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Heyerick L, Dhondt A, Van Vlierberghe H, Verhelst X, Raevens S, Geerts A. Early plasmapheresis in type 2 benign recurrent intrahepatic cholestasis: A case report and review of literature. World J Hepatol 2025; 17:102375. [PMID: 40027565 PMCID: PMC11866144 DOI: 10.4254/wjh.v17.i2.102375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 12/06/2024] [Accepted: 01/07/2025] [Indexed: 02/20/2025] Open
Abstract
BACKGROUND Benign recurrent intrahepatic cholestasis (BRIC) is a rare autosomal recessive liver disease, causing episodic cholestasis with intense pruritus. This case report highlights the effectiveness of early plasmapheresis as a therapeutic option for BRIC type 2, offering rapid symptom relief and early termination of cholestatic episodes. It contributes to the limited evidence supporting plasmapheresis as a treatment for BRIC flares resistant to conventional therapies. CASE SUMMARY A 43-year-old male with BRIC type 2 presented with fatigue, jaundice, and severe pruritus, triggered by a recent mild severe acute respiratory syndrome coronavirus 2 infection. Laboratory results confirmed cholestasis with elevated bilirubin and alkaline phosphatase. First-line pharmacological treatments, including cholestyramine and rifampicin, failed. Endoscopic nasobiliary drainage was ineffective, prompting initiation of plasmapheresis. This intervention rapidly relieved pruritus, with complete biochemical normalisation after 11 sessions. Two years later, a similar episode occurred, and early reinitiation of plasmapheresis led to symptom resolution within two sessions and biochemical recovery within two weeks. The patient tolerated the procedure well, with no adverse effects observed. Follow-up showed no signs of cholestasis recurrence. CONCLUSION Plasmapheresis is a safe and effective option for therapy-refractory BRIC type 2, particularly when initiated early in cholestasis.
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Affiliation(s)
- Lander Heyerick
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent 9000, Belgium.
| | - Annemieke Dhondt
- Department of Nephrology, Ghent University Hospital, Ghent 9000, Belgium
| | - Hans Van Vlierberghe
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent 9000, Belgium
| | - Xavier Verhelst
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent 9000, Belgium
| | - Sarah Raevens
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent 9000, Belgium
| | - Anja Geerts
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent 9000, Belgium
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2
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Hague WB, Williamson C, Beuers U. Intrahepatic cholestasis of pregnancy: Introduction and overview 2024. Obstet Med 2024; 17:138-143. [PMID: 39262909 PMCID: PMC11384812 DOI: 10.1177/1753495x241265772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Accepted: 06/04/2024] [Indexed: 09/13/2024] Open
Abstract
Considerable progress has been made to explain the aetiology of intrahepatic cholestasis of pregnancy (ICP) and of the adverse pregnancy outcomes associated with high maternal total serum bile acids (TSBAs). The reported thresholds for non-fasting TSBA associated with the risk of stillbirth and spontaneous preterm birth can be used to identify pregnancies at risk of these adverse outcomes to decide on appropriate interventions and to give reassurance to women with lower concentrations of TSBA. Data also support the use of ursodeoxycholic acid to protect against the risk of spontaneous preterm birth. A previous history of ICP may be associated with higher rates of subsequent hepatobiliary disease: if there is a suspicion of underlying susceptibility, clinicians caring for women with ICP should screen for associated disorders or for genetic susceptibility and, where appropriate, refer for ongoing hepatology review.
