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Roy A, Premkumar M, Mishra S, Mehtani R, Suri V, Aggarwal N, Singh S, Dhiman RK. Role of ursodeoxycholic acid on maternal serum bile acids and perinatal outcomes in intrahepatic cholestasis of pregnancy. Eur J Gastroenterol Hepatol 2021; 33:571-576. [PMID: 33136720 DOI: 10.1097/meg.0000000000001954] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
AIM Intrahepatic cholestasis of pregnancy (ICP) is associated with safe maternal outcomes but perinatal outcomes have been variable. We assessed clinical factors and impact of bile acid levels on maternal and neonatal outcomes in ICP. METHODS Patients with ICP (defined as pruritus with serum bile acids ≥ 10 mmol/l) were included prospectively with an assessment of risk factors, modes of delivery as well as maternal and neonatal outcomes. Mild and severe ICP were diagnosed when serum bile acid was always <40 mmol/l and ≥40 mmol/l, respectively. Patients with gestational pruritus served as controls. RESULTS Out of 643 patients, 375 patients (mean age 29 ± 7.6 years, 45.8% primigravida) met inclusion criteria. Pregnancy-induced hypertension [PIH: 10.5%; odds ratio (OR): 4.8; 95% confidence interval (CI): 2.4-8.5; P = 0.0014], gestational diabetes (GDM: 12.5%; OR: 2.6; 95% CI: 2.3-4.1; P = 0.045) and spontaneous preterm labor (15.1%; OR: 2.5; 95% CI: 1.2-3.5; P = 0.040) were higher in patients with ICP. Ursodeoxycholic acid (UDCA) (median dose 900 mg; 600-1800 mg) ameliorated symptoms of cholestasis, bile acid levels and liver aminotransferases in 79% cases. When compared with patients with mild ICP, patients with severe ICP presented at a lower gestational period (26 vs. 32 weeks, P = 0.036), required frequent induction (12.5%; OR: 3.2; 95% CI: 2.1-5.6; P = 0.045) and had increased fetal distress (15%; OR: 1.9; 95% CI: 1.3-4.9; P = 0.048).Overall eight stillbirths were recorded. CONCLUSION Severe ICP is associated with a higher incidence of GDM and PIH, risk of pre-term labor, elective induction and stillbirths. UDCA remains a first-line agent in treating ICP.
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Affiliation(s)
| | | | | | | | - Vanita Suri
- Obstetrics and Gynaecology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Neelam Aggarwal
- Obstetrics and Gynaecology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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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: 40] [Impact Index Per Article: 10.0] [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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Liu R, Yu X, Wallqvist A. Using Chemical-Induced Gene Expression in Cultured Human Cells to Predict Chemical Toxicity. Chem Res Toxicol 2016; 29:1883-1893. [PMID: 27768846 DOI: 10.1021/acs.chemrestox.6b00287] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Chemical toxicity is conventionally evaluated in animal models. However, animal models are resource intensive; moreover, they face ethical and scientific challenges because the outcomes obtained by animal testing may not correlate with human responses. To develop an alternative method for assessing chemical toxicity, we investigated the feasibility of using chemical-induced genome-wide expression changes in cultured human cells to predict the potential of a chemical to cause specific organ injuries in humans. We first created signatures of chemical-induced gene expression in a vertebral-cancer of the prostate cell line for ∼15,000 chemicals tested in the US National Institutes of Health Library of Integrated Network-Based Cellular Signatures program. We then used the signatures to create naı̈ve Bayesian prediction models for chemical-induced human liver cholestasis, interstitial nephritis, and long QT syndrome. Detailed cross-validation analyses indicated that the models were robust with respect to false positives and false negatives in the samples we used to train the models and could predict the likelihood that chemicals would cause specific organ injuries. In addition, we performed a literature search for drugs and dietary supplements, not formally categorized as causing organ injuries in humans but predicted by our models to be most likely to do so. We found a high percentage of these compounds associated with case reports of relevant organ injuries, lending support to the idea that in vitro cell-based experiments can be used to predict the toxic potential of chemicals. We believe that this approach, combined with a robust technique to model human exposure to chemicals, may serve as a promising alternative to animal-based chemical toxicity assessment.
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Affiliation(s)
- Ruifeng Liu
- Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, US Army Medical Research and Materiel Command , Fort Detrick, Maryland 21702, United States
| | - Xueping Yu
- Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, US Army Medical Research and Materiel Command , Fort Detrick, Maryland 21702, United States
| | - Anders Wallqvist
- Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, US Army Medical Research and Materiel Command , Fort Detrick, Maryland 21702, United States
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4
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White H, Peters M. Severe Liver Disease in Pregnancy. J Intensive Care Med 2016. [DOI: 10.1177/088506669000500303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Liver disease is uncommon in pregnant women. It can be divided into disorders that occur only during preg nancy and those that can occur during pregnancy, but are not related directly to pregnancy. Jaundice during pregnancy is relatively rare, occurring in 1 in 1,500 pregnancies [ 1 ]. In this review we briefly discuss normal changes in hepatic physiology during pregnancy and then outline the liver disorders of pregnancy, emphasiz ing those that can be severe and result in admission to intensive care units.
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Affiliation(s)
- Heather White
- Gastroenterology Division, Washington University School of Medicine, St. Louis, MO
| | - Marion Peters
- Gastroenterology Division, Washington University School of Medicine, St. Louis, MO
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5
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Immunology of hepatic diseases during pregnancy. Semin Immunopathol 2016; 38:669-685. [PMID: 27324237 DOI: 10.1007/s00281-016-0573-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2016] [Accepted: 05/18/2016] [Indexed: 02/06/2023]
Abstract
The mother's immune system has to adapt to pregnancy accepting the semi-allograft fetus and preventing harmful effects to the developing child. Aberrations in feto-maternal immune adaptation may result in disease of the mother, such as liver injury. Five pregnancy-associated liver disorders have been described so far, however, little is known concerning immune alterations promoting the respective disease. These liver disorders are pre-eclampsia, hemolysis, elevated liver enzymes, low platelet count (HELLP), acute fatty liver, hyperemesis gravidarum, and intrahepatic cholestasis of pregnancy. On the other hand, pre-existing autoimmune liver injury of the mother can be affected by pregnancy. This review intends to summarize current knowledge linking feto-maternal immunology and liver inflammation with a special emphasis on novel potential biomarkers.
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6
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Seike M. Endocrine Disease and Liver. THE LIVER IN SYSTEMIC DISEASES 2016:251-270. [DOI: 10.1007/978-4-431-55790-6_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Ahmed KT, Almashhrawi AA, Rahman RN, Hammoud GM, Ibdah JA. Liver diseases in pregnancy: Diseases unique to pregnancy. World J Gastroenterol 2013; 19:7639-7646. [PMID: 24282353 PMCID: PMC3837262 DOI: 10.3748/wjg.v19.i43.7639] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2013] [Revised: 08/05/2013] [Accepted: 09/05/2013] [Indexed: 02/06/2023] Open
Abstract
Pregnancy is a special clinical state with several normal physiological changes that influence body organs including the liver. Liver disease can cause significant morbidity and mortality in both pregnant women and their infants. This review summarizes liver diseases that are unique to pregnancy. We discuss clinical conditions that are seen only in pregnant women and involve the liver; from Hyperemesis Gravidarum that happens in 1 out of 200 pregnancies and Intrahepatic Cholestasis of Pregnancy (0.5%-1.5% prevalence), to the more frequent condition of preeclampsia (10% prevalence) and its severe form; hemolysis, elevated liver enzymes, and a low platelet count syndrome (12% of pregnancies with preeclampsia), to the rare entity of Acute Fatty Liver of Pregnancy (incidence of 1 per 7270 to 13000 deliveries). Although pathogeneses behind the development of these aliments are not fully understood, theories have been proposed. Some propose the special physiological changes that accompany pregnancy as a precipitant. Others suggest a constellation of factors including both the mother and her fetus that come together to trigger those unique conditions. Reaching a timely and accurate diagnosis of such conditions can be challenging. The timing of the condition in relation toward which trimester it starts at is a key. Accurate diagnosis can be made using specific clinical findings and blood tests. Some entities have well-defined criteria that help not only in making the diagnosis, but also in classifying the disease according to its severity. Management of these conditions range from simple medical remedies to measures such as immediate termination of the pregnancy. In specific conditions, it is prudent to have expert obstetric and medical specialists teaming up to help improve the outcomes.
