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Sentilhes L, Sénat MV, Bouchghoul H, Delorme P, Gallot D, Garabedian C, Madar H, Sananès N, Perrotin F, Schmitz T. [Intrahepatic cholestasis of pregnancy: French College of Obstetricians and Gynecologists guidelines for clinical practice]. GYNECOLOGIE, OBSTETRIQUE, FERTILITE & SENOLOGIE 2023; 51:493-510. [PMID: 37806861 DOI: 10.1016/j.gofs.2023.09.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/10/2023]
Abstract
OBJECTIVE To identify strategies for reducing neonatal and maternal morbidity associated with intrahepatic cholestasis pregnancy (ICP). MATERIAL AND METHODS The quality of evidence of the literature was assessed following the GRADE methodology with questions formulated in the PICO format (Patients, Intervention, Comparison, Outcome) and outcomes defined a priori and classified according to their importance. An extensive bibliographic search was performed on PubMed, Cochrane, EMBASE and Google Scholar databases. The quality of the evidence was assessed (high, moderate, low, very low) and a (i) strong or (ii) weak recommendations or (iii) no recommendation were formulated. The recommendations were reviewed in two rounds with external reviewers (Delphi survey) to select the consensus recommendations. RESULTS Of the 14 questions (from 12 PICO questions and one definition question outside the PICO format), there was agreement between the working group and the external reviewers on 14 (100%). The level of evidence of the literature was insufficient to provide a recommendation on two questions. ICP is defined by the occurrence of suggestive pruritus (palmoplantar, nocturnal) associated with a total bile acid level>10μmol/L or an alanine transaminase level above 2N after ruling out differential diagnoses. In the absence of suggestive symptoms of a differential diagnosis, it is recommended not to carry out additional biological or ultrasound tests. In women with CIP, ursodeoxycholic acid is recommended to reduce the intensity of maternal pruritus (Strong recommendation. Quality of the evidence moderate) and to decrease the level of total bile acids and alanine transaminases. (Strong recommendation. Quality of the evidence moderate). S-adenosyl-methionine, dexamethasone, guar gum or activated charcoal should not be used to reduce the intensity of maternal pruritus (Strong recommendation. Quality of evidence low), and there is insufficient data to recommend the use of antihistamines (No recommendation. Quality of evidence low). Rifampicin (Weak recommendation. Very low quality of evidence) or plasma exchange (Strong recommendation. Very low quality of evidence) should not be used to reduce maternal pruritus and perinatal morbidity. Serum monitoring of bile acids is recommended to reduce perinatal morbidity and mortality (stillbirth, prematurity) (Low recommendation. Quality of the evidence low). The level of evidence is insufficient to determine whether fetal heart rate or fetal ultrasound monitoring are useful to reduce perinatal morbidity (No recommendation). Birth is recommended when bile acid level is above 99μmol/L from 36 weeks gestation to reduce perinatal morbidity, in particular stillbirth. When bile acid level is above 99μmol/L is below 100μmol/L, women should be informed that induction of labor could be considered 37 and 39 weeks gestation to reduce perinatal morbidity. (Strong recommendation. Quality of evidence low). In postpartum, total bile acids and alanine transaminases level should be checked and normalized before prescribing estrogen-progestin contraception, ideally with a low estrogen dose (risk of recurrence of pruritus and cytolysis) (Low recommendation. Quality of evidence very low). CONCLUSION Although the quality of evidence regarding ICP gestational cholestasis remains low, there is a strong consensus in France, as shown by our Delphi study, on how to manage women with ICP. The reference first-line treatment is ursodeoxycholic acid.
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Affiliation(s)
- L Sentilhes
- Service de gynécologie-obstétrique, centre hospitalier universitaire de Bordeaux, Bordeaux, France.
| | - M-V Sénat
- Service de gynécologie-obstétrique, hôpital Bicêtre, AP-HP, Le Kremlin-Bicêtre, France
| | - H Bouchghoul
- Service de gynécologie-obstétrique, centre hospitalier universitaire de Bordeaux, Bordeaux, France
| | - P Delorme
- Service de gynécologie-obstétrique, hôpital Trousseau, AP-HP, Paris, France
| | - D Gallot
- Service de gynécologie-obstétrique, centre hospitalier universitaire de Clermont-Ferrand, Clermont-Ferrand, France
| | - C Garabedian
- Service de gynécologie-obstétrique, CHU de Lille, université de Lille, ULR 2694-METRICS, 59000 Lille, France
| | - H Madar
- Service de gynécologie-obstétrique, centre hospitalier universitaire de Bordeaux, Bordeaux, France
| | - N Sananès
- Service de gynécologie-obstétrique, hôpitaux universitaires de Strasbourg, Strasbourg, France
| | - F Perrotin
- Service de gynécologie-obstétrique, centre hospitalier universitaire de Tours, Tours, France
| | - T Schmitz
- Service de gynécologie obstétrique, hôpital Robert-Debré, AP-HP, Paris, France
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Shan D, Dai S, Chen Q, Xie Y, Hu Y. Hepatoprotective agents in the management of intrahepatic cholestasis of pregnancy: current knowledge and prospects. Front Pharmacol 2023; 14:1218432. [PMID: 37719856 PMCID: PMC10500604 DOI: 10.3389/fphar.2023.1218432] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Accepted: 08/16/2023] [Indexed: 09/19/2023] Open
Abstract
Intrahepatic cholestasis of pregnancy (ICP) is characterized by unexplained distressing pruritus in the mother and poses significant risk to the fetus of perinatal mortality. Occurring in the second and third trimester, the serum bile acid and aminotransferase are usually elevated in ICP patients. Ursodeoxycholic acid (UDCA) is the first line drug for ICP but the effectiveness for hepatoprotection is to a certain extent. In ICP patients with severe liver damage, combination use of hepatoprotective agents with UDCA is not uncommon. Herein, we reviewed the current clinical evidence on application of hepatoprotective agents in ICP patients. The underlying physiological mechanisms and their therapeutic effect in clinical practice are summarized. The basic pharmacologic functions of these hepatoprotective medications include detoxification, anti-inflammation, antioxidation and hepatocyte membrane protection. These hepatoprotective agents have versatile therapeutic effects including anti-inflammation, antioxidative stress, elimination of free radicals, anti-steatohepatitis, anti-fibrosis and anti-cirrhosis. They are widely used in hepatitis, non-alcoholic fatty liver disease, drug induced liver injury and cholestasis. Evidence from limited clinical data in ICP patients demonstrate reliable effectiveness and safety of these medications. Currently there is still no consensus on the application of hepatoprotective agents in ICP pregnancies. Dynamic monitoring of liver biochemical parameters and fetal condition is still the key recommendation in the management of ICP pregnancies.
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Affiliation(s)
- Dan Shan
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, China
| | - Siyu Dai
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, China
| | - Qian Chen
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, China
| | - Yupei Xie
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, China
| | - Yayi Hu
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, China
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Yu L, Liu Y, Wang S, Zhang Q, Zhao J, Zhang H, Narbad A, Tian F, Zhai Q, Chen W. Cholestasis: exploring the triangular relationship of gut microbiota-bile acid-cholestasis and the potential probiotic strategies. Gut Microbes 2023; 15:2181930. [PMID: 36864554 PMCID: PMC9988349 DOI: 10.1080/19490976.2023.2181930] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 02/09/2023] [Indexed: 03/04/2023] Open
Abstract
Cholestasis is a condition characterized by the abnormal production or excretion of bile, and it can be induced by a variety of causes, the factors of which are extremely complex. Although great progress has been made in understanding cholestasis pathogenesis, the specific mechanisms remain unclear. Therefore, it is important to understand and distinguish cholestasis from different etiologies, which will also provide indispensable theoretical support for the development of corresponding therapeutic drugs. At present, the treatment of cholestasis mainly involves several bile acids (BAs) and their derivatives, most of which are in the clinical stage of development. Multiple lines of evidence indicate that ecological disorders of the gut microbiota are strongly related to the occurrence of cholestasis, in which BAs also play a pivotal role. Recent studies indicate that probiotics seem to have certain effects on cholestasis, but further confirmation from clinical trials is required. This paper reviews the etiology of and therapeutic strategies for cholestasis; summarizes the similarities and differences in inducement, symptoms, and mechanisms of related diseases; and provides information about the latest pharmacological therapies currently available and those under research for cholestasis. We also reviewed the highly intertwined relationship between gut microbiota-BA-cholestasis, revealing the potential role and possible mechanism of probiotics in the treatment of cholestasis.
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Affiliation(s)
- Leilei Yu
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China
- School of Food Science and Technology, Jiangnan University, Wuxi, China
- International Joint Research Laboratory for Probiotics, Jiangnan University, Wuxi, Jiangsu, China
| | - Yaru Liu
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China
- School of Food Science and Technology, Jiangnan University, Wuxi, China
| | - Shunhe Wang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China
- School of Food Science and Technology, Jiangnan University, Wuxi, China
| | - Qingsong Zhang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China
- School of Food Science and Technology, Jiangnan University, Wuxi, China
| | - Jianxin Zhao
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China
- School of Food Science and Technology, Jiangnan University, Wuxi, China
- International Joint Research Laboratory for Probiotics, Jiangnan University, Wuxi, Jiangsu, China
- National Engineering Research Center for Functional Food, Jiangnan University, Wuxi, China
| | - Hao Zhang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China
- School of Food Science and Technology, Jiangnan University, Wuxi, China
- International Joint Research Laboratory for Probiotics, Jiangnan University, Wuxi, Jiangsu, China
- National Engineering Research Center for Functional Food, Jiangnan University, Wuxi, China
| | - Arjan Narbad
- International Joint Research Laboratory for Probiotics, Jiangnan University, Wuxi, Jiangsu, China
- Gut Health and Microbiome Institute Strategic Programme, Quadram Institute Bioscience, Norwich, UK
| | - Fengwei Tian
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China
- School of Food Science and Technology, Jiangnan University, Wuxi, China
- International Joint Research Laboratory for Probiotics, Jiangnan University, Wuxi, Jiangsu, China
| | - Qixiao Zhai
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China
- School of Food Science and Technology, Jiangnan University, Wuxi, China
- International Joint Research Laboratory for Probiotics, Jiangnan University, Wuxi, Jiangsu, China
| | - Wei Chen
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China
- School of Food Science and Technology, Jiangnan University, Wuxi, China
- International Joint Research Laboratory for Probiotics, Jiangnan University, Wuxi, Jiangsu, China
- National Engineering Research Center for Functional Food, Jiangnan University, Wuxi, China
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Sahni A, Jogdand SD. Effects of Intrahepatic Cholestasis on the Foetus During Pregnancy. Cureus 2022; 14:e30657. [DOI: 10.7759/cureus.30657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 10/23/2022] [Indexed: 11/05/2022] Open
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Okovityi SV, Raikhelson KL, Prikhodko VA. Combined hepatoprotective pharmacotherapy for liver disease. EXPERIMENTAL AND CLINICAL GASTROENTEROLOGY 2022:5-20. [DOI: 10.31146/1682-8658-ecg-203-7-5-20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Fixed-dose drug products as well as non-fixed hepatoprotective drug combinations are commonly used in modern clinical practice. Combined and concurrent drug use makes it possible to augment the pharmacological effects of individual agents, or extend the range of their potential indications. The drugs most commonly considered for combination therapy include essential phospholipids, glycyrrhizinic acid, ursodeoxycholic acid, silibinin, and S-adenosylmethionine. This paper discusses the rationale for combined use of liver-targeting drugs from a pathogenetic viewpoint, and provides a review of the evidence from clinical trials on combined pharmacotherapy for liver disease.