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Affiliation(s)
- Wm Bill Hague
- Robinson Research Institute, The University of Adelaide, North Adelaide, Australia
| | | | - Ulrich Beuers
- Department of Gastroenterology and Hepatology and Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Centres, Amsterdam, Netherlands
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3
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Abdelhamed W, El-Kassas M. Rare liver diseases in Egypt: Clinical and epidemiological characterization. Arab J Gastroenterol 2024; 25:75-83. [PMID: 38228442 DOI: 10.1016/j.ajg.2023.12.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 12/04/2023] [Accepted: 12/16/2023] [Indexed: 01/18/2024]
Abstract
Illnesses that afflict a tiny number of individuals are referred to as rare diseases (RDs), sometimes called orphan diseases. The local healthcare systems are constantly under financial, psychological, and medical strain due to low incidence rates, unusual presentations, flawed diagnostic standards, and a lack of treatment alternatives for these RDs. The effective management of the once widely spread viral hepatitis B and C has altered the spectrum of liver diseases in Egypt during the last several years. The detection of uncommon disorders such as autoimmune, cholestatic, and hereditary liver diseases has also been made easier by the increasing knowledge and greater accessibility of specific laboratory testing. Finally, despite Egypt's large population, there are more uncommon liver disorders than previously thought. This review article discusses the clinical and epidemiological characteristics of a few uncommon liver disorders and the information currently accessible concerning these illnesses in Egypt.
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Affiliation(s)
- Walaa Abdelhamed
- Endemic Medicine Department, Faculty of Medicine, Sohag University, Sohag, Egypt
| | - Mohamed El-Kassas
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo, Egypt.
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Biermann M, Sundar PR, Veeramachaneni H, Willingham F. Preoperative Nasobiliary Drainage as a Predictor of Response Before Surgical Fistula Creation in Joubert Syndrome With Refractory Cholestatic Pruritis. ACG Case Rep J 2023; 10:e01171. [PMID: 37799488 PMCID: PMC10550019 DOI: 10.14309/crj.0000000000001171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 09/05/2023] [Indexed: 10/07/2023] Open
Abstract
Cholestatic pruritus is a debilitating symptom associated with many liver diseases and is often refractory to medical management. Nasobiliary drainage is a relatively safe and effective method for treating intractable cholestatic pruritus. It should be considered for patients with refractory cholestatic pruritus who have failed or have contraindications to medical therapy as a predictor of response before surgical fistula creation.
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Affiliation(s)
- Maya Biermann
- Department of Medicine, Emory University School of Medicine, Atlanta, GA
| | - Preeyanka Rubiana Sundar
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA
| | - Hima Veeramachaneni
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA
| | - Field Willingham
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA
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Çalhan T, Yivli E. Coronavirus disease 2019 (COVID-19) as a potential trigger for benign recurrent intrahepatic cholestasis. Clin Case Rep 2022; 10:e05557. [PMID: 35310310 PMCID: PMC8908081 DOI: 10.1002/ccr3.5557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 12/21/2021] [Accepted: 01/14/2022] [Indexed: 11/11/2022] Open
Abstract
Benign recurrent intrahepatic cholestasis (BRIC) is a rare disease characterized by recurrent severe itching and jaundice. Coronavirus disease 2019 (COVID-19) is a multisystemic acute viral disease and the liver is frequently affected. Here, we wanted to present a BRIC case triggered by COVID-19 infection, discussing it together with current information.
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Affiliation(s)
- Turan Çalhan
- Department of GastroenterologyHaseki Training and Research HospitalIstanbulTurkey
| | - Elif Yivli
- Department of GastroenterologyHaseki Training and Research HospitalIstanbulTurkey
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6
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Ahmed W, Jeyaraj R, Reffitt D, Devlin J, Suddle A, Hunt J, Heneghan MA, Harrison P, Joshi D. Nasobiliary drainage: an effective treatment for pruritus in cholestatic liver disease. Frontline Gastroenterol 2022; 13:416-422. [PMID: 36051950 PMCID: PMC9380771 DOI: 10.1136/flgastro-2021-102025] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Accepted: 12/21/2021] [Indexed: 02/04/2023] Open
Abstract
INTRODUCTION Nasobiliary drains (NBDs) have been successfully used to manage intrahepatic cholestasis, bile leaks and obstructive cholangitis. It allows external drainage of bile, bypassing the ileum where bile salts are reabsorbed. We assessed the utility of placement with effect on markers of cholestasis and patient symptoms. METHODS Consecutive patients undergoing NBD over 12 years for the management of pruritus were retrospectively analysed. Recorded variables included patient demographics, procedural characteristics and response to therapy. RESULTS Twenty-three patients (14, 61% male) underwent 30 episodes of NBD. The median age was 26 years old (range 2-67 years old). A single procedure was carried out in 20. One patient each had two, three and five episodes of NBD. The most common aetiologies were hereditary cholestatic disease (n=17, 74%) and drug-induced cholestasis (n=5, 22%),NBD remained in situ for a median of 8 days (range 1-45 days). Significant improvement in bilirubin was seen at 7 days post-NBD (p=0.0324), maintained at day 30 (335 μmol/L vs 302 µmol/L vs 167 µmol/L). There was symptomatic improvement in pruritus in 20 (67%, p=0.0494) episodes. One patient underwent NBD during the first trimester of pregnancy after medical therapy failure with a good symptomatic response. The catheters were well tolerated in 27 (90%) of cases. Mild pancreatitis occurred in 4 (13%) cases. CONCLUSION NBD can be used to provide symptomatic improvement to patients with pruritus associated with cholestasis. It is well tolerated by patients. They can be used in pregnancy where medical management has failed.
