research Network of Liver Systems Medicine, Freiburg, Germany
| | - Ahmed Ghallab
- Research Network of Liver Systems Medicine, Freiburg, Germany.,Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany.,Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt
| | - Nachiket Vartak
- Research Network of Liver Systems Medicine, Freiburg, Germany.,Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany
| | - Raymond Reif
- Research Network of Liver Systems Medicine, Freiburg, Germany.,Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany
| | - Frank G Schaap
- Department of Surgery, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Jochen Hampe
- Research Network of Liver Systems Medicine, Freiburg, Germany.,Department of Medicine 1, Technical University Dresden, Dresden, Germany
| | - Jan G Hengstler
- Research Network of Liver Systems Medicine, Freiburg, Germany.,Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany
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48
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Gunaydin B, Tuna AT. Anesthetic considerations for liver diseases unique to pregnancy. World J Anesthesiol 2016; 5:54-61. [DOI: 10.5313/wja.v5.i3.54] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2016] [Revised: 07/01/2016] [Accepted: 08/01/2016] [Indexed: 02/06/2023] Open
Abstract
Liver diseases that are most unique to pregnancy consist of hyperemesis gravidarum, acute fatty liver of pregnancy, intrahepatic cholestasis of pregnancy, and hemolysis, elevated liver enzymes and low platelets syndrome. In this review, risk factors, etiology, symptoms, diagnosis, prognosis and treatment of each entity followed by principles of anesthetic management based on the case reports or retrospective records will be addressed.
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49
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Song Z, Shi Q. The Interaction of PPARα and CYP7B1 with ERα, β Impacted the Occurrence and Development of Intrahepatic Cholestasis in Pregnant Rats. Reprod Sci 2016; 24:627-634. [PMID: 27628953 DOI: 10.1177/1933719116667223] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Intrahepatic cholestasis of pregnancy (ICP) is a disorder of bile acid (BA) synthesis, excretion, and metabolism, with systemic accumulation of BAs, which can lead to prematurity, fetal distress, and intrauterine death. Here, we investigate the expression of peroxisome proliferator-activated receptor alpha and cytochrome P450 oxysterol 7alpha-hydroxylase by exposing to 17α-ethynylestradiol with or without the estrogen receptor signaling pathway in pregnant rats with intrahepatic cholestasis. In vivo and in vitro evidences showed that estrogen receptor alpha (ERα) may be the key point of occurrence and development of intrahepatic cholestasis in pregnant rats. Besides, the abnormalities in genes could be reversed by ERα small interfering RNA. Our findings provide the ERα-centered hypothesis on the mechanisms of ICP. New perspectives are emerging for the treatment of estrogen-induced hepatic complication.
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Affiliation(s)
- Zhaoyi Song
- 1 Department of Obstetrics and Gynecology, Ninth School of Clinical Medicine, Peking University, Beijing, China
| | - Qingyun Shi
- 2 Department of Obstetrics and Gynecology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
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50
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Germain AM, Carvajal JA, Glasinovic JC, C. SK, Williamson C. Intrahepatic Cholestasis of Pregnancy: An Intriguing Pregnancy-Specific Disorder. ACTA ACUST UNITED AC 2016. [DOI: 10.1177/107155760200900103] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Affiliation(s)
- Alfredo M. Germain
- Laboratory of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Pontificia Universidad Católica de Chile, School of Medicine, and Department of Gastroenterology, Pontificia Universidad Católica de Chile, School of Medicine, Santiago, Chile; ICSM Maternal and Fetal Disease Group, MRC Clinical Sciences Center, Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom
| | | | | | | | - Catherine Williamson
- Laboratory of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Pontificia Universidad Católica de Chile, School of Medicine, and Department of Gastroenterology, Pontificia Universidad Católica de Chile, School of Medicine, Santiago, Chile; ICSM Maternal and Fetal Disease Group, MRC Clinical Sciences Center, Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom
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