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Affiliation(s)
- Sergey V. Okovityi
- Scientific, Clinical and Educational Center of Gastroenterology and Hepatology, Saint Petersburg State University; Scientific, Clinical and Educational Center of Gastroenterology and Hepatology, Saint Petersburg State University
| | - Karina L. Raikhelson
- Scientific, Clinical and Educational Center of Gastroenterology and Hepatology, Saint Petersburg State University
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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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Ornoy A, Weinstein-Fudim L, Becker M. SAMe, Choline, and Valproic Acid as Possible Epigenetic Drugs: Their Effects in Pregnancy with a Special Emphasis on Animal Studies. Pharmaceuticals (Basel) 2022; 15:192. [PMID: 35215304 PMCID: PMC8879727 DOI: 10.3390/ph15020192] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 01/27/2022] [Accepted: 01/28/2022] [Indexed: 11/29/2022] Open
Abstract
In this review, we discuss the functions and main effects on pregnancy outcomes of three agents that have the ability to induce epigenetic modifications: valproic acid (VPA), a well-known teratogen that is a histone deacetylase inhibitor; S-adenosylmethionine (SAMe), the most effective methyl donor; and choline, an important micronutrient involved in the one methyl group cycle and in the synthesis of SAMe. Our aim was to describe the possible effects of these compounds when administered during pregnancy on the developing embryo and fetus or, if administered postnatally, their effects on the developing child. These substances are able to modify gene expression and possibly alleviate neurobehavioral changes in disturbances that have epigenetic origins, such as autism spectrum disorder (ASD), depression, Rett syndrome, and fetal alcohol spectrum disorder (FASD). Valproic acid and SAMe are antagonistic epigenetic modulators whether administered in utero or postnatally. However, VPA is a major human teratogen and, whenever possible, should not be used by pregnant women. Most currently relevant data come from experimental animal studies that aimed to explore the possibility of using these substances as epigenetic modifiers and possible therapeutic agents. In experimental animals, each of these substances was able to alleviate the severity of several well-known diseases by inducing changes in the expression of affected genes or by other yet unknown mechanisms. We believe that additional studies are needed to further explore the possibility of using these substances, and similar compounds, for the treatment of "epigenetic human diseases".
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Affiliation(s)
- Asher Ornoy
- Adelson School of Medicine, Ariel University, Ariel 40700, Israel;
- Department of Medical Neurobiology, Hebrew University Hadassah Medical School, Jerusalem 9112102, Israel;
| | - Liza Weinstein-Fudim
- Department of Medical Neurobiology, Hebrew University Hadassah Medical School, Jerusalem 9112102, Israel;
| | - Maria Becker
- Adelson School of Medicine, Ariel University, Ariel 40700, Israel;
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Walker KF, Chappell LC, Hague WM, Middleton P, Thornton JG. Pharmacological interventions for treating intrahepatic cholestasis of pregnancy. Cochrane Database Syst Rev 2020; 7:CD000493. [PMID: 32716060 PMCID: PMC7389072 DOI: 10.1002/14651858.cd000493.pub3] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
BACKGROUND Intrahepatic cholestasis of pregnancy (ICP) is a liver disorder that can develop in pregnancy. It occurs when there is a build-up of bile acids in the maternal blood. It has been linked to adverse maternal and fetal/neonatal outcomes. As the pathophysiology is poorly understood, therapies have been largely empiric. As ICP is an uncommon condition (incidence less than 2% a year), many trials have been small. Synthesis, including recent larger trials, will provide more evidence to guide clinical practice. This review is an update of a review first published in 2001 and last updated in 2013. OBJECTIVES To assess the effects of pharmacological interventions to treat women with intrahepatic cholestasis of pregnancy, on maternal, fetal and neonatal outcomes. SEARCH METHODS For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (13 December 2019), and reference lists of retrieved studies. SELECTION CRITERIA Randomised or quasi-randomised controlled trials, including cluster-randomised trials and trials published in abstract form only, that compared any drug with placebo or no treatment, or two drug intervention strategies, for women with a clinical diagnosis of intrahepatic cholestasis of pregnancy. DATA COLLECTION AND ANALYSIS The review authors independently assessed trials for eligibility and risks of bias. We independently extracted data and checked these for accuracy. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS We included 26 trials involving 2007 women. They were mostly at unclear to high risk of bias. They assessed nine different pharmacological interventions, resulting in 14 different comparisons. We judged two placebo-controlled trials of ursodeoxycholic acid (UDCA) in 715 women to be at low risk of bias. The ten different pharmacological interventions were: agents believed to detoxify bile acids (UCDA) and S-adenosylmethionine (SAMe); agents used to bind bile acids in the intestine (activated charcoal, guar gum, cholestyramine); Chinese herbal medicines (yinchenghao decoction (YCHD), salvia, Yiganling and Danxioling pill (DXLP)), and agents aimed to reduce bile acid production (dexamethasone) Compared with placebo, UDCA probably results in a small improvement in pruritus score measured on a 100 mm visual analogue scale (VAS) (mean difference (MD) -7.64 points, 95% confidence interval (CI) -9.69 to -5.60 points; 2 trials, 715 women; GRADE moderate certainty), where a score of zero indicates no itch and a score of 100 indicates severe itching. The evidence for fetal distress and stillbirth were uncertain, due to serious limitations in study design and imprecision (risk ratio (RR) 0.70, 95% CI 0.35 to 1.40; 6 trials, 944 women; RR 0.33, 95% CI 0.08 to 1.37; 6 trials, 955 women; GRADE very low certainty). We found very few differences for the other comparisons included in this review. There is insufficient evidence to indicate if SAMe, guar gum, activated charcoal, dexamethasone, cholestyramine, Salvia, Yinchenghao decoction, Danxioling and Yiganling, or Yiganling alone or in combination are effective in treating women with intrahepatic cholestasis of pregnancy. AUTHORS' CONCLUSIONS When compared with placebo, UDCA administered to women with ICP probably shows a reduction in pruritus. However the size of the effect is small and for most pregnant women and clinicians, the reduction may fall below the minimum clinically worthwhile effect. The evidence was unclear for other adverse fetal outcomes, due to very low-certainty evidence. There is insufficient evidence to indicate that SAMe, guar gum, activated charcoal, dexamethasone, cholestyramine, YCHD, DXLP, Salvia, Yiganling alone or in combination are effective in treating women with cholestasis of pregnancy. There are no trials of the efficacy of topical emollients. Further high-quality trials of other interventions are needed in order to identify effective treatments for maternal itching and preventing adverse perinatal outcomes. It would also be helpful to identify those women who are mostly likely to respond to UDCA (for example, whether bile acid concentrations affect how women with ICP respond to treatment with UDCA).
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Affiliation(s)
- Kate F Walker
- Division of Child Health, Obstetrics and Gynaecology, School of Medicine, University of Nottingham, Nottingham, UK
| | - Lucy C Chappell
- Department of Women and Children's Health, King's College London, London, UK
| | - William M Hague
- Women's and Children's Hospital, North Adelaide, Australia
- Robinson Research Institute, The University of Adelaide, North Adelaide, Australia
| | - Philippa Middleton
- Healthy Mothers, Babies and Children, South Australian Health and Medical Research Institute, Adelaide, Australia
| | - Jim G Thornton
- Division of Child Health, Obstetrics and Gynaecology, School of Medicine, University of Nottingham, Nottingham, UK
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Taylor Levine M, Gao J, Satyanarayanan SK, Berman S, Rogers JT, Mischoulon D. S-adenosyl-l-methionine (SAMe), cannabidiol (CBD), and kratom in psychiatric disorders: Clinical and mechanistic considerations. Brain Behav Immun 2020; 85:152-161. [PMID: 31301401 DOI: 10.1016/j.bbi.2019.07.013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 06/19/2019] [Accepted: 07/09/2019] [Indexed: 10/26/2022] Open
Abstract
Given the limitations of prescription antidepressants, many individuals have turned to natural remedies for the management of their mood disorders. We review three selected natural remedies that may be of potential use as treatments for depressive disorders and other psychiatric or neurological conditions. The best studied and best supported of these three remedies is S-adenosyl-l-methionine (SAMe), a methyl donor with a wide range of physiological functions in the human organism. With the increasing legalization of cannabis-related products, cannabidiol (CBD) has gained popularity for various potential indications and has even obtained approval in the United States and Canada for certain neurological conditions. Kratom, while potentially useful for certain individuals with psychiatric disorders, is perhaps the most controversial of the three remedies, in view of its greater potential for abuse and dependence. For each remedy, we will review indications, doses and delivery systems, potential anti-inflammatory and immunomodulatory action, adverse effects, and will provide recommendations for clinicians who may be considering prescribing these remedies in their practice.