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Affiliation(s)
- Wafaa Ahmed
- Institute of Liver Studies, King's College Hospital NHS Trust, London, UK
| | - Rebecca Jeyaraj
- Institute of Liver Studies, King's College Hospital NHS Trust, London, UK
| | - David Reffitt
- Institute of Liver Studies, King's College Hospital NHS Trust, London, UK
| | - John Devlin
- Institute of Liver Studies, King's College Hospital NHS Trust, London, UK
| | - Abid Suddle
- Institute of Liver Studies, King's College Hospital NHS Trust, London, UK
| | - John Hunt
- Institute of Liver Studies, King's College Hospital NHS Trust, London, UK
| | - Michael A Heneghan
- Institute of Liver Studies, King's College Hospital NHS Trust, London, UK
| | - Phillip Harrison
- Institute of Liver Studies, King's College Hospital NHS Trust, London, UK
| | - Deepak Joshi
- Institute of Liver Studies, King's College Hospital NHS Trust, London, UK
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7
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Pantzaris ND, Lord T, Sotheran R, Hutchinson J, Millson C. Nasobiliary Drain Diverted through a Percutaneous Endoscopic Gastrostomy Tube: A Novel Approach to Nasobiliary Drainage. Case Rep Gastroenterol 2021; 15:891-897. [PMID: 34720840 PMCID: PMC8543278 DOI: 10.1159/000518057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Accepted: 06/11/2021] [Indexed: 11/23/2022] Open
Abstract
Intractable pruritus is a common, debilitating symptom and a well-defined entity occurring in chronic cholestatic disorders. Treatment options include cholestyramine, rifampicin, naltrexone, gabapentin, and sertraline, as well as more interventional measures, such as plasmapheresis, extracorporeal albumin dialysis, nasobiliary drains (NBDs), and UVB phototherapy in patients who fail to respond to medical therapy. Despite the limited data, NBD seems to be a highly effective treatment in the relief of refractory cholestatic pruritus. In this article, we present the case of a 73-year-old woman with primary biliary cholangitis and intractable pruritus, refractory to medical treatment. The patient had a complete resolution of her symptoms following an NBD placement, in which, with a novel approach, the nasal end was redirected and exited through a percutaneous endoscopic gastrostomy port, significantly improving her quality of life.