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Ghosh S, Chaudhuri S. Intra-hepatic Cholestasis of Pregnancy: A Comprehensive Review. Indian J Dermatol 2013; 58:327. [PMID: 23919027 PMCID: PMC3726904 DOI: 10.4103/0019-5154.113971] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Intra-hepatic cholestasis of pregnancy is a cholestatic disorder characterized by i) pruritus, with onset in the third trimester of pregnancy, without any primary skin lesions, ii) elevated fasting serum bile acids > 10 μmol/L (and elevated serum transaminases), iii) spontaneous relief of signs and symptoms within two to three weeks after delivery, and iv) absence of other disease that cause pruritus and jaundice. It is believed to be a multi-factorial disease with interplay between genetic, environmental and hormonal factors. Incidence is between 0.02% to 2.4% of all pregnancies; with wide geographical variations. Maternal prognosis is usually good but can result in adverse fetal outcomes like meconium staining of amniotic fluid, fetal bradycardia and even fetal loss. Response to anti-histaminic is poor. Of all the medical therapies that have been described for the treatment for IHCP, ursodeoxycholic acid has the best response in relieving pruritus in mother, and probably has a role in preventing even the perinatal complications. Timely diagnosis and treatment is urged in order to prevent fetal complications and an early delivery between 37 to 38 weeks should be contemplated in severe cases, especially once fetal lung maturity is attained.
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Affiliation(s)
- Sangita Ghosh
- Department of Skin and VD, PGIMS, Rohtak, Haryana, India
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9
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Liver abnormalities and endocrine diseases. Best Pract Res Clin Gastroenterol 2013; 27:553-63. [PMID: 24090942 DOI: 10.1016/j.bpg.2013.06.014] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2013] [Accepted: 06/12/2013] [Indexed: 01/31/2023]
Abstract
The liver and its pleotropic functions play a fundamental role in regulating metabolism, and is also an inevitable target of multiple metabolic disorders. The numerous and constant relationships and feedback mechanisms between the liver and all endocrine organs is reflected by the fact that an alteration of one oftentimes results in the malfunction of the other. Hypo- and hyperthyroidism are frequently associated with hepatic alterations, and thyroid diseases must be excluded in transaminase elevation of unknown cause. Drugs such as propylthiouracil, used in the treatment of hyperthyroidism, may induce liver damage, and other drugs such as amiodarone, carbamazepine, and several chemotherapeutic agents can lead to both thyroid and liver abnormalities. Liver diseases such as hepatitis, hepatocellular carcinoma, and cirrhosis may cause altered levels of thyroid hormones, and alcoholic liver disease, both due to the noxious substance ethanol as well as to the hepatic damage it causes, may be responsible for altered thyroid function. Both excess and insufficiency of adrenal function may result in altered liver function, and adrenocortical dysfunction may be present in patients with cirrhosis, especially during episodes of decompensation. Again an important player which affects both the endocrine system and the liver, alcohol may be associated with pseudo-Cushing syndrome. Sex hormones, both intrinsic as well as extrinsically administered, have an important impact on liver function. While oestrogens are related to cholestatic liver damage, androgens are the culprit of adenomas and hepatocellular carcinoma, among others. Chronic liver disease, on the other hand, has profound repercussions on sex hormone metabolism, inducing feminization in men and infertility and amenorrhoea in women. Lastly, metabolic syndrome, the pandemia of the present and future centuries, links the spectrum of liver damage ranging from steatosis to cirrhosis, to the array of endocrine alterations that are features of the syndrome, including insulin resistance, central obesity, and hyperlipidaemia. Clinical practice must integrally evaluate the effects of the intricate and tight relationship between the liver and the endocrine system, in order to better address all manifestations, complications, and prevent deterioration of one or the other organ-system.
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Catalino F, Scarponi S, Cesa F, Loiacono G, Bortolini M. Efficacy and Safety of Intravenous S-Adenosyl-L-Methionine Therapy in the Management of Intrahepatic Cholestasis of Pregnancy. ACTA ACUST UNITED AC 2012. [DOI: 10.1007/bf03258367] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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Bonfirraro G, Chieffi O, Quinti R, Tedesco R, Grazie C, Bortolini M. S-Adenosyl-L-Methionine (SAMe)-Induced Amelioration of Intrahepatic Cholestasis of Pregnancy. ACTA ACUST UNITED AC 2012. [DOI: 10.1007/bf03258251] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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12
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Stieger B, Geier A. Genetic variations of bile salt transporters as predisposing factors for drug-induced cholestasis, intrahepatic cholestasis of pregnancy and therapeutic response of viral hepatitis. Expert Opin Drug Metab Toxicol 2011; 7:411-25. [PMID: 21320040 DOI: 10.1517/17425255.2011.557067] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Drug-induced cholestasis, intrahepatic cholestasis of pregnancy and viral hepatitis are acquired forms of liver disease. Cholestasis is a pathophysiologic state with impaired bile formation and subsequent accumulation of bile salts in hepatocytes. The bile salt export pump (BSEP) (ABCB11) is the key export system for bile salts from hepatocytes. AREAS COVERED This article provides an introduction into the physiology of bile formation followed by a summary of the current knowledge on the key bile salt transporters, namely, the sodium-taurocholate co-transporting polypeptide NTCP, the organic anion transporting polypeptides (OATPs), BSEP and the multi-drug resistance protein 3. The pathophysiologic consequences of altered functions of these transporters, with an emphasis on molecular and genetic aspects, are then discussed. EXPERT OPINION Knowledge of the role of hepatocellullar transporters, especially BSEP, in acquired cholestasis is continuously increasing. A common variant of BSEP (p.V444A) is now a well-established susceptibility factor for acquired cholestasis and recent evidence suggests that the same variant also influences the therapeutic response and disease progression of viral hepatitis C. Studies in large independent cohorts are now needed to confirm the relevance of p.V444A. Genome-wide association studies should lead to the identification of additional genetic factors underlying cholestatic liver disease.
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Affiliation(s)
- Bruno Stieger
- University Hospital Zurich, Division of Clinical Pharmacology and Toxicology, 8091 Zurich, Switzerland.
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Abstract
Liver disease and endocrine disorders, both common in the general population, have a bidirectional and complex relationship. Certain liver diseases are more commonly associated with endocrine disorders, including nonalcoholic fatty liver disease, autoimmune hepatitis, and primary biliary cirrhosis. There may be an association between hepatitis C and type 2 diabetes mellitus as well as thyroid disorders, and sex hormonal preparations may cause specific hepatic lesions. The presence of relative adrenal insufficiency in patients with end-stage liver disease may have therapeutic implications in patients admitted with acute-on-chronic liver failure. The objective of this review is to focus on the effect of endocrine disorders on liver.
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Affiliation(s)
- Anurag Maheshwari
- Institute for Digestive Health & Liver Diseases, Mercy Medical Center, 301 Saint Paul Place, Physician Office Building 718, Baltimore, MD 21202, USA
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Hussein MA, Abdel-Gawad SM. Protective effect of Jasonia montana against ethinylestradiol-induced cholestasis in rats. Saudi Pharm J 2010; 18:27-33. [PMID: 23960717 PMCID: PMC3731018 DOI: 10.1016/j.jsps.2009.12.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2009] [Accepted: 11/11/2009] [Indexed: 11/22/2022] Open
Abstract
Estrogens, and particularly glucuronides such as ethinylestradiol (EE), have been shown to cause cholestasis in animal studies, by reducing bile acid uptake by hepatocytes. The aim of the present article is to investigate anticholestatic activity of the ethanolic extract of the aerial parts of Jasonia montana against liver cholestasis induced by EE in adult female rats in an attempt to understand its mechanism of action, which may pave the way for possible therapeutic applications. Subcutaneous administration of 100 μg/kg b.w. ethinylestradiol to rats induced hepatocellular cholestasis with a significant decrease in serum cholesterol, bile acids and bilirubin levels as well as in hepatic superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR) activities and hepatic total, protein-bound and non-protein sulfhydryl groups. Also, treatment with EE produced significant increase in serum Pi-glutathione-s-transferase (Pi-GST), gamma glutamyl transpeptidase (γ-GT) and alpha-glutathione-s-transferase (α-GST) activities as well as serum nitric oxide (NO) and tumor necrosis factor alpha (TNF-α) level and hepatic malondialdehyde (MDA) level as compare to control group. Oral administration of the aerial parts of ethanolic extract at a concentration of 150 mg/kg b.w. daily to rats treated with EE for 15 days showed a significant protection against-induced decrease in serum cholesterol, bile acids and bilirubin levels. The treatment also resulted in a significant increase in hepatic SOD, GPx and GR activities as well as hepatic total, protein-bound and non-protein sulfhydryl groups. In addition, the extract could inhibit serum Pi-GST, γ-GT and α-GST activities as well as reduce serum TNF-α, NO and hepatic MDA as compare to ethinylestradiol treated rats. High content of flavonoids and phenolic compounds was found in ethanolic extract, which may be responsible for free radical activity. The results clearly suggest that the aerial parts of J. montana extract may effectively normalize the impaired antioxidant status in ethinylestradiol (EE)-cholestatic model. Thus the extract may have a therapeutic value in drug-induced biliary cholestasis as well as in hormonal therapy.