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Affiliation(s)
- M Taylor Levine
- Depression Clinical and Research Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Jin Gao
- Neurochemistry Laboratory, Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Clinical Psychology, Qilu Hospital of Shandong University, Qingdao, Shandong Province, China
| | - Senthil Kumaran Satyanarayanan
- Department of Psychiatry & Mind-Body Interface Laboratory (MBI-Lab), China Medical University Hospital, Taichung, Taiwan; State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau
| | - Sarah Berman
- Depression Clinical and Research Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Jack T Rogers
- Neurochemistry Laboratory, Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - David Mischoulon
- Depression Clinical and Research Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
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Dąbrowski K, Kierach R, Grabarek BO, Boroń D, Kukla M. Effect of ursodeoxycholic acid therapy due to pregnant intrahepatic cholestasis on chemerin and irisin levels. Dermatol Ther 2020; 33:e13272. [PMID: 32061000 DOI: 10.1111/dth.13272] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 02/08/2020] [Accepted: 02/11/2020] [Indexed: 12/15/2022]
Abstract
The purpose of the work was to assess changes in chemerin and irisin levels in women with diagnosed intrahepatic cholestasis of pregnant women treated with ursodeoxycholic acid. The study group consisted of 50 patients with diagnosed and confirmed intrahepatic cholestasis of pregnant women at 24-25 weeks of pregnancy treatment by ursodeoxycholic acid (UDCA). The study also included a group of 40 pregnant women, without concomitant intrahepatic cholestasis of pregnancy (ICP). In the pregnant ICP group, whole blood was collected 4 times: before the first dose of drug, 4 and 8 weeks after the first dose, and day after delivery. It was observed that statistically significant differences in the concentration of irisine occur between the time before starting treatment and the 8-week therapy and 1 day after delivery. The Pearson correlation analysis (r's) showed two statistically significant relationships (p < .05). The first of these can be found between the concentration of irisine and chemerin in the group of nonpregnant women and the second in the group of patients with intrahepatic pregnant cholestasis before the first dose of UDCA. A significant relationship between irisin and chemerin concentrations was confirmed in the group of pregnant ICP patients during UDCA acid therapy and among healthy pregnant women.
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Affiliation(s)
| | - Rafał Kierach
- Gynecology and Obstetrics Ward District Railway Hospital, Katowice, Poland
| | - Beniamin O Grabarek
- Maria Sklodowska-Curie National Research Institute of Oncology, Krakow Branch, Kraków, Poland.,Department of Histology, Cytophysiology and Embryology in Zabrze, University of Technology, Faculty of Medicine, Katowice, Poland
| | - Dariusz Boroń
- Department of Histology, Cytophysiology and Embryology in Zabrze, University of Technology, Faculty of Medicine, Katowice, Poland.,Faculty of Health Science, Public Higher Medical Professional School, Opole, Poland.,Department of Gynecology and Obstetrics with Gynecologic Oncology, Ludwik Rydygier Memorial Specialized Hospital, Kraków, Poland
| | - Michał Kukla
- Department of Endoscopy, University Hospital, Kraków, Poland
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Intrahepatic Cholestasis of Pregnancy: A Case Study of the Rare Onset in the First Trimester. ACTA ACUST UNITED AC 2019; 55:medicina55080454. [PMID: 31404990 PMCID: PMC6723234 DOI: 10.3390/medicina55080454] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 08/06/2019] [Accepted: 08/07/2019] [Indexed: 12/27/2022]
Abstract
Intrahepatic cholestasis of pregnancy (ICP) is a gestation-specific liver disorder, defined most often as the onset of pruritus, usually from the third trimester of pregnancy, associated with abnormal liver test results and/or increased total serum bile acids and spontaneous relief after delivery. The 21-year-old patient was admitted to our ward in the 11th week of pregnancy due to raised liver enzymes. The first onset of pruritus and jaundice appeared a month before hospitalization. Immunology tests and Toxoplasma gondii were negative. We excluded viral etiology, while alpha-1-antitrypsin, serum and urine copper levels, and thyroid hormones were within the reference values. The patient denied she had taken any medicines and herbal preparations before and during pregnancy. Total bile acids in the serum were significantly elevated (242 μmol/L). The abdominal ultrasound revealed a regular finding. Liver biopsy suggested a cholestatic liver disorder. After a presentation of all risks, the patient decided to stop the pregnancy. After a month, the hepatogram was within the reference values. Very rarely an ICP can occur in early pregnancy (first trimester), which calls for close monitoring. The risk of serious adverse fetal outcomes and spontaneous preterm delivery is proportional with increased levels of maternal serum bile acid.
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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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Henkel SAF, Squires JH, Ayers M, Ganoza A, Mckiernan P, Squires JE. Expanding etiology of progressive familial intrahepatic cholestasis. World J Hepatol 2019; 11:450-463. [PMID: 31183005 PMCID: PMC6547292 DOI: 10.4254/wjh.v11.i5.450] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Revised: 04/19/2019] [Accepted: 04/27/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Progressive familial intrahepatic cholestasis (PFIC) refers to a disparate group of autosomal recessive disorders that are linked by the inability to appropriately form and excrete bile from hepatocytes, resulting in a hepatocellular form of cholestasis. While the diagnosis of such disorders had historically been based on pattern recognition of unremitting cholestasis without other identified molecular or anatomic cause, recent scientific advancements have uncovered multiple specific responsible proteins. The variety of identified defects has resulted in an ever-broadening phenotypic spectrum, ranging from traditional benign recurrent jaundice to progressive cholestasis and end-stage liver disease.
AIM To review current data on defects in bile acid homeostasis, explore the expanding knowledge base of genetic based diseases in this field, and report disease characteristics and management.
METHODS We conducted a systemic review according to PRISMA guidelines. We performed a Medline/PubMed search in February-March 2019 for relevant articles relating to the understanding, diagnosis, and management of bile acid homeostasis with a focus on the family of diseases collectively known as PFIC. English only articles were accessed in full. The manual search included references of retrieved articles. We extracted data on disease characteristics, associations with other diseases, and treatment. Data was summarized and presented in text, figure, and table format.
RESULTS Genetic-based liver disease resulting in the inability to properly form and secrete bile constitute an important cause of morbidity and mortality in children and increasingly in adults. A growing number of PFIC have been described based on an expanded understanding of biliary transport mechanism defects and the development of a common phenotype.
CONCLUSION We present a summary of current advances made in a number of areas relevant to both the classically described FIC1 (ATP8B1), BSEP (ABCB11), and MDR3 (ABCB4) transporter deficiencies, as well as more recently described gene mutations -- TJP2 (TJP2), FXR (NR1H4), MYO5B (MYO5B), and others which expand the etiology and understanding of PFIC-related cholestatic diseases and bile transport.
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Affiliation(s)
- Sarah AF Henkel
- Division of Gastroenterology, Hepatology, and Nutrition, Emory School of Medicine, Atlanta, GA 30322, United States
| | - Judy H Squires
- Department of Radiology, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, United States
| | - Mary Ayers
- Division of Gastroenterology, Hepatology, and Nutrition, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, United States
| | - Armando Ganoza
- Division of Pediatric Transplantation, Department of Surgery, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, United States
| | - Patrick Mckiernan
- Division of Gastroenterology, Hepatology, and Nutrition, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, United States
| | - James E Squires
- Division of Gastroenterology, Hepatology, and Nutrition, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, United States
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Shen Y, Zhou J, Zhang S, Wang XL, Jia YL, He S, Wang YY, Li WC, Shao JG, Zhuang X, Liu YL, Qin G. Is It Necessary to Perform the Pharmacological Interventions for Intrahepatic Cholestasis of Pregnancy? A Bayesian Network Meta-Analysis. Clin Drug Investig 2019; 39:15-26. [PMID: 30357607 DOI: 10.1007/s40261-018-0717-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND OBJECTIVE Although many meta-analyses have evaluated the pharmacotherapy of intrahepatic cholestasis of pregnancy (ICP) and recommended ursodeoxycholic acid (UDCA) as an effective treatment, the defect of the pair-wise analyses and the mixture of the control group made the outcome uncertain and unclear. We aimed to employ Bayesian network meta-analysis (NMA) to compare the maternal and fetal outcomes after UDCA, S-adenosylmethionine (SAMe) mono-therapy or the combination treatment of these two drugs for ICP patients. METHODS Multiple electronic database searches were conducted for articles published up to 1 September 2018. The relevant information was extracted from the published reports with a predefined data extraction sheet, and the risk of bias was assessed with the Cochrane risk-of-bias tool. Poisson Bayesian network meta-analysis was employed to identify the synthesized evidence from the relevant trials, with reporting hazard risks (HRs) and 95% credible intervals (CrIs). RESULTS The pooled outcomes of the 13 randomized controlled trials (RCTs) with 625 participants indicated that none of the three regimens can significantly improve maternal and fetal outcomes. CONCLUSION This NMA of the RCTs clarified that the current intervention has no favorable effect on pruritus and other symptoms in ICP patients.
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Affiliation(s)
- Yi Shen
- Department of Epidemiology and Medical Statistics, School of Public Health, Nantong University, Nantong, China
| | - Jie Zhou
- Department of Epidemiology and Medical Statistics, School of Public Health, Nantong University, Nantong, China
| | - Sheng Zhang
- Department of Epidemiology and Medical Statistics, School of Public Health, Nantong University, Nantong, China
| | - Xu-Lin Wang
- Department of Epidemiology and Medical Statistics, School of Public Health, Nantong University, Nantong, China
| | - Yu-Long Jia
- Department of Epidemiology and Medical Statistics, School of Public Health, Nantong University, Nantong, China
| | - Shu He
- Department of Epidemiology and Medical Statistics, School of Public Health, Nantong University, Nantong, China
| | - Yuan-Yuan Wang
- Department of Epidemiology and Medical Statistics, School of Public Health, Nantong University, Nantong, China
| | - Wen-Chao Li
- Department of Epidemiology and Medical Statistics, School of Public Health, Nantong University, Nantong, China
| | - Jian-Guo Shao
- Center for Liver Diseases, Nantong Third People's Hospital, Nantong University, 60 Mid-Youth Road, Nantong, 226006, Jiangsu, China
| | - Xun Zhuang
- Department of Epidemiology and Medical Statistics, School of Public Health, Nantong University, Nantong, China
| | - Yuan-Lin Liu
- Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Nantong, China
| | - Gang Qin
- Center for Liver Diseases, Nantong Third People's Hospital, Nantong University, 60 Mid-Youth Road, Nantong, 226006, Jiangsu, China.
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New Insights in Genetic Cholestasis: From Molecular Mechanisms to Clinical Implications. Can J Gastroenterol Hepatol 2018; 2018:2313675. [PMID: 30148122 PMCID: PMC6083523 DOI: 10.1155/2018/2313675] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Revised: 07/10/2018] [Accepted: 07/17/2018] [Indexed: 02/06/2023] Open
Abstract
Cholestasis is characterised by impaired bile secretion and accumulation of bile salts in the organism. Hereditary cholestasis is a heterogeneous group of rare autosomal recessive liver disorders, which are characterised by intrahepatic cholestasis, pruritus, and jaundice and caused by defects in genes related to the secretion and transport of bile salts and lipids. Phenotypic manifestation is highly variable, ranging from progressive familial intrahepatic cholestasis (PFIC)-with onset in early infancy and progression to end-stage liver disease-to a milder intermittent mostly nonprogressive form known as benign recurrent intrahepatic cholestasis (BRIC). Cases have been reported of initially benign episodic cholestasis that subsequently transitions to a persistent progressive form of the disease. Therefore, BRIC and PFIC seem to represent two extremes of a continuous spectrum of phenotypes that comprise one disease. Thus far, five representatives of PFIC (named PFIC1-5) caused by pathogenic mutations present in both alleles of ATP8B1, ABCB11, ABCB4, TJP2, and NR1H4 have been described. In addition to familial intrahepatic cholestasis, partial defects in ATP8B1, ABCB11, and ABCB4 predispose patients to drug-induced cholestasis and intrahepatic cholestasis in pregnancy. This review summarises the current knowledge of the clinical manifestations, genetics, and molecular mechanisms of these diseases and briefly outlines the therapeutic options, both conservative and invasive, with an outlook for future personalised therapeutic strategies.