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Affiliation(s)
| | - Tim Lord
- Endoscopy Department, Scarborough Hospital, Scarborough, United Kingdom
| | - Robyn Sotheran
- Medical Illustration Department, York Teaching Hospital NHS Foundation Trust, York, United Kingdom
| | - John Hutchinson
- Hepatology Department, York Teaching Hospital NHS Foundation Trust, York, United Kingdom
| | - Charles Millson
- Hepatology Department, York Teaching Hospital NHS Foundation Trust, York, United Kingdom
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8
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Langedijk JAGM, Beuers UH, Oude Elferink RPJ. Cholestasis-Associated Pruritus and Its Pruritogens. Front Med (Lausanne) 2021; 8:639674. [PMID: 33791327 PMCID: PMC8006388 DOI: 10.3389/fmed.2021.639674] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 02/12/2021] [Indexed: 12/17/2022] Open
Abstract
Pruritus is a debilitating symptom of various cholestatic disorders, including primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and inherited progressive familial intrahepatic cholestasis (PFIC). The molecular mechanisms leading to cholestasis-associated pruritus are still unresolved and the involved pruritogens are indecisive. As a consequence of pruritus, patients suffer from sleep deprivation, loss of daytime concentration, auto-mutilation and sometimes even suicidal ideations. Current guideline-approved therapy of cholestasis-associated pruritus includes stepwise administration of several medications, which may alleviate complaints in some, but not all affected patients. Therefore, also experimental therapeutic approaches are required to improve patients' quality of life. This article reviews the current state of research on pruritogens and their receptors, and shortly discusses the most recent experimental therapies.
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Affiliation(s)
| | | | - Ronald P. J. Oude Elferink
- Amsterdam University Medical Centers, Tytgat Institute for Liver and Intestinal Research, Research Institute Amsterdam Gastroenterology, Endocrinology and Metabolism (AGEM), University of Amsterdam, Amsterdam, Netherlands
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Mizutani A, Sabu Y, Naoi S, Ito S, Nakano S, Minowa K, Mizuochi T, Ito K, Abukawa D, Kaji S, Sasaki M, Muroya K, Azuma Y, Watanabe S, Oya Y, Inomata Y, Fukuda A, Kasahara M, Inui A, Takikawa H, Kusuhara H, Bessho K, Suzuki M, Togawa T, Hayashi H. Assessment of Adenosine Triphosphatase Phospholipid Transporting 8B1 (ATP8B1) Function in Patients With Cholestasis With ATP8B1 Deficiency by Using Peripheral Blood Monocyte-Derived Macrophages. Hepatol Commun 2021; 5:52-62. [PMID: 33437900 PMCID: PMC7789840 DOI: 10.1002/hep4.1605] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 07/11/2020] [Accepted: 08/20/2020] [Indexed: 11/29/2022] Open
Abstract
Adenosine triphosphatase phospholipid transporting 8B1 (ATP8B1) deficiency, an ultrarare autosomal recessive liver disease, includes severe and mild clinical forms, referred to as progressive familial intrahepatic cholestasis type 1 (PFIC1) and benign recurrent intrahepatic cholestasis type 1 (BRIC1), respectively. There is currently no practical method for determining PFIC1 or BRIC1 at an early disease course phase. Herein, we assessed the feasibility of developing a diagnostic method for PFIC1 and BRIC1. A nationwide Japanese survey conducted since 2015 identified 25 patients with cholestasis with ATP8B1 mutations, 15 of whom agreed to participate in the study. Patients were divided for analysis into PFIC1 (n = 10) or BRIC1 (n = 5) based on their disease course. An in vitro mutagenesis assay to evaluate pathogenicity of ATP8B1 mutations suggested that residual ATP8B1 function in the patients could be used to identify clinical course. To assess their ATP8B1 function more simply, human peripheral blood monocyte-derived macrophages (HMDMs) were prepared from each patient and elicited into a subset of alternatively activated macrophages (M2c) by interleukin-10 (IL-10). This was based on our previous finding that ATP8B1 contributes to polarization of HMDMs into M2c. Flow cytometric analysis showed that expression of M2c-related surface markers cluster of differentiation (CD)14 and CD163 were 2.3-fold and 2.1-fold lower (95% confidence interval, 2.0-2.5 for CD14 and 1.7-2.4 for CD163), respectively, in patients with IL-10-treated HMDMs from PFIC1 compared with BRIC1. Conclusion: CD14 and CD163 expression levels in IL-10-treated HMDMs may facilitate diagnosis of PFIC1 or BRIC1 in patients with ATP8B1 deficiency.