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Affiliation(s)
- Mohammed A. Hussein
- Department of Biochemistry, Faculty of Pharmacy, October 6th University, Cairo, Egypt
| | - Soad M. Abdel-Gawad
- Department of Chemistry, Faculty of Science (Girl’s), Al-Azhar University, Cairo, Egypt
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Lahita RG, Schaefer RA, Bradlow HL, Kreek MJ. Clues to understanding the oxidation of estradiol in humans: effects of acute infectious hepatitis, autoimmune hepatitis, and chronic liver disease. Ann N Y Acad Sci 2009; 1155:242-51. [PMID: 19250211 PMCID: PMC3057168 DOI: 10.1111/j.1749-6632.2009.04359.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
Determination of 2- and 16alpha-hydroxylation of estradiol in patients with a variety of liver disorders using a dynamic method of quantitating the extent of hydroxylation revealed specific and characteristic differences in the metabolic response. Patients with acute or silent variants of hepatitis B had estrogen metabolite patterns that were indistinguishable from those found in the control subjects. Female patients with autoimmune hepatitis (formerly known as lupoid hepatitis), however, showed a moderate significant decrease (P < 0.01) in 2-hydroxylation as compared with normal controls (mean 16.3 +/- 1.9 vs. 33.9 +/- 2.5), with no significant change in 16alpha-hydroxylation. Male and female subjects with chronic alcoholic cirrhosis were almost devoid of 2-hydroxylation (mean 2.9 +/- 0.5, P < 0.01), but did show a significant increase in 16alpha-hydroxylation (P < 0.01). The results, therefore, show that the alterations in patterns of biological oxidation are highly specific and do not reflect a general inability to metabolize estrogens in the cirrhotic patient. However, the results also suggest the possibility that a substantial fraction of 16alpha-hydroxylation may occur elsewhere in the body at sites other than in the liver, explaining why this biotransformation pathway is elevated, while the reaction at C-2 is almost absent in the alcoholic cirrhotic subjects.
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Kondrackiene J, Kupcinskas L. Intrahepatic cholestasis of pregnancy-current achievements and unsolved problems. World J Gastroenterol 2008; 14:5781-8. [PMID: 18855975 PMCID: PMC2751886 DOI: 10.3748/wjg.14.5781] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Intrahepatic cholestasis of pregnancy (ICP) is the most common pregnancy-related liver disorder. Maternal effects of ICP are mild; however, there is a clear association between ICP and higher frequency of fetal distress, preterm delivery, and sudden intrauterine fetal death. The cause of ICP remains elusive, but there is evidence that mutations in genes encoding hepatobiliary transport proteins can predispose for the development of ICP. Recent data suggest that ursodeoxycholic acid is currently the most effective pharmacologic treatment, whereas obstetric management is still debated. Clinical trials are required to identify the most suitable monitoring modalities that can specifically predict poor perinatal outcome. This article aims to review current achievements and unsolved problems of ICP.
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Wong LFA, Shallow H, O'Connell MP. Comparative study on the outcome of obstetric cholestasis. J Matern Fetal Neonatal Med 2008; 21:327-30. [PMID: 18446660 DOI: 10.1080/14767050802034446] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
OBJECTIVES The aim of this study was to determine the characteristics and outcomes of obstetric cholestasis (OC) and the significance of measuring total bile acid (TBA) to aid diagnosis. METHODS This study was conducted over a 27-month period at a tertiary referral maternity hospital (>8000 deliveries annually). In the study period, 753 women presented with pruritus of no specific origin. This group was divided into OC (TBA > or =6 micromol/L, N=151) and idiopathic pruritus of pregnancy (TBA <6 micromol/L, N=602). The latter group served as controls. Data were collected retrospectively and analyzed using SPSS 11.4 for Windows (SPSS Inc., Chicago, IL, USA). RESULTS Patients were matched for age, ethnicity, parity, and smoking status, sex of baby, and Apgar scores at 1 and 5 minutes. OC was noted to be higher in twin pregnancies. Twice as many mothers in the OC group were induced compared to controls. Of the OC group, 18.0% delivered preterm versus 7.7% of controls. Of the mothers with OC, 48.3% had a TBA in the range of 11-39.9 micromol/L, 21.2% had a TBA >40 micromol/L, and the remaining 30.5% had a TBA between 6 and 10.9 micromol/L. Of the OC group with preterm delivery, all had a raised TBA >11 micromol/L. CONCLUSIONS The presence of OC increases preterm delivery, both idiopathic and iatrogenic. Increasing induction, admission to the neonatal intensive care unit, and low birth weight were also noted. A TBA cut-off value of >11 micromol/L will more accurately aid the diagnosis of OC in the absence of raised liver function test results, reducing the over-diagnosis of this condition.
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Affiliation(s)
- L F A Wong
- Department of Obstetrics and Gynaecology, Coombe Women's Hospital, Dolphin's Barn, Dublin 8, Republic of Ireland.
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Van Mil SWC, Milona A, Dixon PH, Mullenbach R, Geenes VL, Chambers J, Shevchuk V, Moore GE, Lammert F, Glantz AG, Mattsson LA, Whittaker J, Parker MG, White R, Williamson C. Functional variants of the central bile acid sensor FXR identified in intrahepatic cholestasis of pregnancy. Gastroenterology 2007; 133:507-16. [PMID: 17681172 DOI: 10.1053/j.gastro.2007.05.015] [Citation(s) in RCA: 178] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2006] [Accepted: 05/03/2007] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Intrahepatic cholestasis of pregnancy (ICP) is characterized by liver impairment, pruritus, and elevated maternal serum bile acids. It can cause premature delivery and intrauterine death. Bile acid synthesis, metabolism, and transport are regulated by the bile acid sensor FXR, and we hypothesized that genetic variation in FXR confers susceptibility to ICP. METHODS The coding regions and intron/exon boundaries of FXR were sequenced in 92 British ICP cases of mixed ethnicity. Subsequently, a case-control study of allele frequencies of these variants in 2 independent cohorts of Caucasian ICP patients and controls was performed. Variants were cloned into an FXR expression plasmid and tested in functional assays. RESULTS We identified 4 novel heterozygous FXR variants (-1g>t, M1V, W80R, M173T) in ICP. W80R was not present in Caucasians and M1V was detected uniquely in 1 British case. M173T and -1g>t occur both in Caucasian cases and controls, and we found a significant association of M173T with ICP (OR, 3.2; 95% confidence interval, 1.1-11.2; P = .02) when the allele frequencies of both Caucasian cohorts were analyzed together. We demonstrate functional defects in either translation efficiency or activity for 3 of the 4 variants (-1g>t, M1V, M173T). CONCLUSIONS This is the first report of functional variants in FXR. We propose that these variants may predispose to ICP, and because FXR has a central role in regulating bile and lipid homeostasis they may be associated with other cholestatic and dyslipidemic disorders.
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Affiliation(s)
- Saskia W C Van Mil
- Maternal and Fetal Disease Group, Institute of Reproductive and Developmental Biology, Imperial College London, London, England
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19
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Pusl T, Beuers U. Intrahepatic cholestasis of pregnancy. Orphanet J Rare Dis 2007; 2:26. [PMID: 17535422 PMCID: PMC1891276 DOI: 10.1186/1750-1172-2-26] [Citation(s) in RCA: 111] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2007] [Accepted: 05/29/2007] [Indexed: 12/13/2022] Open
Abstract
Intrahepatic cholestasis of pregnancy (ICP) is a cholestatic disorder characterized by (i) pruritus with onset in the second or third trimester of pregnancy, (ii) elevated serum aminotransferases and bile acid levels, and (iii) spontaneous relief of signs and symptoms within two to three weeks after delivery. ICP is observed in 0.4–1% of pregnancies in most areas of Central and Western Europe and North America, while in Chile and Bolivia as well as Scandinavia and the Baltic states roughly 5–15% and 1–2%, respectively, of pregnancies are associated with ICP. Genetic and hormonal factors, but also environmental factors may contribute to the pathogenesis of ICP. Intrahepatic cholestasis of pregnancy increases the risk of preterm delivery (19–60%), meconium staining of amniotic fluid (27%), fetal bradycardia (14%), fetal distress (22–41%), and fetal loss (0.4–4.1%), particularly when associated with fasting serum bile acid levels > 40 μmol/L. The hydrophilic bile acid ursodeoxycholic acid (10–20 mg/kg/d) is today regarded as the first line treatment for intrahepatic cholestasis of pregnancy. Delivery has been recommended in the 38th week when lung maturity has been established.
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Affiliation(s)
- Thomas Pusl
- Department of Medicine II, Klinikum Grosshadern, University of Munich, Munich, Germany
| | - Ulrich Beuers
- Department of Gastroenterology & Hepatology, AMC, University of Amsterdam, The Netherlands
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Abstract
Bile acids and bile salts have essential functions in the liver and in the small intestine. Their synthesis in the liver provides a metabolic pathway for the catabolism of cholesterol and their detergent properties promote the solubilisation of essential nutrients and vitamins in the small intestine. Inherited conditions that prevent the synthesis of bile acids or their excretion cause cholestasis, or impaired bile flow. These disorders generally lead to severe human liver disease, underscoring the essential role of bile acids in metabolism. Recent advances in the elucidation of gene defects underlying familial cholestasis syndromes has greatly increased knowledge about the process of bile flow. The expression of key proteins involved in bile flow is tightly regulated by transcription factors of the nuclear hormone receptor family, which function as sensors of bile acids and cholesterol. Here we review the genetics of familial cholestasis disorders, the functions of the affected genes in bile flow, and their regulation by bile acids and cholesterol.