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Sanhal CY, Daglar K, Kara O, Yılmaz ZV, Turkmen GG, Erel O, Uygur D, Yucel A. An alternative method for measuring oxidative stress in intrahepatic cholestasis of pregnancy: thiol/disulphide homeostasis. J Matern Fetal Neonatal Med 2017; 31:1477-1482. [DOI: 10.1080/14767058.2017.1319922] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Cem Yasar Sanhal
- Department of Perinatology, Zekai Tahir Burak Women's Health Care, Training and Research Hospital, Ankara, Turkey
| | - Korkut Daglar
- Department of Perinatology, Zekai Tahir Burak Women's Health Care, Training and Research Hospital, Ankara, Turkey
| | - Ozgur Kara
- Department of Perinatology, Zekai Tahir Burak Women's Health Care, Training and Research Hospital, Ankara, Turkey
| | - Zehra Vural Yılmaz
- Department of Perinatology, Zekai Tahir Burak Women's Health Care, Training and Research Hospital, Ankara, Turkey
| | | | - Ozcan Erel
- Department of Clinical Biochemistry, Faculty of Medicine, Yildirim Beyazit University, Ankara, Turkey
| | - Dilek Uygur
- Department of Perinatology, Zekai Tahir Burak Women's Health Care, Training and Research Hospital, Ankara, Turkey
| | - Aykan Yucel
- Department of Perinatology, Zekai Tahir Burak Women's Health Care, Training and Research Hospital, Ankara, Turkey
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Kong X, Kong Y, Zhang F, Wang T, Yan J. Evaluating the effectiveness and safety of ursodeoxycholic acid in treatment of intrahepatic cholestasis of pregnancy: A meta-analysis (a prisma-compliant study). Medicine (Baltimore) 2016; 95:e4949. [PMID: 27749550 PMCID: PMC5059052 DOI: 10.1097/md.0000000000004949] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Intrahepatic cholestasis of pregnancy (ICP) is a specific pregnancy-related disorder without standard medical therapies. Ursodeoxycholic acid (UDCA) is the most used medicine, but the efficacy and safety of UDCA remain uncertain. Several meta-analyses had been made to assess the effects of UDCA in ICP. However, the samples were not large enough to convince obstetricians to use UDCA. We conducted a meta-analysis to evaluate the effects and safety of UDCA in patients with ICP, which included only randomized controlled trials (RCTs). METHODS Six databases were searched. The search terms were "ursodeoxycholicacid," "therapy," "management," "treatment," "intrahepatic cholestasis of pregnancy," "obstetric cholestasis," "recurrent jaundice of pregnancy," "pruritus gravidarum," "idiopathic jaundice of pregnancy," "intrahepatic jaundice of pregnancy," and "icterus gravidarum."Randomized controlled trials of UDCA versus control groups (included using other medicines) among patients with ICP were included. The primary outcomes were improved pruritus scores and liver function. Secondary outcomes were the maternal and fetal outcomes in patients with ICP.Data were extracted from included RCTs. The Mantel-Haenzel random-effects model or fixed-effects model was used for meta-analysis. RESULTS A total of 12 RCTs involving 662 patients were included in the meta-analysis. In pooled analyses that compared UDCA with all controls, UDCA was associated with resolution of pruritus (risk ratio [RR], 1.68; 95% confidence interval [CI],1.12-2.52; P = 0.01),decrease of serum levels of alanine aminotransferase (ALT) (standardized mean difference (SMD), -1.36; 95% CI, -2.08 to -0.63; P <0.001), reduced serum levels of bile acid (SMD, -0.68; 95% CI, -1.15 to -0.20; P <0.001), fewer premature births (RR, 0.56; 95% CI, 0.43-0.72; P <0.001),reduced fetal distress (RR, 0.68; 95% CI, 0.49-0.94; P = 0.02), high Apgar scores at 5 minutes (RR, 0.44; 95% CI, 0.24-0.82; P = 0.009), less frequent respiratory distress syndrome (RDS) (RR, 0.33; 95% CI, 0.13-0.86; P = 0.02), and fewer neonates in the intensive care unit (NICU) (RR, 0.55; 95% CI, 0.35-0.87; P <0.05), increased gestational age (SMD,0.44; 95% CI, 0.26-0.63; P <0.001), and birth weight (SMD, 0.21; 95% CI, 0.02-0.40; P = 0.03). There were no differences in meconium staining and intrauterine growth retardation (IUGR) between the groups (P >0.05). No trials reported adverse effects on mothers and fetuses except nausea and emesis. CONCLUSION UDCA is effective and safe to improve pruritus and liver function in ICP. UDCA also reduced adverse maternal and fetal outcomes in pregnant women with ICP.
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Affiliation(s)
- Xiang Kong
- Department of Obstetrics and Gynecology, Clinical Medical College of Yangzhou University, Yangzhou, Jiangsu, China
- Correspondence: Xiang Kong, No. 98, West Nantong Road, Yangzhou, 225001, Jiangsu Province, China (e-mail: )
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Zhang Y, Lu L, Victor DW, Xin Y, Xuan S. Ursodeoxycholic Acid and S-adenosylmethionine for the Treatment of Intrahepatic Cholestasis of Pregnancy: A Meta-analysis. HEPATITIS MONTHLY 2016; 16:e38558. [PMID: 27799965 PMCID: PMC5075145 DOI: 10.5812/hepatmon.38558] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/17/2016] [Revised: 06/22/2016] [Accepted: 06/28/2016] [Indexed: 12/11/2022]
Abstract
CONTEXT An optimal therapeutic strategy has not yet been identified for the pharmacological treatment of intrahepatic cholestasis of pregnancy (ICP). The aim of this study was to evaluate the efficacy and safety of ursodeoxycholic acid (UDCA) and S-adenosylmethionine (SAMe) in the treatment of ICP, both individually and in combination. EVIDENCE ACQUISITION A meta-analysis of all randomized controlled trials (RCTs) comparing UDCA, SAMe, and combination therapy was performed. We carried out a literature search using pubmed, embase, the cochrane register of controlled trials, and the science citation index of web of science. The maternal clinical and biochemical responses, including pruritus scores, total bilirubin, total bile acids, alanine aminotransferase, and aspartate transaminase, were evaluated. Safety assessments, including preterm delivery, cesarean section, and meconium-stained amniotic fluid, were also analyzed. RESULTS Five RCTs including 311 patients were evaluated. In comparison to SAMe, UDCA significantly reduced the pruritus score (OR = -0.45, 95% confidence interval [CI]: -0.66 to -0.25, P < 0.0001) and improved the levels of total bile acids (TBAs; OR = -0.59, 95% CI: -0.99 to -0.30, P < 0.0001) and alanine aminotransferase (ALT; OR = -0.38, 95% CI: -0.66 to -0.09, P = 0.01). UDCA was associated with significantly lower preterm delivery rates than SAMe (RR = 0.48, 95% CI: 0.32-0.72, P = 0.0004). Interestingly, combination therapy significantly reduced total bilirubin (TB; vs. SAMe, OR = -0.41, 95% CI, -0.74 to -0.08, P = 0.02), aspartate transaminase (AST; vs. UDCA, OR = -0.40, 95% CI, -0.74 to -0.06, P = 0.02), and the rate of preterm delivery (vs. SAMe, OR = 0.62, 95% CI, 0.42 - 0.91, P = 0.02), in comparison with either drug administered alone. CONCLUSIONS UDCA decreased the pruritus score, TBA, and ALT levels more effectively than SAMe, reducing the rate of preterm delivery for ICP.
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Affiliation(s)
- Yang Zhang
- Medical College, Qingdao University, Qingdao, China
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao, China
| | - Linlin Lu
- Digestive Disease Key Laboratory of Qingdao, Qingdao, China
- Central Laboratories, Qingdao Municipal Hospital, Qingdao, China
| | - David W Victor
- Hepatology and Transplant Medicine, Department of Medicine, Houston Methodist Hospital, Houston, USA
| | - Yongning Xin
- Medical College, Qingdao University, Qingdao, China
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao, China
- Digestive Disease Key Laboratory of Qingdao, Qingdao, China
- Corresponding Authors: Shiying Xuan, Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao, Shandong Province, China. Tel: +86-53288905508, Fax: +86-53288905293, E-mail: ; Yongning Xin, Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao, Shandong Province, China. Tel: +86-53282789463, Fax: +86-53285968434, E-mail:
| | - Shiying Xuan
- Medical College, Qingdao University, Qingdao, China
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao, China
- Digestive Disease Key Laboratory of Qingdao, Qingdao, China
- Corresponding Authors: Shiying Xuan, Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao, Shandong Province, China. Tel: +86-53288905508, Fax: +86-53288905293, E-mail: ; Yongning Xin, Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao, Shandong Province, China. Tel: +86-53282789463, Fax: +86-53285968434, E-mail:
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Abstract
Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disease during pregnancy, characterized by otherwise unexplained pruritus in late second and third trimester of pregnancy and elevated bile acids and/or transaminases. ICP is associated with an increased risk of adverse perinatal outcomes for the fetus and the later development of hepatobiliary disease for the mother. Bile acids should be monitored throughout pregnancy since fetal risk is increased at serum bile acids >40 µmol/l. Management of ICP consists of treatment with ursodeoxycholic acid, which reduces pruritus. Early elective delivery is common practice but should be performed on an individualized basis as long as strong evidence supporting this practice is lacking. Mothers should be followed-up for normalization of liver function tests 6-12 weeks after delivery. Future research in large-scale studies is needed to address the impact of ursodeoxycholic acid and early elective delivery on fetal outcome.