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Affiliation(s)
- Ayumu Mizutani
- Laboratory of Molecular PharmacokineticsGraduate School of Pharmaceutical SciencesUniversity of TokyoTokyoJapan
| | - Yusuke Sabu
- Laboratory of Molecular PharmacokineticsGraduate School of Pharmaceutical SciencesUniversity of TokyoTokyoJapan
| | - Sotaro Naoi
- Laboratory of Molecular PharmacokineticsGraduate School of Pharmaceutical SciencesUniversity of TokyoTokyoJapan
| | - Shogo Ito
- Department of Pediatrics and NeonatologyNagoya City University Graduate School of Medical SciencesNagoyaJapan
| | - Satoshi Nakano
- Department of PediatricsJuntendo University School of MedicineTokyoJapan
| | - Kei Minowa
- Department of PediatricsJuntendo University School of MedicineTokyoJapan
| | - Tatsuki Mizuochi
- Department of Pediatrics and Child HealthKurume University School of MedicineFukuokaJapan
| | - Koichi Ito
- Department of Pediatrics and NeonatologyNagoya City University Graduate School of Medical SciencesNagoyaJapan
| | - Daiki Abukawa
- Department of Gastroenterology and HepatologyMiyagi Children's HospitalMiyagiJapan
| | - Shunsaku Kaji
- Department of PediatricsTsuyama‐Chuo HospitalOkayamaJapan
| | - Mika Sasaki
- Department of PediatricsSchool of MedicineIwate Medical UniversityIwateJapan
| | - Koji Muroya
- Department of Endocrinology and MetabolismKanagawa Children's Medical CenterKanagawaJapan
| | - Yoshihiro Azuma
- Department of PediatricsYamaguchi University Graduate School of MedicineYamaguchiJapan
| | - Satoshi Watanabe
- Department of PediatricsNagasaki University HospitalNagasakiJapan
| | - Yuki Oya
- Department of Transplantation/Pediatric SurgeryKumamoto UniversityKumamotoJapan
- Kumamoto UniversityKumamotoJapan
| | - Yukihiro Inomata
- Department of Transplantation/Pediatric SurgeryKumamoto UniversityKumamotoJapan
- Kumamoto UniversityKumamotoJapan
| | - Akinari Fukuda
- Organ Transplantation CenterNational Center for Child Health and DevelopmentTokyoJapan
| | - Mureo Kasahara
- Organ Transplantation CenterNational Center for Child Health and DevelopmentTokyoJapan
| | - Ayano Inui
- Department of Pediatric Hepatology and GastroenterologyEastern Yokohama HospitalKanagawaJapan
| | - Hajime Takikawa
- Department of MedicineTeikyo University School of MedicineTokyoJapan
| | - Hiroyuki Kusuhara
- Laboratory of Molecular PharmacokineticsGraduate School of Pharmaceutical SciencesUniversity of TokyoTokyoJapan
| | - Kazuhiko Bessho
- Department of PediatricsOsaka University Graduate School of MedicineOsakaJapan
| | - Mitsuyoshi Suzuki
- Department of PediatricsJuntendo University School of MedicineTokyoJapan
| | - Takao Togawa
- Department of Pediatrics and NeonatologyNagoya City University Graduate School of Medical SciencesNagoyaJapan
| | - Hisamitsu Hayashi
- Laboratory of Molecular PharmacokineticsGraduate School of Pharmaceutical SciencesUniversity of TokyoTokyoJapan
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Nasobiliary drainage prior to surgical biliary diversion in progressive familial intrahepatic cholestasis type II. Eur J Pediatr 2020; 179:1547-1552. [PMID: 32291498 DOI: 10.1007/s00431-020-03646-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Revised: 03/18/2020] [Accepted: 03/27/2020] [Indexed: 12/12/2022]
Abstract
Progressive familial intrahepatic cholestasis (PFIC) can cause intense pruritus that is refractory to medical therapy. Surgical biliary diversion techniques, including partial internal biliary diversion (PIBD), have been developed over the years to relieve pruritus without requiring liver transplantation. No clinical or genetic features can currently predict postoperative pruritus response. We present three PFIC type 2 (PIFC 2) patients who underwent transient endoscopic nasobiliary drainage (NBD) prior to PIBD surgery. Two patients repeatedly responded to NBD and presented with complete pruritus resolution after subsequent PIBD. NBD failed technically in the third patient, and PIBD was partially successful. Mild post-endoscopic biological pancreatitis occurred in 2/6 NBD procedures and resolved spontaneously. The only adverse effect observed within 7 years post-PIBD was very mild transient osmotic diarrhea.Conclusion: Our limited data suggest that NBD is a safe and effective way to predict pruritus response before performing permanent biliary diversion surgery in PFIC patients. What is Known: • Surgical biliary diversion techniques have been developed to relieve intractable pruritus in progressive familial intrahepatic cholestasis (PFIC). • No clinical or genetic features can currently predict pruritus response to surgery. What is New: • Our data suggest that nasobiliary drainage could be a safe and effective tool to predict pruritus response to biliary diversion and avoid unnecessary surgery in PFIC patients.