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Affiliation(s)
- S W C van Mil
- Department of Metabolic and Endocrine Disorders, University Medical Center, Lundlaan 6, 3584 EA Utrecht, The Netherlands
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Di Martino V, Lebray P, Myers RP, Pannier E, Paradis V, Charlotte F, Moussalli J, Thabut D, Buffet C, Poynard T. Progression of liver fibrosis in women infected with hepatitis C: long-term benefit of estrogen exposure. Hepatology 2004; 40:1426-1433. [PMID: 15565616 DOI: 10.1002/hep.20463] [Citation(s) in RCA: 197] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Female sex is a protective factor for the progression of fibrosis in patients with chronic hepatitis C virus (HCV) infection. Experimental data suggest that estrogens may have an antifibrotic effect. The objective of this study was to evaluate the influence of past pregnancies, oral contraceptives, menopause, and hormone replacement therapy (HRT) on liver fibrosis progression in HCV-infected women. Four hundred seventy-two HCV-infected women received a survey regarding prior pregnancies, menopause, and the use of oral contraceptives and HRT. The impact of these variables on liver fibrosis and its progression were evaluated using multivariate analyses considering all putative confounding factors. Two hundred one women completed the survey (43% response rate), 157 of whom had an estimated date of HCV infection (96 postmenopausal women, 96 women with previous pregnancies, and 105 women with past use of oral contraceptives). Through multivariate analyses, the estimated rate of fibrosis progression was higher in postmenopausal (P < .05) and nulliparous (P = .02) women and was associated with greater histological activity (P < .001). Prior use of oral contraceptives had no significant influence. Among postmenopausal women, the estimated rate of fibrosis progression (+/-SE) was lower in women who received HRT compared with untreated patients (0.099 +/- 0.016 vs. 0.133 +/- 0.006 METAVIR units/yr; P = .02) and was similar to that of premenopausal women (0.093 +/- 0.012 METAVIR units/yr; P value not significant). In conclusion, menopause appears to be associated with accelerated liver fibrosis progression in HCV-infected women, an effect that may be prevented by HRT. Pregnancies may have a beneficial impact on the long-term progression of liver fibrosis.
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Affiliation(s)
- Vincent Di Martino
- Service d'Hépato-Gastroentérologie, GH Pitié-Salpêtrière, Paris, France.
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23
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Abstract
Liver disease has an impact on women's health during pregnancy because of the complex interactions between the physiologic changes induced by pregnancy and the pathophysiologic changes of liver disease. In particular, liver diseases that predominantly afflict females, such as primary biliary cirrhosis and autoimmune hepatitis, pose a special problem for conception and management of pregnancy. Pregnancy, moreover, specifically is associated with several potentially life-threatening liver diseases. This article reviews comprehensively the impact of liver diseases on pregnancy and of pregnancy on liver function and liver disease.
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Affiliation(s)
- Bimaljit S Sandhu
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University Health System, Richmond, VA,
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24
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Fox JC, Szyjkowski RS, Sanderson SO, Levine RA. Progressive cholestatic liver disease associated with clarithromycin treatment. J Clin Pharmacol 2002; 42:676-80. [PMID: 12043957 DOI: 10.1177/00970002042006011] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The authors report a case of an acute toxic cholestatic reaction to clarithromycin, proven by liver biopsy, in a patient with comorbid diseases, prior exposure to erythromycin and ultimate death. No autopsy was performed. A 59-year-old woman with diabetes mellitus and chronic renal insufficiency received clarithromycin 500 mg twice daily for 3 days for acute maxillary sinusitis and then developed a rash and jaundice. She was hospitalized 11 days after stopping clarithromycin. Progressive cholestatic jaundice accompanied by oligo-anuric renal failure requiring hemodialysis ensued. Liver biopsy showed pure bilirubinostasis without parenchymal inflammation. On the 22nd hospital day, after clinical deterioration, she died from an apparent cardiopulmonary death. This is the first report in the literature of a fatality associated with a short-term, low (1 g) daily dose of drug-induced pure cholestasis, an entity not previously identified with severe drug-induced hepatotoxicity.
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Affiliation(s)
- Jean C Fox
- Department of Medicine, State University of New York, Upstate Medical University, Syracuse 13210, USA
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25
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Cuevas MJ, Almar M, González-Gallego J. Effects of epomediol on ethinyloestradiol-induced changes in glutathione homeostasis in the rat. PHARMACOLOGY & TOXICOLOGY 2002; 90:121-6. [PMID: 12071332 DOI: 10.1034/j.1600-0773.2002.900302.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Epomediol is a synthetic terpenoid compound that has been reported to reduce ethinyloestradiol-induced cholestasis. The choleretic action of epomediol is related to an increase in both the bile acid-dependent and independent fractions of bile flow, but the role of glutathione metabolism and transport is still unknown. This study was aimed to evaluate if changes in glutathione homeostasis could contribute to the beneficial effects of epomediol in rats with ethinyloestradiol-induced cholestasis. When compared to control animals, ethinyloestradiol treatment resulted in a significant decrease in the liver concentration of reduced (GSH) and oxidized glutathione. Both GSH and oxidized glutathione concentrations returned to normal in animals receiving ethinyloestradiol plus epomediol. Ethinyloestradiol administration induced a significant decrease in plasma and renal GSH and the tripeptide was almost absent from bile. Combined treatment with epomediol plus ethinyloestradiol normalised renal GSH and both biliary and liver cysteine were significantly increased. Liver and kidney gamma-glutamyltranspeptidase activities were higher in rats receiving ethinyloestradiol and still remained elevated in animals with the combined treatment. Liver gamma-glutamylcysteine synthetase activity rose significantly by administration of ethinyloestradiol plus epomediol but the corresponding mRNA levels were not modified. Changes in glutathione homeostasis and higher biliary levels of GSH amino acid constituents could contribute to the beneficial effects of epomediol in rats with ethinyloestradiol-induced cholestasis.
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26
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Cuevas MJ, Mauriz JL, Almar M, Collado PS, González-Gallego J. Effect of epomediol on ethinyloestradiol-induced changes in bile acid and cholesterol metabolism in rats. Clin Exp Pharmacol Physiol 2001; 28:637-42. [PMID: 11473529 DOI: 10.1046/j.1440-1681.2001.03496.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
1. Epomediol is a terpenoid compound that has been reported to stimulate bile acid synthesis and to reverse 17alpha- ethinyloestradiol-induced cholestasis. The aim of the present study was to investigate the contribution of changes in bile acid and cholesterol metabolism to the protective effects of epomediol in ethinyloestradiol-treated rats. Animals received epomediol for 5 days at 100 mg/kg daily, i.p., ethinyloestradiol for 5 days at 5 mg/kg, s.c., or a combination of both drugs. 2. When compared with control animals, epomediol treatment resulted in a significant increase in bile flow (+42%) and in the secretion of bile acids (+74%) and cholesterol (+42%). Ethinyloestradiol administration caused a significant decrease in bile flow (-43%), bile acid secretion (-37%) and cholesterol secretion (-45%). Bile flow, bile acid secretion and cholesterol secretion were significantly increased in animals receiving ethinyloestradiol plus epomediol compared with ethinyloestradiol-treated rats (+13, +29 and +31%, respectively). 3. Both cholesterol 7alpha-hydroxylase and hydroxy-3- methylglutaryl coenzyme A reductase activities were significantly increased in epomediol-treated rats (+30 and +96%, respectively). Cholesterol 7alpha-hydroxylase activity was significantly reduced by ethinyloestradiol (-22%) and did not differ from control values in animals receiving epomediol plus ethinyloestradiol. Levels of cholesterol 7alpha-hydroxylase mRNA were elevated (+41%) by epomediol, but were not significantly modified by ethinyloestradiol or ethinyloestradiol plus epomediol. 4. It is concluded that epomediol enhances bile acid secretion by increasing the expression of cholesterol 7alpha-hydroxylase. Changes in bile acid metabolism contribute to the effects of epomediol in rats with ethinyloestradiol-induced cholestasis.