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Affiliation(s)
- Hanns-Ulrich Marschall
- a Department of Molecular and Clinical Medicine, University of Gothenburg, Sahlgrenska Academy, Institute of Medicine, S-41345 Gothenburg, Sweden
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Grymowicz M, Czajkowski K, Smolarczyk R. Pregnancy course in patients with intrahepatic cholestasis of pregnancy treated with very low doses of ursodeoxycholic acid. Scand J Gastroenterol 2016; 51:78-85. [PMID: 26152830 DOI: 10.3109/00365521.2015.1064990] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Ursodeoxycholic acid (UDCA) has been proposed as the optimal pharmacological treatment for intrahepatic cholestasis of pregnancy (ICP). The lowest effective dosage of UDCA in women with ICP has not been established. The objective is to determine the risk of adverse pregnancy outcomes resulting from ICP and to measure changes in liver function parameters and pruritus severity in ICP patients treated with low doses of UDCA. MATERIAL AND METHODS ICP was diagnosed in 203 patients on the basis of pruritus and elevated liver biochemical parameters. Patients with total bile acids (TBA) ≥ 10 μmol/l (n = 157) received UDCA (300-450 mg/day; 4-6 mg/kg/day) until delivery. Maternal and fetal outcomes of women with ICP were compared with 100 patients without cholestasis. Patients with ICP were hospitalized for treatment and fetal surveillance. RESULTS There was no correlation between fetal and neonatal complication rates in ICP patients and biochemical markers of cholestasis. Significant declines in serum TBA (p = 0.003), bilirubin concentration (p = 0.026) and aminotransferase activity (p < 0.001) were observed during treatment with low doses of UDCA. Moreover, severity of pruritus was ameliorated during the 2 weeks of therapy (p = 0.037). A total of 17 patients (10.9%) did not respond to treatment. CONCLUSIONS UDCA at low doses improved biochemical markers and clinical symptoms in almost 90% of ICP patients.
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Affiliation(s)
- Monika Grymowicz
- a 1 Department of Gynecological Endocrinology, Warsaw Medical University , Warsaw, Poland
| | - Krzysztof Czajkowski
- b 2 II Department of Obstetrics and Gynaecology, Warsaw Medical University , Warsaw, Poland
| | - Roman Smolarczyk
- a 1 Department of Gynecological Endocrinology, Warsaw Medical University , Warsaw, Poland
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Abstract
Intrahepatic cholestasis of pregnancy is the most common pregnancy-specific liver disease that typically presents in the third trimester. The clinical features are maternal pruritus in the absence of a rash and deranged liver function tests, including raised serum bile acids. Intrahepatic cholestasis of pregnancy is associated with an increased risk of adverse perinatal outcomes, including spontaneous preterm delivery, meconium staining of the amniotic fluid, and stillbirth. It is commonly treated with ursodeoxycholic acid. There is accumulating evidence to suggest that intrahepatic cholestasis of pregnancy has a lasting influence on both maternal and fetal health. We review the etiology, diagnosis, and management of this intriguing condition.
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Nguyen KD, Sundaram V, Ayoub WS. Atypical causes of cholestasis. World J Gastroenterol 2014; 20:9418-9426. [PMID: 25071336 PMCID: PMC4110573 DOI: 10.3748/wjg.v20.i28.9418] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2013] [Revised: 03/13/2014] [Accepted: 04/05/2014] [Indexed: 02/06/2023] Open
Abstract
Cholestatic liver disease consists of a variety of disorders. Primary sclerosing cholangitis and primary biliary cirrhosis are the most commonly recognized cholestatic liver disease in the adult population, while biliary atresia and Alagille syndrome are commonly recognized in the pediatric population. In infants, the causes are usually congenital or inherited. Even though jaundice is a hallmark of cholestasis, it is not always seen in adult patients with chronic liver disease. Patients can have "silent" progressive cholestatic liver disease for years prior to development of symptoms such as jaundice and pruritus. In this review, we will discuss some of the atypical causes of cholestatic liver disease such as benign recurrent intrahepatic cholestasis, progressive familial intrahepatic cholestasis, Alagille Syndrome, biliary atresia, total parenteral nutrition induced cholestasis and cholestasis secondary to drug induced liver injury.
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Grand’Maison S, Durand M, Mahone M. The Effects of Ursodeoxycholic Acid Treatment for Intrahepatic Cholestasis of Pregnancy on Maternal and Fetal Outcomes: A Meta-Analysis Including Non-Randomized Studies. JOURNAL OF OBSTETRICS AND GYNAECOLOGY CANADA 2014; 36:632-641. [DOI: 10.1016/s1701-2163(15)30544-2] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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25
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Kroumpouzos G. Specific dermatoses of pregnancy: advances and controversies. ACTA ACUST UNITED AC 2014. [DOI: 10.1586/edm.10.59] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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26
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Kia L, Rinella ME. Interpretation and management of hepatic abnormalities in pregnancy. Clin Gastroenterol Hepatol 2013; 11:1392-8. [PMID: 23707777 DOI: 10.1016/j.cgh.2013.05.016] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2013] [Revised: 05/09/2013] [Accepted: 05/09/2013] [Indexed: 02/06/2023]
Abstract
The spectrum of liver disease in pregnancy includes liver disease unrelated to pregnancy, liver diseases that occur with increased frequency or severity in pregnancy, and liver disease specific to pregnancy. Diseases of the liver unique to pregnancy reliably occur at specific points in the gestational spectrum. Thus, gestational age, a comprehensive history, and a clinically driven diagnostic evaluation is critical in approaching a pregnant patient with abnormal liver chemistries or function. Early recognition of these conditions is important and although management may be expectant, some patients require targeted therapy or necessitate prompt delivery, which can be life-saving to both mother and child.
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Affiliation(s)
- Leila Kia
- Department of Medicine, Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
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27
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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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28
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Gurung V, Stokes M, Middleton P, Milan SJ, Hague W, Thornton JG. Interventions for treating cholestasis in pregnancy. Cochrane Database Syst Rev 2013; 2013:CD000493. [PMID: 23794285 PMCID: PMC7043272 DOI: 10.1002/14651858.cd000493.pub2] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND Obstetric cholestasis has been linked to adverse maternal and fetal/neonatal outcomes. As the pathophysiology is poorly understood, therapies have been empiric. The first version of this review, published in 2001, and including nine randomised controlled trials involving 227 women, concluded that there was insufficient evidence to recommend any of the interventions alone or in combination. This is the first update. OBJECTIVES To evaluate the effectiveness and safety of therapeutic and delivery interventions in women with cholestasis of pregnancy. SEARCH METHODS We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (20 February 2013) and reference lists of identified studies. SELECTION CRITERIA Randomised controlled trials that compared two intervention strategies for women with a clinical diagnosis of obstetric cholestasis. DATA COLLECTION AND ANALYSIS The review authors independently assessed trials for eligibility and risk of bias. We independently extracted data and checked these for accuracy. MAIN RESULTS We included 21 trials with a total of 1197 women. They were mostly at moderate to high risk of bias. They assessed 11 different interventions resulting in 15 different comparisons.Compared with placebo, ursodeoxycholic acid (UDCA) showed improvement in pruritus in five (228 women) out of seven trials. There were no significant differences in instances of fetal distress in the UDCA groups compared with placebo (average risk ratio (RR) 0.67; 95% confidence interval (CI) 0.22 to 2.02; five trials, 304 women; random-effects analysis: T² = 0.74; I² = 48%). There were significantly fewer total preterm births with UDCA (RR 0.46; 95% CI 0.28 to 0.73; two trials, 179 women). The difference for spontaneous preterm births was not significant (RR 0.99; 95% CI 0.41 to 2.36, two trials, 109 women).Two trials (48 women) reported lower (better) pruritus scores for S-adenosylmethionine (SAMe) compared with placebo, while two other trials of 34 women reported no significant differences between groups.UDCA was more effective in improving pruritus than either SAMe (four trials; 133 women) or cholestyramine (one trial; 84 women), as was combined UDCA+SAMe when compared with placebo (one trial; 16 women) and SAMe alone (two trials; 68 women). However, combined UDCA+SAMe was no more effective than UDCA alone in regard to pruritus improvement (one trial; 53 women) and two trials (80 women) reported data were insufficient to draw any conclusions from. In one trial comparing UDCA and dexamethasone (83 women), a significant improvement with UDCA was seen only in a subgroup of women with severe obstetric cholestasis (23 women).Danxiaoling significantly improved pruritus in comparison to Yiganling. No significant differences were seen in pruritus improvement with other interventions.Eight trials reported fetal or neonatal deaths, with two deaths reported overall (both in the placebo groups).Women receiving UDCA and cholestyramine experienced nausea, vomiting and diarrhoea. Guar gum caused mild abdominal distress, diarrhoea and flatulence during the first days of treatment. Women found charcoal suspension unpleasant to swallow. Dexamethasone caused nausea, dizziness and stomach pain in one woman.One trial (62 women) looked at the timing of delivery intervention. There were no stillbirths or neonatal deaths in 'early delivery' or the 'await spontaneous labour' group. There were no significant differences in the rates of caesarean section, meconium passage or admission to neonatal intensive care unit between the two groups. AUTHORS' CONCLUSIONS Different approaches to assessing and reporting pruritus precluded pooling of trials comparing the effects of UDCA versus placebo on pruritus, but examination of individual trials suggests that UDCA significantly improves pruritus, albeit by a small amount. Fewer instances of fetal distress/asphyxial events were seen in the UDCA groups when compared with placebo but the difference was not statistically significant. Large trials of UDCA to determine fetal benefits or risks are needed.A single trial was too small to rule in or out a clinically important effect of early term delivery on caesarean section.There is insufficient evidence to indicate that SAMe, guar gum, activated charcoal, dexamethasone, cholestyramine, Salvia, Yinchenghao decoction (YCHD), Danxioling and Yiganling, or Yiganling alone or in combination are effective in treating women with cholestasis of pregnancy.