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Sanjel B, Shim WS. Recent advances in understanding the molecular mechanisms of cholestatic pruritus: A review. Biochim Biophys Acta Mol Basis Dis 2020; 1866:165958. [PMID: 32896605 DOI: 10.1016/j.bbadis.2020.165958] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 08/21/2020] [Accepted: 09/01/2020] [Indexed: 02/06/2023]
Abstract
Cholestasis, a condition characterized by an abnormal decrease in bile flow, is accompanied by various symptoms such as pruritus. Although cholestatic pruritus is a prominent condition, its precise mechanisms have largely been elusive. Recently, advancements have been made for understanding the etiology and pathogenesis of cholestatic pruritus. The current review therefore focuses on summarizing the overall progress made in the elucidation of its molecular mechanisms. We have reviewed the available animal models on cholestasis to compare the differences between them, characterized potential pruritogens involved in cholestatic pruritus, and have summarized the receptor and ion channels implicated in the condition. Finally, we have discussed the available treatment options for alleviation of cholestatic pruritus. As our understanding of the mechanisms of cholestatic pruritus deepens, novel strategies to cure this condition are awaited.
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Affiliation(s)
- Babina Sanjel
- College of Pharmacy, Gachon University, Hambakmoero 191, Yeonsu-gu, Incheon 21936, Republic of Korea; Gachon Institute of Pharmaceutical Sciences, Hambakmoero 191, Yeonsu-gu, Incheon 21936, Republic of Korea
| | - Won-Sik Shim
- College of Pharmacy, Gachon University, Hambakmoero 191, Yeonsu-gu, Incheon 21936, Republic of Korea; Gachon Institute of Pharmaceutical Sciences, Hambakmoero 191, Yeonsu-gu, Incheon 21936, Republic of Korea.
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12
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Abstract
Progressive familial intrahepatic cholestasis (PFIC) and Alagille syndrome (AS) are conditions caused by either an autosomal recessive or an autosomal dominant genetic defect, and they are both characterized by cholestasis, jaundice, and severe debilitating pruritus refractory to medical management. Before the advent of liver transplantation, most PFIC patients would die from end-stage liver disease in the first decade of life. Although liver transplantation has led to patients' survival, disease recurrence (PFIC-2) and severe extra-hepatic manifestations of the disease (PFIC-1) occurred post transplant. In the late 1980s, Whitington described the use of partial external biliary diversion in PFIC and AS patients as a successful way to improve symptoms and decrease circulating bile acid serum concentrations. Since then, other diversion techniques have been described (ileal exclusion and partial internal biliary diversion). These techniques have the benefit of avoiding a stoma, but equivalent results have not been demonstrated (recurrence of cholestasis after ileal exclusion, limited follow up after internal biliary diversion). Overall, studies have showed that biliary diversions in children with cholestasis are safe procedures with low morbidity and mortality, and that they can reduce inflammation and ongoing liver injury, therefore delaying or avoiding the need for liver transplantation in some patients.