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Affiliation(s)
- M J Cuevas
- Department of Physiology, University of León, University Campus, 24071 León, Spain
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27
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Lammert F, Marschall HU, Glantz A, Matern S. Intrahepatic cholestasis of pregnancy: molecular pathogenesis, diagnosis and management. J Hepatol 2000; 33:1012-21. [PMID: 11131439 DOI: 10.1016/s0168-8278(00)80139-7] [Citation(s) in RCA: 259] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Affiliation(s)
- F Lammert
- Department of Internal Medicine III, Aachen University of Technology RWTH, Germany
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28
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Accatino L, Pizarro M, Solís N, Arrese M, Vollrath V, Ananthanarayanan M, Chianale J, Koenig CS. Differential expression of canalicular membrane Ca2+/Mg(2+)-ecto-ATPase in estrogen-induced and obstructive cholestasis in the rat. THE JOURNAL OF LABORATORY AND CLINICAL MEDICINE 2000; 136:125-37. [PMID: 10945241 DOI: 10.1067/mlc.2000.108151] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Extracellular adenosine triphosphate (ATP) may regulate hepatocyte and cholangiocyte functions, and under some conditions it may have deleterious effects on bile secretion and cause cholestasis. The canalicular membrane enzyme Ca2+/Mg2+-ecto-ATPase (ecto-ATPase) hydrolyzes ATP/adenosine diphosphate (ATP/ADP) and regulates hepatic extracellular ATP concentration. Changes in liver ecto-ATPase in estrogen-induced cholestasis were examined in male rats receiving 17alpha-ethinylestradiol (E groups) for 1, 3, or 5 days (5 mg/kg/day, sc) and compared with changes in rats subjected to obstructive cholestasis (O groups) for 1, 3, or 8 days. Activity of ecto-ATPase, protein mass in canalicular membranes and bile (estimated by Western blotting), steady state mRNA levels (by Northern blotting), and cellular and acinar distributions of the enzyme (histochemistry and immunocytochemistry) were assessed in these groups. Activity of ecto-ATPase, protein mass in isolated canalicular membranes, and enzyme mRNA levels were significantly increased in E group rats as compared with controls. In contrast, these parameters were markedly decreased in O group rats, and the enzyme protein was undetectable in bile. The ecto-ATPase histochemical reaction was markedly increased in the canalicular membrane of E group rats, extending from acinar zone 2 to zone 1, whereas it decreased in the O group. The ecto-ATPase immunocytochemical reaction was present in the canalicular membrane and pericanalicular vesicles in control and E group hepatocytes, but it decreased in obstructive cholestasis and was localized only to the canalicular membrane. Thus, significant changes in liver ecto-ATPase were apparent in 17alpha-ethinylestradiol-induced cholestasis that were opposite to those observed in obstructive cholestasis. Assuming that the alterations observed in obstructive cholestasis are the result of the cholestatic phenomenon, we conclude that changes in ecto-ATPase in 17alpha-ethinylestradiol-treated rats might be either primary events or part of an adaptive response in 17alpha-ethinylestradiol-induced cholestasis.
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Affiliation(s)
- L Accatino
- Department of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago
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29
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Leslie KK, Reznikov L, Simon FR, Fennessey PV, Reyes H, Ribalta J. Estrogens in intrahepatic cholestasis of pregnancy. Obstet Gynecol 2000. [PMID: 10711547 DOI: 10.1097/00006250-200003000-00012] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVE To determine whether estrogen production and excretion are impaired in gravidas with intrahepatic cholestasis. METHODS Plasma and urine samples were collected from 13 women from the United States and Chile at 35-38 weeks' gestation with mild (n = 9) or severe (n = 4) intrahepatic cholestasis of pregnancy. Urinary and plasma steroid levels from women with cholestasis were compared with levels from 27 normal pregnant women within the same gestational age range. Urinary concentrations of dehydroepiandrosterone (DHEA), estrone (E1), estradiol (E2), estriol (E3), estetrol, progesterone, and 16-hydroxy-pregnenolone were measured by gas chromatography mass spectrometry, and plasma concentrations of DHEA sulfate, progesterone, unconjugated E1, unconjugated E2, unconjugated E3, sulfated E3 derivatives, glucuronidated E3 derivatives, and total E3 were measured by radioimmunoassay. RESULTS Compared with normal pregnant women, women with cholestasis had significantly lower plasma levels of estrogens and DHEA sulfate, the precursor to placental estrogen production synthesized by the fetal adrenal gland (Hotelling-Lawley trace = 0.81; F4,19 = 3.9; P = .02). The mean plasma DHEA sulfate, unconjugated E2, unconjugated E3, and total E3 concentrations were 0.271, 10.21, 9.80, and 99.53 ng/mL, respectively, in women with cholestasis compared with 0.802, 18.98, 16.28, and 145.07 ng/mL for controls. CONCLUSION Fetal adrenal production of DHEA sulfate, and in response, downstream placental production of estrogens, was compromised by intrahepatic cholestasis of pregnancy.
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Affiliation(s)
- K K Leslie
- Department of Obstetrics and Gynecology, University of Colorado Health Sciences Center, Denver 80262, USA.
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30
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Accatino L, Pizarro M, Solís N, Koenig CS. Effects of diosgenin, a plant-derived steroid, on bile secretion and hepatocellular cholestasis induced by estrogens in the rat. Hepatology 1998; 28:129-40. [PMID: 9657105 DOI: 10.1002/hep.510280118] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Increased biliary secretion of cholesterol and lipid vesicles (unilamellae and multilamellae) induced by diosgenin (D), a plant-derived steroid, has cytoprotective effects in the rat liver subjected to obstructive cholestasis. In this study, our aims were to investigate the following: 1) the effects of D on the bile secretory process and on the cholestasis induced by estradiol-17beta-(beta-D-glucuronide) (E17G) or 17 alpha-ethynylestradiol (E) administration; 2) whether the potentially protective effects of D are related to D-induced increase of biliary cholesterol and lipid lamellae; and 3) whether D has other effects capable of modifying specific bile secretory processes or preventing the cholestatic effects of estrogens. Rats were fed a standard ground chow (control group) or chow containing D for 6 days. E17G was administered i.v. to control and D-fed rats and bile flow, bile salt output, and alkaline phosphatase excretion were examined. 17alpha-E was administered from days 4 to 6 to rats fed standard chow or chow plus D for 6 days and different functional parameters of the bile secretory process as well as the ultrastructure of hepatocytes and histochemistry of alkaline phosphatase and Mg2+-adenosine triphosphatase (ATPase) were examined. D-treatment markedly increased cholesterol and lamellar structures in bile and attenuated the acute cholestatic effects of E17G. D-feeding prevented the decrease of taurocholate maximum secretory rate and the increase of biliary alkaline phosphatase and Ca2+,Mg2+-EctoATPase (EctoATPase) excretion, as well as the increase of cholesterol/ phospholipids ratio, alkaline phosphatase activity, and EctoATPase content in canalicular plasma membranes induced by E. D-feeding did not prevent E-induced decrease of basal bile flow, bile salt, cholesterol, and phospholipid secretory rates nor the decrease of Na+,K+-ATPase activity and Na+-taurocholate cotransporting polypeptide (Ntcp) content in isolated sinusoidal membranes. Cholestatic alterations of canalicular domain were apparent in E-treated rats. D administration was also associated with changes of ultrastructure and histochemistry of hepatocytes. E-induced alterations in ultrastructure and acinar distribution and intensity of histochemical reaction of both enzymes were partially prevented by D-feeding. We conclude that D administration, in addition to inducing a marked increase of biliary cholesterol and lipid lamellar structures output, was associated to changes in hepatocyte morphology and plasma membrane composition, enzymes activity, and histochemistry. D-feeding attenuated the acute cholestatic effects of E17G. D-induced increase of bile cholesterol and lipid lamellae content was not apparent when D-fed rats received E. Despite this fact, D administration prevented some cholestatic effects of E, probably through different metabolic effects and/or direct membrane effects, not related to increased lipid lamellae excretion.
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Affiliation(s)
- L Accatino
- Department of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago de Chile
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31
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Colvin PL, Wagner JD, Adams MR, Sorci-Thomas MG. Sex steroids increase cholesterol 7alpha-hydroxylase mRNA in nonhuman primates. Metabolism 1998; 47:391-5. [PMID: 9550534 DOI: 10.1016/s0026-0495(98)90048-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
One mechanism that may account for our prior observation that oral contraceptives decrease the hepatic cholesterol concentration independently of the low-density lipoprotein (LDL) receptor in sexually intact nonhuman primates is that sex hormones increase biliary cholesterol secretion by increasing hepatic mRNA abundance for cholesterol 7alpha-hydroxylase, the rate-limiting enzyme in the conversion of cholesterol into bile acids. To examine the independent effect of estrogen, progestin, and combined estrogen and progestin on the hepatic cholesterol concentration and cholesterol 7alpha-hydroxylase mRNA abundance, 34 ovariectomized adult female cynomolgus monkeys were fed a moderately atherogenic diet for 12 weeks with either oral conjugated equine estrogen ([CEE] n = 8), medroxyprogesterone acetate ([MPA] n = 9), or combined CEE + MPA (n = 9) and compared with a control group (n = 8) that did not receive exogenous sex hormones. After 12 weeks, hepatic cholesterol was significantly lower in CEE-treated (6.2 +/- 1.2 mg/g liver) and CEE + MPA-treated (6.4 +/- 0.9 mg/g liver) animals compared with the control (12.6 +/- 1.9 mg/g liver) and MPA-treated (14.6 +/- 1.6 mg/g liver) groups. Hepatic cholesterol 7alpha-hydroxylase mRNA abundance was significantly increased in CEE-treated (0.553 +/- 0.08 pg/microg RNA), MPA-treated (0.734 +/- 0.12 pg/microg RNA), and CEE + MPA-treated (0.487 +/- 0.07 pg/microg RNA) animals compared with the controls (0.318 +/- 0.03 pg/microg RNA). There was no significant difference in the plasma LDL cholesterol concentration and hepatic LDL receptor mRNA abundance between the groups. These data support but do not prove the hypothesis that low-dose oral estrogen induces an increase in cholesterol 7alpha-hydroxylase mRNA abundance, which is correlated with biliary cholesterol secretion and may result in depletion of hepatic cholesterol.