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Affiliation(s)
- Vinita Gurung
- University of NottinghamDepartment of Obstetrics and GynaecologyNottingham City Hospital NHS TrustHucknall RoadNottinghamNottinghamshireUKNG5 1PB
| | - Michael Stokes
- The University of AdelaideDiscipline of Obstetrics and Gynaecology1st Floor, Queen Victoria Building, Women's and Children's Hospital72 King William RoadNorth AdelaideSAAustralia5006
| | - Philippa Middleton
- Healthy Mothers, Babies and Children, South Australian Health and Medical Research InstituteWomen's and Children's Hospital72 King William RoadAdelaideSouth AustraliaAustralia5006
| | | | - William Hague
- Women's and Children's HospitalKing William RoadAdelaideSouth AustraliaAustraliaSA 5006
| | - Jim G Thornton
- University of NottinghamDivision of Child Health, Obstetrics and Gynaecology, School of MedicineNottingham City Hospital NHS TrustHucknall RoadNottinghamNottinghamshireUKNG5 1PB
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Malek S, Sinclair E, Hosgood G, Moens NMM, Baily T, Boston SE. Clinical findings and prognostic factors for dogs undergoing cholecystectomy for gall bladder mucocele. Vet Surg 2013; 42:418-26. [PMID: 23330871 DOI: 10.1111/j.1532-950x.2012.01072.x] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
OBJECTIVE To report clinical findings and explore prognostic factors for dogs that had cholecystectomy for gall bladder mucocele. STUDY DESIGN Retrospective case series. ANIMALS Dogs (n = 43) with gall bladder mucoceles. RESULTS Diagnosis of gall bladder mucoceles was confirmed by histopathology and 74% were diagnosed based on preoperative abdominal ultrasonography. Intraoperative evidence of gall bladder rupture was noted in 10 dogs (23%), and 16 (37%) had evidence of previous leakage in the abdominal cavity. One dog had positive bacterial growth from the gall bladder content. The most common histopathologic findings in liver biopsies obtained at surgery were cholangiohepatitis, biliary hyperplasia, or cholestasis. Univariate analysis showed evidence of postoperative hypotension (P = .05) to be significantly negatively associated with survival. Significant difference in mean postoperative serum lactate (P = .034) and postoperative packed cell volume (P = .063) between dogs that survived and died was also noted. CONCLUSIONS Elevations in postoperative serum lactate concentrations and immediate postoperative hypotension in dogs undergoing cholecystectomy for gall bladder mucoceles are associated with poor clinical outcome.
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Affiliation(s)
- Sarah Malek
- Department of Companion Animals, Atlantic Veterinary College, University of Prince Edward Island, Canada.
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30
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Bacq Y, Sentilhes L, Reyes HB, Glantz A, Kondrackiene J, Binder T, Nicastri PL, Locatelli A, Floreani A, Hernandez I, Di Martino V. Efficacy of ursodeoxycholic acid in treating intrahepatic cholestasis of pregnancy: a meta-analysis. Gastroenterology 2012; 143:1492-1501. [PMID: 22892336 DOI: 10.1053/j.gastro.2012.08.004] [Citation(s) in RCA: 152] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2011] [Revised: 07/14/2012] [Accepted: 08/07/2012] [Indexed: 12/21/2022]
Abstract
BACKGROUND & AIMS We performed a meta-analysis to evaluate the effects of ursodeoxycholic acid (UDCA) on pruritus, liver test results, and outcomes of babies born to women with intrahepatic cholestasis of pregnancy (ICP). METHODS We performed a systematic review of 9 published, randomized controlled trials (3 double blinded) that compared the effects of UDCA to other drugs, placebo, or no specific treatment (controls) in patients with ICP. We analyzed data from 454 patients: 207 received only UDCA, 70 received only placebo, 42 received cholestyramine, 36 received dexamethasone for 1 week and then placebo for 2 weeks, 65 received S-adenosyl-methionine, and 34 received no specific treatment. To achieve consistency among end points, a standard questionnaire was sent to all corresponding authors. For each end point, we performed pooled analysis that compared the effects of UDCA with those of all controls and UDCA with those of placebos. RESULTS In pooled analyses that compared UDCA with all controls, UDCA was associated with total resolution of pruritus (odds ratio [OR], 0.23; 95% confidence interval [CI], 0.07-0.74; P < .01), reduced pruritis (OR, 0.27; 95% CI, 0.13-0.55; P < .0001), normalization of serum levels of alanine aminotransferase (ALT) (OR, 0.23; 95% CI, 0.10-0.50; P < .001), decreased serum level of ALT (OR, 0.24; 95% CI, 0.11-0.52; P < .0001), reduced serum levels of bile acids (OR, 0.37; 95% CI, 0.19-0.75; P < .001), fewer premature births (OR, 0.44; 95% CI, 0.24-0.79; P < .01), reduced fetal distress (OR, 0.46; 95% CI, 0.25-0.86; P < .01), less frequent respiratory distress syndrome (OR, 0.30; 95% CI, 0.12-0.74; P < .01), and fewer neonates in the intensive care unit (OR, 0.49; 95% CI, 0.25-0.98; P = .046). In pooled analyses that compared the effects of UDCA with placebo, UDCA reduced pruritus (OR, 0.21; 95% CI, 0.07-0.62; P < .01), normalized (OR, 0.18; 95% CI, 0.06-0.52; P < .001) or decreased serum levels of ALT (OR, 0.12; 95% CI, 0.05-0.31; P < .0001), and reduced serum levels of bile acids (OR, 0.30; 95% CI, 0.12-0.73; P < .01). CONCLUSIONS Based on a meta-analysis, UDCA is effective in reducing pruritus and improving liver test results in patients with ICP; UDCA therapy might also benefit fetal outcomes.
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Affiliation(s)
- Yannick Bacq
- Service d'Hépatogastroentérologie, CHRU de Tours, Tours, France.
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Carey EJ, Lindor KD. Current pharmacotherapy for cholestatic liver disease. Expert Opin Pharmacother 2012; 13:2473-84. [PMID: 23094715 DOI: 10.1517/14656566.2012.736491] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
IMPORTANCE OF THE FIELD The cholestatic liver diseases comprise a heterogeneous group of disorders which, left untreated, usually progresses to cirrhosis and liver failure. Most are recognized before the onset of advanced fibrosis, thereby affording an opportunity for disease modifying therapy. AREAS COVERED This review will cover the current pharmacologic management of the most common causes of cholestatic liver disease in adults, including primary biliary cirrhosis, primary biliary cirrhosis-autoimmune hepatitis overlap syndrome, primary sclerosing cholangitis, intrahepatic cholestasis of pregnancy, intestinal failure-associated liver disease, and immunoglobulin G4-associated cholangitis. Pharmacologic management of complications of cholestasis will also be reviewed. EXPERT OPINION Effective therapy for most cholestatic liver disease is lacking. Ursodeoxycholic acid (UDCA) slows the progression of primary biliary cirrhosis but the majority of patients do not have a full response. Even in those with a complete response, UDCA does not cure the disease. There is currently no effective medical therapy for primary sclerosing cholangitis. Symptoms and serum liver biochemistry values in intrahepatic cholestasis of pregnancy are improved with UDCA, but it is not certain if this alters the course of disease. Immunoglobulin G4-associated cholangitis is responsive to steroids but may relapse. The farnesoid X receptor agonists are a promising new class of drugs currently being tested in cholestatic liver disease.
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Affiliation(s)
- Elizabeth J Carey
- Mayo Clinic in Arizona, Division of Hepatology, Phoenix, AZ 85054, USA.
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32
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Abstract
Pruritus is a troublesome complication in patients with cholestatic liver disease. Several links to its pathogenesis have been proposed, including the role of bile acids, endogenous opioid and serotonins, and lysophosphatidic acid. The management of pruritus in cholestasis is challenging. Medical treatment of the underlying cholestatic condition may provide benefit. Extracorporeal albumin dialysis can be pursued for those who have a poor quality of life and failed the various therapeutic interventions, while awaiting liver transplantation. Experimental interventions, and the management of pruritus in certain conditions such as intrahepatic cholestasis of pregnancy and benign recurrent intrahepatic cholestasis, are also briefly reviewed.
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Affiliation(s)
- Chalermrat Bunchorntavakul
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania, Philadelphia, USA
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Arlicot C, Le Louarn A, Bacq Y, Potin J, Denis C, Perrotin F. Prise en charge de la cholestase intrahépatique gravidique en France : enquête nationale des pratiques auprès des gynécologues-obstétriciens. ACTA ACUST UNITED AC 2012; 41:182-93. [DOI: 10.1016/j.jgyn.2011.09.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2011] [Revised: 09/07/2011] [Accepted: 09/15/2011] [Indexed: 12/27/2022]
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Spezielle Arzneimitteltherapie in der Schwangerschaft. ARZNEIMITTEL IN SCHWANGERSCHAFT UND STILLZEIT 2012. [PMCID: PMC7271212 DOI: 10.1016/b978-3-437-21203-1.10002-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Abstract
ABCB4 (MDR3), a lipid translocator, moves phosphatidylcholine from the inner to the outer leaflet of the canalicular membrane. Genetic mutations of ABCB4 lead to three distinct but related hepatobiliary diseases. Progressive familial intrahepatic cholestasis (PFIC) type 3 is a chronic cholestatic syndrome characterized by a markedly elevated gamma-glutamyltranspeptidase. Patients present with jaundice, pruritus, and hepatosplenomegaly. Periportal inflammation progresses to biliary cirrhosis and causes portal hypertension. Ursodeoxycholic acid (UDCA) normalizes liver function tests in approximately one half of treated PFIC type 3 patients. Partial responders or nonresponders eventually will require liver transplantation. Gallstone patients with ABCB4 mutations may have low phospholipid-associated cholelithiasis syndrome, characterized by cholesterol gallstones and intrahepatic microlithiasis, along with recurrent biliary symptoms, despite cholecystectomy. Patients with ABCB4 mutations also may develop intrahepatic brown pigment stones. UDCA may improve biliary symptoms even before the dissolution of stones occurs. Additional therapies such as farnesoid X receptor ligands/agonists and benzfibrates show future therapeutic promise. Intrahepatic cholestasis of pregnancy affects pregnant women with abnormal ABCB4. These women suffer from disabling pruritus and also may experience steatorrhea. Fetuses are at high risk for prematurity and stillbirths. The definitive treatment is delivery of the baby. In the interim, limited fat intake, fat-soluble vitamin supplementation, and UDCA with or without S-adenosylmethionine can provide symptomatic relief. Additional hepatobiliary diseases related to ABCB4 mutations are likely to be identified. This may result in the discovery of additional therapies for PFIC type 3, gallstones, and intrahepatic cholestasis of pregnancy.
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Affiliation(s)
- Shikha S Sundaram
- Shikha S. Sundaram, MD, MSCI Section of Pediatric Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital, 1056 East 19th Avenue, B290, Denver, CO 80218-1088, USA.
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36
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Abstract
This article briefly discusses gestational physiologic changes and thereafter reviews liver diseases during pregnancy, which are divided into 3 main categories. The first category includes conditions that are unique to pregnancy and generally resolve with the termination of pregnancy, the second category includes liver diseases that are not unique to the pregnant population but occur commonly or are severely affected by pregnancy, and the third category includes diseases that occur coincidentally with pregnancy and in patients with underlying chronic liver disease, with cirrhosis, or after liver transplant who become pregnant.
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Affiliation(s)
- Ayaz Matin
- Division of Gastroenterology and Hepatology, Drexel University College of Medicine, 12th Floor New College Building, 245 North 15th Street, Suite 12324, Philadelphia, PA 19102, USA
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Bacq Y. Liver diseases unique to pregnancy: a 2010 update. Clin Res Hepatol Gastroenterol 2011; 35:182-93. [PMID: 21310683 DOI: 10.1016/j.clinre.2010.11.011] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2010] [Revised: 11/19/2010] [Accepted: 11/23/2010] [Indexed: 02/08/2023]
Abstract
Liver disorders occurring during pregnancy may be specifically pregnancy-related, or may be due to an intercurrent or chronic liver disease, which may present in anyone, pregnant or not. This review focuses on the liver diseases unique to pregnancy. Hyperemesis gravidarum, which occurs during early pregnancy, may be associated with liver dysfunction. Intrahepatic cholestasis of pregnancy typically occurs during the second or third trimester. Pruritus and the associated biological signs of cholestasis improve rapidly after delivery. Mutations in gene encoding biliary transporters, especially ABCB4 encoding the multidrug resistance 3 protein, have been found to be associated with this complex disease. Ursodeoxycholic acid is currently the most effective medical treatment in improving pruritus and liver tests. Pre-eclampsia, which presents in late pregnancy frequently involves the liver, and HELLP syndrome (Hemolysis-Elevated Liver enzymes-Low Platelets) is a life-threatening complication. Prognosis of acute fatty liver of pregnancy has been radically transformed by early delivery, and clinicians must have a high index of suspicion for this condition when a woman presents nausea or vomiting, epigastric pain, jaundice, or polyuria-polydipsia during the third trimester. Acute fatty liver of pregnancy has been found to be associated with a defect of long-chain 3-hydroxyacyl coenzyme A dehydrogenase in the fetus, and mothers and their offspring should undergo DNA testing at least for the main associated genetic mutation (c.1528G>C).
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Affiliation(s)
- Yannick Bacq
- Service d'hépatogastro-entérologie, hôpital Trousseau, Tours cedex, France.
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Abstract
Liver diseases related to pregnancy may be associated with preeclampsia (liver dysfunction related to preeclampsia; hemolysis, elevated liver enzymes, and low platelets with or without preeclampsia [HELLP syndrome]; and acute fatty liver of pregnancy) or may not involve preeclampsia (hyperemesis gravidarum and intrahepatic cholestasis of pregnancy). Liver diseases associated with pregnancy have unique presentations, but it can be difficult differentiating these from liver diseases that occur coincidentally with pregnancy. Recently, advances have been made in the disease mechanism and intervention of pregnancy-related liver diseases. Early diagnosis and delivery remains the key element in managing the liver diseases associated with preeclampsia, but emerging data suggest that incorporating advance supportive management into current strategies can improve both maternal and fetal outcomes.
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Affiliation(s)
- Calvin Pan
- Division of Liver Diseases, Department of Medicine, Mount Sinai Medical Center, Mount Sinai School of Medicine, One Gustave L. Levy Place, PO Box 1123, New York, NY 11355, USA.
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Abstract
Intrahepatic cholestasis (ICP) of pregnancy is a disease that is likely multifactorial in etiology and has a prevalence that varies by geography and ethnicity. The diagnosis is made when patients have a combination of pruritus and abnormal liver-function tests. It is associated with a high risk for adverse perinatal outcome, including preterm birth, meconium passage, and fetal death. As of yet, the cause for fetal death is unknown. Because fetal deaths caused by ICP appear to occur predominantly after 37 weeks, it is suggested to offer delivery at approximately 37 weeks. Ursodeoxycholic acid appears to be the most effective medication to improve maternal pruritus and liver-function tests; however, there is no medication to date that has been shown to reduce the risk for fetal death.
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Affiliation(s)
- Bhuvan Pathak
- Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Southern California, 2020 Zonal Avenue, IRD, Room 203, Los Angeles, CA 90033, USA
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Abstract
New insights into the molecular mechanisms of bile formation and cholestasis have provided new concepts for pharmacotherapy of cholestatic liver diseases. The major aim in all forms of cholestasis is the reduction of hepatocellular retention of bile acids and other potentially toxic constituents of bile. Reduction of hepatocellular retention may be achieved by drugs that stimulate hepatocellular secretion via the canalicular route into the bile or via the alternative route across the basolateral membrane into the blood, and by drugs that stimulate the hepatocellular metabolism of hydrophobic bile acids to hydrophilic, less toxic metabolites. In cholestatic liver diseases that start with an injury of the biliary epithelium (e.g., primary biliary cirrhosis; PBC), protection of the cholangiocytes against the toxic effects of hydrophobic bile acids is most important. When hepatocellular retention of bile acids has occurred, the inhibition of bile acid-induced apoptosis becomes another target of therapy. Ursodeoxycholic acid protects the biliary epithelium by reducing the toxicity of bile, stimulates hepatobiliary secretion by upregulating transporters and inhibits apoptosis. It is the mainstay of therapy in PBC but of benefit also in a number of other cholestatic liver diseases. New drugs such as 6-ethyl-chenodeoxycholic acid and 24-nor-ursodeoxycholic acid are being evaluated for the treatment of cholestatic liver diseases.
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Affiliation(s)
- Gustav Paumgartner
- Department of Medicine II, Klinikum Grosshadern, University of Munich, Munich, Germany.
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Maillette de Buy Wenniger L, Beuers U. Bile salts and cholestasis. Dig Liver Dis 2010; 42:409-18. [PMID: 20434968 DOI: 10.1016/j.dld.2010.03.015] [Citation(s) in RCA: 126] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2010] [Accepted: 03/13/2010] [Indexed: 12/11/2022]
Abstract
Bile salts have a crucial role in hepatobiliary and intestinal homeostasis and digestion. Primary bile salts are synthesized by the liver from cholesterol, and may be modified by the intestinal flora to form secondary and tertiary bile salts. Bile salts are efficiently reabsorbed from the intestinal lumen to undergo enterohepatic circulation. In addition to their function as a surfactant involved in the absorption of dietary lipids and fat-soluble vitamins bile salts are potent signaling molecules in both the liver and intestine. Under physiological conditions the bile salt pool is tightly regulated, but the adaptive capacity may fall short under cholestatic conditions. Elevated serum and tissue levels of potentially toxic hydrophobic bile salts during cholestasis may cause mitochondrial damage, apoptosis or necrosis in susceptible cell types. Therapeutic nontoxic bile salts may restore impaired hepatobiliary secretion in cholestatic disorders. The hydrophilic bile salt ursodeoxycholate is today regarded as the effective standard treatment of primary biliary cirrhosis and intrahepatic cholestasis of pregnancy, and is implicated for use in various other cholestatic conditions. Novel therapeutic bile salts that are currently under evaluation may also prove valuable in the treatment of these diseases.
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Affiliation(s)
- Lucas Maillette de Buy Wenniger
- Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, The Netherlands
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42
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Sinakos E, Lindor KD. Bile acid profiles in intrahepatic cholestasis of pregnancy: is this the solution to the enigma of intrahepatic cholestasis of pregnancy? Am J Gastroenterol 2010; 105:596-598. [PMID: 20203641 DOI: 10.1038/ajg.2009.639] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Intrahepatic cholestasis of pregnancy (ICP) is a rare pregnancy-related liver disease characterized by pruritus, abnormal liver function tests, and an increased risk of fetal complications. An increase in the levels of bile acids is considered to be the diagnostic hallmark of the disease. Ursodeoxycholic acid (UDCA) is currently the most effective therapy. Tribe et al. (this issue) hypothesized that measuring the longitudinal profiles of individual bile acids would provide further insight into the mechanisms of disease. They used a novel chromatography method, which allowed the simultaneous measurement of 15 serum bile acids between 16 weeks of pregnancy and 4 weeks post-partum. ICP was associated with a predominant rise in cholic acid conjugated with taurine and glycine from 24 weeks of pregnancy. UDCA treatment significantly reduced serum taurocholic and taurodeoxycholic acid concentrations. Finally, bile acid profiles were similar in normal pregnancy and pregnancy associated with pruritus gravidarum. The study by Tribe et al. (this issue) presents a significant contribution to the solution of this enigmatic disease by expanding our knowledge on the pathophysiology of ICP and proposing a convenient method for diagnosis and monitoring of this disorder.
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Tribe RM, Dann AT, Kenyon AP, Seed P, Shennan AH, Mallet A. Longitudinal profiles of 15 serum bile acids in patients with intrahepatic cholestasis of pregnancy. Am J Gastroenterol 2010; 105:585-95. [PMID: 19904249 DOI: 10.1038/ajg.2009.633] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Increased maternal serum bile acids are implicated in intrahepatic cholestasis of pregnancy. Individual bile acid profiles and their relationship with disease progression, however, remain unknown. The purpose of this prospective study was to determine the temporal changes in bile acids in normal pregnancy and in pregnancies complicated with intrahepatic cholestasis of pregnancy and pruritus gravidarum. METHODS A validated method for the evaluation of 15 bile acids (conjugated and unconjugated) in a single serum sample was developed using high-performance liquid chromatography/mass spectrometry (HPLC-MS) with an electrospray interface. Bile acid concentrations were assessed in samples (16 weeks of gestation to 4 weeks postpartum) from women with, or who later developed, intrahepatic cholestasis of pregnancy (n=63) and were compared with those from normal pregnant women (n=26) and from women with pruritus gravidarum (n=43). RESULTS Intrahepatic cholestasis of pregnancy was associated with a predominant increase in cholic acid conjugated with taurine and glycine, from 24 weeks of pregnancy. Ursodeoxycholic acid (UDCA) treatment (> or =21 days, n=15) significantly reduced serum taurocholic and taurodeoxycholic acid concentrations (P<0.01). Bile acid profiles were similar in normal pregnancy and pregnancy associated with pruritus gravidarum. CONCLUSIONS The bile acid profiles and effects of treatment by UDCA implicate a role for taurine-conjugated bile acids in the syndrome of intrahepatic cholestasis of pregnancy. [corrected] With regard to individual bile acid profiles, pruritus gravidarum is a disorder quite distinct from intrahepatic cholestasis of pregnancy.
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Affiliation(s)
- Rachel M Tribe
- Division of Reproduction and Endocrinology, King's College London, London, UK.