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Affiliation(s)
- P L Colvin
- Department of Internal Medicine, University of Maryland School of Medicine and the Baltimore Veterans Affairs Medical Center, Geriatrics Research, Education, and Clinical Center, 21201-1524, USA
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32
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Abstract
The long-term use of oral contraceptives (OCs) may be associated with an increased, though quite small, risk of certain types of liver disease: acute intrahepatic canalicular idiosyncratic cholestasis, benign hepatic tumors (hepatic adenoma, focal nodular hyperplasia, hemangiomas), hepatocellular carcinoma, peliosis hepatis, hepatic vein thrombosis, and portal vein thrombosis. Estrogens have lithogenic properties, as shown by a rise in biliary cholesterol secretion and cholesterol saturation index, yet no substantial increase in the risk of gallstones among estrogen users has been found. Hormone replacement therapy (HRT), given after oophorectomy or menopause, is not associated with clinically significant liver injury. Generally speaking, synthetic sex hormones should not be used in patients with acute and chronic liver disease. A trial of a low-dose estrogen can be instituted under close monitoring for adverse reactions and HRT preparations are not contraindicated in patients with chronic liver disease. Moreover, OCs and HRT can be prescribed quite safely following successful liver transplantation. The incidence of hepatic abnormalities in patients taking androgen hormones is very high. Liver adenomas, cholestasis, peliosis, nodular regenerative hyperplasia and, particularly, hepatocellular carcinoma may complicate long-term use of C17-substituted testosterone and anabolic steroids.
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Affiliation(s)
- S P Dourakis
- Academic Department of Medicine, Hippokration General Hospital, Athens, Greece
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33
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Koopen NR, Wolters H, Havinga R, Vonk RJ, Jansen PL, Müller M, Kuipers F. Impaired activity of the bile canalicular organic anion transporter (Mrp2/cmoat) is not the main cause of ethinylestradiol-induced cholestasis in the rat. Hepatology 1998; 27:537-45. [PMID: 9462655 DOI: 10.1002/hep.510270231] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
To test the hypothesis that impaired activity of the bile canalicular organic anion transporting system mrp2 (cmoat) is a key event in the etiology of 17alpha-ethinylestradiol (EE)-induced intrahepatic cholestasis in rats, EE (5 mg/kg subcutaneously daily) was administered to male normal Wistar (NW) and mrp2-deficient Groningen Yellow/Transport-deficient Wistar (GY/TR-) rats. Elevated plasma bilirubin levels in GY/TR- rats increased upon EE-treatment from 65 +/- 8.4 micromol/L to 183 +/- 22.7 micromol/L within 3 days, whereas bilirubin levels remained unaffected in NW rats. Biliary bilirubin secretion was 1.5-fold increased in NW rats but remained unaltered in GY/TR- rats. Plasma bile salt concentrations remained unchanged in both strains, although hepatic levels of the sinusoidal Na+-taurocholate cotransporting protein (ntcp) were markedly reduced. Biliary secretion of endogenous bile salt was not affected in either strain. A clear reduction of mrp2 levels in liver plasma membranes of NW rats was found after 3 days of treatment. The bile salt-independent fraction of bile flow (BSIF) was reduced from 2.6 to 2.0 microL/min/100 g body weight in NW rats with a concomitant 62% reduction of biliary glutathione secretion. The absence of mrp2 and biliary glutathione in GY/TR- rats did not prevent induction of EE-cholestasis; a similar absolute reduction of BSIF, i.e., from 1.1 to 0.6 microL/min/100 g bodyweight, was found in these animals. EE treatment caused a reduction of the maximal biliary secretory rate (S(RM)) of the mrp2 substrate, dibromosulphthalein (DBSP), from 1,040 to 695 nmol/min/100 g body weight (-38%) in NW rats and from 615 to 327 nmol/min/100 g body weight (-46%) in GY/TR- rats. These results demonstrate that inhibition of mrp2 activity and/or biliary glutathione secretion is not the main cause of EE-induced cholestasis in rats. The data indicate that alternative pathways exist for the biliary secretion of bilirubin and related organic anions that are also affected by EE.
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Affiliation(s)
- N R Koopen
- Groningen Institute for Drug Studies, Laboratory of Nutrition and Metabolism, University Hospital Groningen, The Netherlands
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34
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Meng LJ, Reyes H, Palma J, Hernandez I, Ribalta J, Sjövall J. Effects of ursodeoxycholic acid on conjugated bile acids and progesterone metabolites in serum and urine of patients with intrahepatic cholestasis of pregnancy. J Hepatol 1997; 27:1029-40. [PMID: 9453429 DOI: 10.1016/s0168-8278(97)80147-x] [Citation(s) in RCA: 65] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND/AIMS AND METHODS The mechanism(s) behind the effects of ursodeoxycholic acid on serum steroid sulphate profiles in patients with intrahepatic cholestasis of pregnancy is not clear. Conjugated progesterone metabolites and bile acids have therefore been analysed in serum and urine of patients with intrahepatic cholestasis of pregnancy before and during treatment with ursodeoxycholic acid using chromatographic and mass spectrometric methods. RESULTS The concentration of glycine-/taurine-conjugated bile acids decreased from 8.9+/-3 micromol/l (mean+/-SEM) before treatment to 1.8+/-0.6 micromol/l during treatment with ursodeoxycholic acid. The total bile acid excretion in urine decreased from 56+/-14 to 32+/-5.6 micromol/g creatinine. The proportion of cholic acid in serum and urine, and of 1beta-, 2beta- and 6alpha-hydroxylated cholic acids in urine decreased markedly during ursodeoxycholic acid while the percentages of 3alpha,12alpha-dihydroxy-3-oxo-4-cholenoic acid and chenodeoxycholic acid were unchanged. The levels in serum and excretion in urine of sulphated steroids decreased during ursodeoxycholic acid, by 45-49% for disulphates and 33-35% for monosulphates. The ratios of 3alpha- to 3beta-hydroxysteroid disulphates were lowered by ursodeoxycholic acid from 1.1 (mean) to 0.68 in serum, and from 1.2 to 0.70 in urine. The corresponding ratios for monosulphates before and during ursodeoxycholic acid were 6.9 and 4.5, respectively, in serum, and 21 and 5.2, respectively, in urine. The major monosulphates in urine, dominated by 5alpha-pregnane-3alpha, 20alpha-diol, were also conjugated with N-acetylglucosamine. The excretion of these double conjugates decreased from 27+/-8.4 to 15+/-5.3 micromol/g creatinine during ursodeoxycholic acid. In contrast to sulphated steroids, the concentrations of glucuronides were unchanged in serum and their excretion in urine tended to increase during ursodeoxycholic acid. The metabolism of ursodeoxycholic acid was similar to that described in nonpregnant subjects. In addition to metabolites hydroxylated in the 1beta-, 5beta-, 6alpha/beta and 22-positions, a 4-hydroxy-ursodeoxycholic acid was tentatively identified. This occurred predominantly as a double conjugate with glycine/taurine and glucuronic acid, as did other 4-hydroxylated bile acids of probable foetal origin. CONCLUSIONS The results are compatible with the contention that ursodeoxycholic acid stimulates the biliary excretion of sulphated progesterone metabolites, particularly those with a 3alpha-hydroxy-5alpha(H) configuration and disulphates. The effect(s) appears to be independent of the stimulation of bile acid secretion. An effect of ursodeoxycholic acid on the reductive metabolism of progesterone cannot be excluded.
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Affiliation(s)
- L J Meng
- Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
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Sturgill MG, Lambert GH. Xenobiotic-induced hepatotoxicity: mechanisms of liver injury and methods of monitoring hepatic function. Clin Chem 1997. [DOI: 10.1093/clinchem/43.8.1512] [Citation(s) in RCA: 143] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
AbstractXenobiotic-induced liver injury is a clinically important etiology of hepatic disease that, if not recognized, can lead to hepatic failure. In this article we discuss the mechanisms of xenobiotic-induced liver injury, various factors that can alter the risk and severity of injury, the clinical and laboratory manifestations of injury, and the methods used to detect the presence of injury and (or) functioning liver mass.