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Webster CRL, Cooper J. Therapeutic use of cytoprotective agents in canine and feline hepatobiliary disease. Vet Clin North Am Small Anim Pract 2010; 39:631-52. [PMID: 19524797 DOI: 10.1016/j.cvsm.2009.02.002] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Many medicinal, nutraceutical, and botanic extracts have been used as cytoprotective agents in liver disease. This article explains the mechanisms of action, pertinent pharmacokinetics, side effects, and clinical indications for the use of S-adenosylmethionine, N-acetylcysteine, ursodeoxycholic acid, silymarin, and vitamin E. The literature pertaining to in vitro studies, laboratory animal models, and human and veterinary clinical trials is reviewed with regards to the efficacy and use of these cytoprotective agents in hepatobiliary disease.
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Affiliation(s)
- Cynthia R L Webster
- Department of Clinical Sciences, Tufts Cummings School of Veterinary Medicine, 200 Westborough Road, North Grafton, MA 01589, USA
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MESH Headings
- Adult
- Child
- Cholangitis/diagnosis
- Cholangitis/immunology
- Cholangitis/therapy
- Cholangitis, Sclerosing/diagnosis
- Cholangitis, Sclerosing/therapy
- Cholestasis, Intrahepatic/diagnosis
- Cholestasis, Intrahepatic/etiology
- Cholestasis, Intrahepatic/prevention & control
- Cholestasis, Intrahepatic/therapy
- Cystic Fibrosis/complications
- Female
- Hepatitis, Autoimmune/diagnosis
- Hepatitis, Autoimmune/therapy
- Humans
- Immunoglobulin G/metabolism
- Infant
- Liver Cirrhosis, Biliary/diagnosis
- Liver Cirrhosis, Biliary/therapy
- Male
- Osteoporosis/etiology
- Osteoporosis/therapy
- Pregnancy
- Pregnancy Complications/diagnosis
- Pregnancy Complications/therapy
- Syndrome
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46
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Menezes EV, Yakoob MY, Soomro T, Haws RA, Darmstadt GL, Bhutta ZA. Reducing stillbirths: prevention and management of medical disorders and infections during pregnancy. BMC Pregnancy Childbirth 2009; 9 Suppl 1:S4. [PMID: 19426467 PMCID: PMC2679410 DOI: 10.1186/1471-2393-9-s1-s4] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND An estimated two-thirds of the world's 3.2 million stillbirths occur antenatally, prior to labour, and are often overlooked in policy and programs. Poorly recognised, untreated or inadequately treated maternal infections such as syphilis and malaria, and maternal conditions including hypertensive disorders, are known risk factors for stillbirth. METHODS We undertook a systematic review of the evidence for 16 antenatal interventions with the potential to prevent stillbirths. We searched a range of sources including PubMed and the Cochrane Library. For interventions with prior Cochrane reviews, we conducted additional meta-analyses including eligible newer randomised controlled trials following the Cochrane protocol. We focused on interventions deliverable at the community level in low-/middle-income countries, where the burden of stillbirths is greatest. RESULTS Few of the studies we included reported stillbirth as an outcome; most that did were underpowered to assess this outcome. While Cochrane reviews or meta-analyses were available for many interventions, few focused on stillbirth or perinatal mortality as outcomes, and evidence was frequently conflicting. Several interventions showed clear evidence of impact on stillbirths, including heparin therapy for certain maternal indications; syphilis screening and treatment; and insecticide-treated bed nets for prevention of malaria. Other interventions, such as management of obstetric intrahepatic cholestasis, maternal anti-helminthic treatment, and intermittent preventive treatment of malaria, showed promising impact on stillbirth rates but require confirmatory studies. Several interventions reduced known risk factors for stillbirth (e.g., anti-hypertensive drugs for chronic hypertension), yet failed to show statistically significant impact on stillbirth or perinatal mortality rates. Periodontal disease emerged as a clear risk factor for stillbirth but no interventions have reduced stillbirth rates. CONCLUSION Evidence for some newly recognised risk factors for stillbirth, including periodontal disease, suggests the need for large, appropriately designed randomised trials to test whether intervention can minimise these risks and prevent stillbirths. Existing evidence strongly supports infection control measures, including syphilis screening and treatment and malaria prophylaxis in endemic areas, for preventing antepartum stillbirths. These interventions should be incorporated into antenatal care programs based on attributable risks and burden of disease.
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MESH Headings
- Anthelmintics/therapeutic use
- Anti-Bacterial Agents/therapeutic use
- Anticoagulants/therapeutic use
- Antihypertensive Agents/therapeutic use
- Antioxidants/therapeutic use
- Antiviral Agents/therapeutic use
- Causality
- Cholestasis, Intrahepatic/epidemiology
- Cholestasis, Intrahepatic/prevention & control
- Comorbidity
- Dental Care/methods
- Dietary Supplements
- Evidence-Based Medicine
- Female
- Fetal Death/epidemiology
- Fetal Death/prevention & control
- Fetal Membranes, Premature Rupture/epidemiology
- Fetal Membranes, Premature Rupture/prevention & control
- Global Health
- HIV Infections/epidemiology
- HIV Infections/prevention & control
- Humans
- Hypertension/epidemiology
- Hypertension/prevention & control
- Hypertension, Pregnancy-Induced/epidemiology
- Hypertension, Pregnancy-Induced/prevention & control
- Infectious Disease Transmission, Vertical/prevention & control
- Platelet Aggregation Inhibitors/therapeutic use
- Pregnancy
- Pregnancy Complications, Cardiovascular/epidemiology
- Pregnancy Complications, Cardiovascular/prevention & control
- Pregnancy Complications, Infectious/epidemiology
- Pregnancy Complications, Infectious/prevention & control
- Pregnancy Complications, Infectious/therapy
- Prenatal Care/methods
- Risk Factors
- Stillbirth/epidemiology
- Venous Thromboembolism/epidemiology
- Venous Thromboembolism/prevention & control
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Affiliation(s)
- Esme V Menezes
- Division of Maternal and Child Health, The Aga Khan University, Karachi-74800, Pakistan
| | - Mohammad Yawar Yakoob
- Division of Maternal and Child Health, The Aga Khan University, Karachi-74800, Pakistan
| | - Tanya Soomro
- Division of Maternal and Child Health, The Aga Khan University, Karachi-74800, Pakistan
| | - Rachel A Haws
- Department of International Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA
| | - Gary L Darmstadt
- Department of International Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA
| | - Zulfiqar A Bhutta
- Division of Maternal and Child Health, The Aga Khan University, Karachi-74800, Pakistan
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Kremer AE, Beuers U, Oude-Elferink RPJ, Pusl T. Pathogenesis and treatment of pruritus in cholestasis. Drugs 2009; 68:2163-82. [PMID: 18840005 DOI: 10.2165/00003495-200868150-00006] [Citation(s) in RCA: 77] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Pruritus is an enigmatic, seriously disabling symptom accompanying cholestatic liver diseases and a broad range of other disorders. Most recently, novel itch-specific neuronal pathways, itch mediators and their relevant receptors have been identified. In addition, new antipruritic therapeutic strategies have been developed and/or are under evaluation. This review highlights recent experimental and clinical findings focusing on the pathogenesis and actual treatment of pruritus in cholestatic liver disease. Evidence-based therapeutic recommendations, including the use of anion exchange resins cholestyramine, colestipol and colesevelam, the microsomal enzyme inducer rifampicin, the opioid receptor antagonists naltrexone and naloxone, and the serotonin reuptake inhibitor sertraline, are provided.
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Affiliation(s)
- Andreas E Kremer
- Liver Center, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
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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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Hepburn IS, Schade RR. Pregnancy-associated liver disorders. Dig Dis Sci 2008; 53:2334-58. [PMID: 18256934 DOI: 10.1007/s10620-007-0167-9] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2007] [Accepted: 11/26/2007] [Indexed: 12/14/2022]
Abstract
Liver disorders associated with pregnancy include hyperemesis gravidarum (HG), intrahepatic cholestasis of pregnancy (ICP), preeclampsia, syndrome of hemolysis, elevated liver enzymes and low platelets (HELLP), and acute fatty liver of pregnancy (AFLP). These conditions are relatively common and unique to pregnancy and are more likely to occur at certain terms of gestation specific to each condition. They can be associated with significant maternal and fetal morbidity and mortality. Although managing such patients may be very challenging, spontaneous resolution of the disease occurs shortly after termination of the pregnancy, usually without hepatic sequellae. Early diagnosis and timely treatment is a key to therapeutic success. This article explores the clinical features, pathophysiology, and management of these disorders.
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Affiliation(s)
- Iryna S Hepburn
- Department of Medicine, Medical College of Georgia, 1120 15th Street, Augusta, GA 30912, USA.
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Abstract
Abnormal liver tests occur in 3%-5% of pregnancies, with many potential causes, including coincidental liver disease (most commonly viral hepatitis or gallstones) and underlying chronic liver disease. However, most liver dysfunction in pregnancy is pregnancy-related and caused by 1 of the 5 liver diseases unique to the pregnant state: these fall into 2 main categories depending on their association with or without preeclampsia. The preeclampsia-associated liver diseases are preeclampsia itself, the hemolysis (H), elevated liver tests (EL), and low platelet count (LP) (HELLP) syndrome, and acute fatty liver of pregnancy. Hyperemesis gravidarum and intrahepatic cholestasis of pregnancy have no relationship to preeclampsia. Although still enigmatic, there have been recent interesting advances in understanding of these unique pregnancy-related liver diseases. Hyperemesis gravidarum is intractable, dehydrating vomiting in the first trimester of pregnancy; 50% of patients with this condition have liver dysfunction. Intrahepatic cholestasis of pregnancy is pruritus and elevated bile acids in the second half of pregnancy, accompanied by high levels of aminotransferases and mild jaundice. Maternal management is symptomatic with ursodeoxycholic acid; for the fetus, however, this is a high-risk pregnancy requiring close fetal monitoring and early delivery. Severe preeclampsia itself is the commonest cause of hepatic tenderness and liver dysfunction in pregnancy, and 2%-12% of cases are further complicated by hemolysis (H), elevated liver tests (EL), and low platelet count (LP)-the HELLP syndrome. Immediate delivery is the only definitive therapy, but many maternal complications can occur, including abruptio placentae, renal failure, subcapsular hematomas, and hepatic rupture. Acute fatty liver of pregnancy is a sudden catastrophic illness occurring almost exclusively in the third trimester; microvesicular fatty infiltration of hepatocytes causes acute liver failure with coagulopathy and encephalopathy. Early diagnosis and immediate delivery are essential for maternal and fetal survival.
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Affiliation(s)
- J Eileen Hay
- Division of Gastroenterology and Hepatology, The Mayo Clinic, Rochester, MN, USA.
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