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Affiliation(s)
- Marc G Sturgill
- Department of Pharmacy Practice and Administration, Rutgers University College of Pharmacy, PO Box 789 William Levine Hall, Piscataway, NJ 08855-0789
- Division of Pediatric Pharmacology and Toxicology, University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, 681 Frelinghuysen Rd., PO Box 1179, Piscataway, NJ 08855-1179
| | - George H Lambert
- Division of Pediatric Pharmacology and Toxicology, University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, 681 Frelinghuysen Rd., PO Box 1179, Piscataway, NJ 08855-1179
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Abstract
In summary, the data suggest that E217G is transported by both MOAT and P-glycoprotein into bile, but that P-glycoprotein serves as the target site for cholestasis. We postulate that this target site may be accessed from either the intracellular compartment or the canaliculus, and that MOAT serves as the major delivery route for E217G to the canaliculus. At low, physiologic concentrations of E217G, MOAT-mediated excretion into bile is a detoxification mechanism, serving to prevent intracellular accumulation of a toxic metabolite. However, following administration of high, cholestatic doses, MOAT-mediated excretion into bile results in very high concentrations in bile, on the other of 2-3 mM (see Fig. 4). It is likely that the hydrophobic nature of E217G allows it to partition from bile into the canalicular membrane, from which it can access P-glycoprotein and thus induce cholestasis. Much work is still needed to validate this model of E217G cholestasis. Definitive evidence of P-glycoprotein-mediated transport of E217G must be obtained in cell lines transfected with P-glycoprotein where MRP is absent. More importantly, the mechanism by which interaction of E217G with P-glycoprotein influences bile flow is unknown. Higgins and colleagues have provided evidence that P-glycoprotein regulates a Cl- channel in a manner analogous to that of CFTR, the cystic fibrosis transmembrane conductance regulator. While Cl- channels have been shown to be important in the regulation of the volume of the hepatocyte in the presence of altered osmotic conditions, a role for this channel in bile flow has not been demonstrated. Nevertheless, these studies implicate a role of P-glycoprotein in the regulation of bile secretion by the liver.
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Affiliation(s)
- M Vore
- Department of Pharmacology, University of Kentucky, Lexington 40536-0305, USA.
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Alvaro D, Gigliozzi A, Piat C, Carli L, Fraioli F, Romeo R, Francia C, Attili AF, Capocaccia L. Inhibition of biliary bicarbonate secretion in ethinyl estradiol-induced cholestasis is not associated with impaired activity of the Cl-/HCO-3 exchanger in the rat. J Hepatol 1997; 26:146-57. [PMID: 9148006 DOI: 10.1016/s0168-8278(97)80021-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND/AIMS Bicarbonate is a major component of bile salt independent bile flow, which is impaired in ethinyl estradiol (EE)-cholestasis. To examine this subject in EE-cholestasis, we studied: 1) basal and glucagon-stimulated biliary bicarbonate secretion both in vivo and in the isolated perfused rat liver (IPRL); 2) H+/HCO-3 transport processes in isolated rat hepatocyte couplets. METHODS Rats received EE (5 mg.kg b.w.-1) for 5 days. Intracellular pH (pHi) was measured (BCECF-AM) using a single-cell microfluorimetric setup. RESULTS Bile flow was markedly (p < 0.01) decreased in EE-treated rats. Bicarbonate concentration in bile was decreased (p < 0.01) and bicarbonate secretion was 2.5-fold lower in EE-treated animals than in controls, both in bile-fistula rats [19.5 +/- 5.1 (n = 23) vs 54.2 +/- 5.7 (n = 20) nmol.min-1g liver-1; p < 0.01] and in the IPRL [11 +/- 2 (n = 8) vs 24 +/- 3 (n = 8) nmol.min-1.g liver-1; p < 0.01]. In control IPRL, a bile/perfusate gradient for bicarbonate is maintained, while it is lost in EE-treated IPRL because of the lower bicarbonate concentration in bile. Glucagon stimulated bile flow and bicarbonate secretion to a similar extent in EE-treated and control IPRL (+25% vs +23%). Resting pHi of EE-treated hepatocyte couplets was higher in comparison with controls in KRB [7.25 +/- 0.07 (n = 35) vs 7.20 +/- 0.05 (n = 33); p < 0.02] but similar in Hepes [7.08 +/- 0.07 (n = 24) vs 7.05 +/- 0.06 (n = 26)]. Basal activity of the Cl-/HCO-3 exchanger was similar in EE-treated and control hepatocyte couplets [H+ flux = 2.87 +/- 1.12 (n = 18) vs 3.01 +/- 1.23 mM/min (n = 15)] and was stimulated to a similar extent by glucagon. Na+/HCO3-symport activity was increased in EE-treated hepatocyte couplets (p < 0.05) while the Na+/H+ exchanger was unchanged. CONCLUSIONS Bicarbonate biliary secretion is markedly impaired during EE-cholestasis in association with a marked decrease of bile salt independent bile flow. However, the Cl-/HCO-3 exchanger and its hormonal regulation are normal, indicating that the lower bicarbonate excretion in EE-cholestasis is not due to a compromised activity of this anion exchanger. Since the bile/perfusate gradient for bicarbonate is dissipated in EE-treated IPRL, the impaired bicarbonate excretion could be caused by a reflux of biliary bicarbonate via leaky tight junctions.
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Affiliation(s)
- D Alvaro
- II Department of Gastroenterology, University of Rome, La Sapienza, Italy
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Omar HM, Sanders RA, Watkins JB. Hepatobiliary excretion of cysteinyl leukotrienes in three experimental models of acute hepatic injury. Inflamm Res 1996; 45:519-23. [PMID: 8912018 DOI: 10.1007/bf02311089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
The acute phase response to chemically-induced organ damage involves inflammation and the production of leukotrienes. The liver ordinarily takes up, metabolizes and excretes into bile cysteinyl leukotrienes, but the effect of hepatic injury on these processes is unknown. The hepatic uptake and biliary excretion of LTC4 was studied in male Sprague-Dawley rats after exposure to either streptozotocin (45 mg/kg iv 30 days before experimentation), estradiol-17 beta-valerate (1 mg/kg sc once a week for 3 weeks) or lipopolysaccharide/D-galactosamine (33 micrograms/ kg ip; 300 mg/kg ip at 6 h and 3 h, respectively, before experimentation). Acute liver injury is produced by these treatment paradigms. Glucose concentrations and activities of several marker enzymes in plasma were measured to demonstrate hepatic injury. Biliary excretion of 3H-LTC4 was similar to normal control rats in the three types of acute liver injury. Bile flow rates after 3H-LTC4 injection were reduced in lipopolysaccharide-pretreated rats and increased in estradiol-treated animals. Total biliary excretion of leukotrienes was not altered in any disease group. Thus, these models of acute hepatic injury do not appear to influence the hepatobiliary clearance of leukotrienes.
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Affiliation(s)
- H M Omar
- Medical Sciences Program, Indiana University School of Medicine, Bloomington 47405-4201, USA
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39
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Smith P. Mid-Western Regional Society of Toxicology: Novel Mechanisms of Hepatobiliary Toxicity. Toxicol Pathol 1996. [DOI: 10.1177/019262339602400318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Affiliation(s)
- P.F. Smith
- G. D. Searle and Co., Skokie, Illinois 60077, USA
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Abstract
The initial report is reviewed, as well as the results of subsequent investigations, and the current status of the following side effects attributed to the use of oral contraceptives: subjective symptoms such as mood and libido changes, also headache; melanoma; gallbladder disease; liver tumors, sickle cell disease exacerbation; teratogenesis; "post-Pill" amenorrhea; atherogenesis; and diminished carbohydrate tolerance. In many instances a cause-and-effect relationship appears to be incorrect or highly improbable. In other instances the side effects are clinically insignificant or so rare as to be of minimal importance. Yet they continue to be listed by various authorities as validated side effects or relative contraindications to oral contraceptive use. This, in turn, limits the access of many women to a highly effective form of contraception. This re-examination of past history is intended to modernize our concepts of the safety of this modality.
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Affiliation(s)
- J W Goldzieher
- Department of Obstetrics and Gynecology, Texas Tech University Health Sciences Center, Amarillo, TX, USA
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Ayyad N, Cohen BI, Mosbach EH, Mikami T, Mikami Y, Ohshima A. Hormonal control of cholesterol cholelithiasis in the female hamster. J Lipid Res 1995. [DOI: 10.1016/s0022-2275(20)39735-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
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Azer SA, Canfield PJ, Stacey NH. Hepatoprotection in ethinylestradiol-treated rats is provided by tauroursodeoxycholic acid, but not by ursodeoxycholic acid. J Gastroenterol Hepatol 1995; 10:261-269. [PMID: 7548801 DOI: 10.1111/j.1440-1746.1995.tb01091.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Ursodeoxycholic acid (UDCA) and tauroursodeoxycholic acid (TUDCA) have been suggested as potential treatments for drug-induced cholestasis. It was therefore decided to study the effects of administration of UDCA or TUDCA on individual serum bile acid concentration, conventional liver tests and associated hepatic ultrastructural changes in ethinylestradiol-treated (EE) rats mg/kg per day). Control rats were treated s.c. with propylene glycol. EE-treated rats were randomly assigned to receive daily i.p. injections of placebo, TUDCA or UDCA. Four rats in each group were treated for 4 consecutive days, and a second four for 14 days. After 4 days of treatment, the serum levels of cholic acid and taurocholic acid were significantly increased in EE-treated rats. None of the conventional liver tests were significantly different among the four groups. After 14 days of treatment the serum levels of cholic acid, chenodeoxycholic acid, glycocholic acid, glycochenodeoxycholic acid, taurocholic acid, taurochenodeoxycholic acid, bilirubin, alkaline phosphatase and gamma glutamyltransferase were significantly raised in EE and EE plus UDCA treated rats. EE plus TUDCA treated rats, however, had no significant changes in these individual serum bile acids or conventional liver tests. The ultrastructure of livers from EE plus TUDCA treated rats was similar to those of controls. On the other hand, EE and EE plus UDCA rats both showed a significant reduction in sinusoidal microvilli. These results show that treatment of rats for 4 days with EE induces significant rises in the serum concentrations of two individual bile acids and that TUDCA protects against this.(ABSTRACT TRUNCATED AT 250 WORDS)
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Affiliation(s)
- S A Azer
- Toxicology Unit, University of Sydney, New South Wales, Australia
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Bacq Y, Myara A, Brechot MC, Hamon C, Studer E, Trivin F, Metman EH. Serum conjugated bile acid profile during intrahepatic cholestasis of pregnancy. J Hepatol 1995; 22:66-70. [PMID: 7751589 DOI: 10.1016/0168-8278(95)80261-4] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
BACKGROUND/AIMS Intrahepatic cholestasis of pregnancy is a specific liver disease of pregnancy of unknown cause. The serum bile acid profile has not been clearly described in this disease and the aim of this study was to investigate the serum conjugated bile acid profile. METHODS Thirteen patients with intrahepatic cholestasis of pregnancy were studied. Ten patients had been treated with natural progestatin before the onset of pruritus. The glyco- and tauroconjugated bile acids were quantified by high-performance liquid chromatography and direct spectrometric detection at 199 nm. RESULTS There was no difference between total bile acid concentrations measured by high-performance liquid chromatography (43.5 +/- 22.6 microM, mean +/- S.D.) or by an enzymatic procedure (43.4 +/- 24.6 microM), indicating a low concentration of free bile acids. Primary bile acids represented 88% of total bile acids, i.e. 72.7% for cholic acid and 15.3% for chenodeoxycholic acid. For both cholic and chenodeoxycholic acids glyco- and tauroconjugates were equivalent. Secondary bile acids represented 11.3% of total bile acids. Ursodeoxycholic acid was identified at very low concentrations in only three samples. CONCLUSIONS We conclude that in intrahepatic cholestasis of pregnancy primary bile acids are very predominant.
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Affiliation(s)
- Y Bacq
- Service d'Hépatogastroentérologie, Hôpital Trousseau, Tours, France
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Pansini F, Campobasso C, Giorgetti L, Locorotondo GC, Agnello G, Bassi P, Costantino D, Sighinolfi D, Alvisi V, Mollica G. Influence of oral contraceptives on fasting gallbladder volume. Gynecol Endocrinol 1993; 7:267-71. [PMID: 8147236 DOI: 10.3109/09513599309152511] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
A total of 615 healthy fertile women (518 pill users and 97 non-users) were examined by real-time ultrasonography for fasting gallbladder volume, gallstones and biliary dysmorphism. None of the six examined combinations of oral contraceptives appeared to influence fasting gallbladder volume significantly. When fasting gallbladder volumes were reanalyzed according to the presence or absence of recognized biliary risk factors, significant modifications were detected, in both pill users and non-users. These changes related only to age and parity. Relative risks of cholelithiasis and biliary dysmorphism were not affected by contraceptive treatment.
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Affiliation(s)
- F Pansini
- Department of Obstetrics and Gynecology, University of Ferrara, Italy
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Jacquemin E, Dumont M, Mallet A, Erlinger S. Ursodeoxycholic acid improves ethinyl estradiol-induced cholestasis in the rat. Eur J Clin Invest 1993; 23:794-802. [PMID: 8143756 DOI: 10.1111/j.1365-2362.1993.tb00733.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
The effect of oral chronic administration of ursodeoxycholic acid has been examined in rats with cholestasis induced by ethinyl estradiol. Ursodeoxycholic acid at the dose of 25 mg kg-1 per day during 4 days, did not improve the decrease in basal bile flow and bile acid secretion induced by ethinyl estradiol alone. In contrast, when ursodeoxycholic acid was given at the same dose during 10 days, basal bile flow was significantly improved and basal bile acid secretion was restored to control values. When ursodeoxycholic acid was given at the dose of 500 mg kg-1 per day, basal bile flow and bile acid output were not further improved. However, bile flow and bile acid output under taurocholate infusion were restored to control values. Bile of rats treated with ursodeoxycholic acid was enriched with this bile acid. These results show a significant improvement of ethinyl estradiol-induced cholestasis in rats after chronic administration of ursodeoxycholic acid and support the use of this bile acid in intrahepatic cholestasis in man.
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Affiliation(s)
- E Jacquemin
- Unité de Recherches de Physiopathologie Hépatique (Inserm U-24), Hôpital Beaujon, Clichy, France
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Bouchard G, Yousef IM, Tuchweber B. Influence of oral treatment with ursodeoxycholic and tauroursodeoxycholic acids on estrogen-induced cholestasis in rats: effects on bile formation and liver plasma membranes. LIVER 1993; 13:193-202. [PMID: 8377596 DOI: 10.1111/j.1600-0676.1993.tb00630.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
In this study, we examined whether ursodeoxycholic acid (UDC) and its taurine conjugate, tauroursodeoxycholic acid (TUDC), given per os, can prevent the cholestasis induced in rats by 17-alpha-ethynyl estradiol (EE) and whether this protection is mediated by choleretic activity or altered plasma membrane composition. EE (5 mg/kg body weight/day for 5 days) markedly reduced bile flow and bile salt secretion without significantly affecting plasma membrane composition and function. Treatment with UDC or TUDC (100, 150 or 200 (TUDC only) mumol/100 g body weight/day for 5 days) did not significantly modify bile flow, but the bile salt secretion rate increased in a dose-dependent manner. UDC was the main biliary bile acid secreted in groups given higher doses of UDC or TUDC. At these dose levels, bile acid treatment did not affect plasma membrane fluidity as assessed by fluorescence anisotropy, the cholesterol/phospholipid molar ratio as well as Na+K(+)- and Mg(++)-ATPase activities. The highest dose of UDC and TUDC prevented the reduction of both bile flow and bile salt secretion induced by EE, re-establishing these parameters to the values of the corresponding control for the UDC group. In conclusion, UDC and TUDC, given per os, improve EE-induced cholestasis, an effect that cannot be attributed to choleretic activity or altered plasma membrane composition.
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Affiliation(s)
- G Bouchard
- Department of Pharmacology, Université de Montréal, Quebec, Canada
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Bossard R, Stieger B, O'Neill B, Fricker G, Meier PJ. Ethinylestradiol treatment induces multiple canalicular membrane transport alterations in rat liver. J Clin Invest 1993; 91:2714-20. [PMID: 8514879 PMCID: PMC443336 DOI: 10.1172/jci116511] [Citation(s) in RCA: 96] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
We investigated the effects of 17 alpha-ethinylestradiol treatment of rats on various transport functions in isolated basolateral and canalicular liver plasma membrane vesicles. Both membrane subfractions were purified to a similar degree from control and cholestatic livers. Although moderate membrane lipid alterations were predominantly observed in basolateral vesicles, no change in basolateral Na+/K(+)-ATPase activity was found. Furthermore, while Na(+)-dependent taurocholate uptake was decreased by approximately 40% in basolateral vesicles, the maximal velocity of ATP-dependent taurocholate transport was decreased by 63% in canalicular membranes. In contrast, only minimal changes or no changes at all were observed for electrogenic taurocholate transport in "cholestatic" canalicular membranes and total microsomes, respectively. However, canalicular vesicles from cholestatic livers also exhibited marked reductions in ATP-dependent transport of S-(2,4-dinitrophenyl)glutathione and in Na(+)-dependent uptake of adenosine, while in the same vesicles HCO3-/SO4- exchange and Na+/glycine cotransport activities were markedly stimulated. These data show that in addition to the previously demonstrated sinusoidal transport abnormalities ethinylestradiol-induced cholestasis is also associated with multiple canalicular membrane transport alterations in rat liver. Hence, functional transport alterations at both polar surface domains might ultimately be responsible for the inhibitory effects of estrogens on the organic anion excretory capacity and on bile formation in rat liver.
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Affiliation(s)
- R Bossard
- Department of Medicine, University Hospital, Zurich, Switzerland
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