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13
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Hussain AB, Samuel R, Hegade VS, Jones DE, Reynolds NJ. Pruritus secondary to primary biliary cholangitis: a review of the pathophysiology and management with phototherapy. Br J Dermatol 2019; 181:1138-1145. [PMID: 30920648 DOI: 10.1111/bjd.17933] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/28/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Primary biliary cholangitis (PBC) is an autoimmune hepatobiliary disorder characterized by destruction of liver bile ducts leading to intrahepatic cholestasis. It causes intractable pruritus for which ultraviolet (UV)B phototherapy is an experimental treatment when alternative therapies fail. The pathophysiology of cholestatic itch and the mechanism of action of narrowband UVB in this condition remains poorly understood. OBJECTIVES To summarize the current literature and propose testable hypotheses for the mechanism of action of phototherapy in attenuating itch. METHODS A focused PubMed search for articles relating to the pathogenesis of itch in cholestatic disease was performed. A total of 3855 articles were screened and 50 were found suitable for literature review. Evidence from this literature review was combined with author expertise in the area. RESULTS Formulated hypotheses focus on the role of bile salts, autotaxin and specific receptors including G-protein-coupled bile acid receptor, Gpbar1 (also known as TGR5) and the nuclear transcription factor farnesoid X receptor. CONCLUSIONS Several testable mechanisms through which phototherapy may exert its effects are discussed in this review. The next steps are to carry out an objective assessment of the efficacy of phototherapy in cholestatic pruritus, gain further knowledge on the underlying pathways, and subsequently trial its use against current licensed therapies. Such studies could lead to increased mechanistic understanding, identification of novel therapeutic targets and the potential to refine phototherapy protocols, leading to improved control of itch and quality of life in patients with PBC. What's already known about this topic? Primary biliary cholangitis (PBC) is frequently associated with intractable pruritus for which current treatment options are often unsuccessful. Phototherapy is used as an experimental treatment for PBC-associated pruritus when alternative better-studied treatments fail. What does this study add? This study reviews the current literature on the pathophysiology and management of cholestatic pruritus, an area which remains poorly understood. We propose testable hypotheses of the mechanisms behind the attenuation of cholestatic pruritus with phototherapy.
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Affiliation(s)
- A B Hussain
- Newcastle Dermatology, Royal Victoria Infirmary, Newcastle upon Tyne, NHS Foundation Trust, Newcastle upon Tyne, U.K
| | - R Samuel
- Newcastle Dermatology, Royal Victoria Infirmary, Newcastle upon Tyne, NHS Foundation Trust, Newcastle upon Tyne, U.K
- Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, U.K
| | - V S Hegade
- Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, U.K
- Liver Unit, Freeman Hospital, Newcastle upon Tyne, NHS Foundation Trust, Newcastle upon Tyne, U.K
| | - D E Jones
- Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, U.K
- Liver Unit, Freeman Hospital, Newcastle upon Tyne, NHS Foundation Trust, Newcastle upon Tyne, U.K
| | - N J Reynolds
- Newcastle Dermatology, Royal Victoria Infirmary, Newcastle upon Tyne, NHS Foundation Trust, Newcastle upon Tyne, U.K
- Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, U.K
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14
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Kremer AE. What are new treatment concepts in systemic itch? Exp Dermatol 2019; 28:1485-1492. [DOI: 10.1111/exd.14024] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2019] [Revised: 08/02/2019] [Accepted: 08/23/2019] [Indexed: 12/20/2022]
Affiliation(s)
- Andreas E. Kremer
- Department of Medicine 1 & Translational Research Center Friedrich‐Alexander‐University Erlangen‐Nürnberg Erlangen Germany
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15
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Vitale G, Gitto S, Vukotic R, Raimondi F, Andreone P. Familial intrahepatic cholestasis: New and wide perspectives. Dig Liver Dis 2019; 51:922-933. [PMID: 31105019 DOI: 10.1016/j.dld.2019.04.013] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Revised: 04/01/2019] [Accepted: 04/12/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND Progressive familial intrahepatic cholestasis (PFIC) includes autosomal recessive cholestatic rare diseases of childhood. AIMS To update the panel of single genes mutations involved in familial cholestasis. METHODS PubMed search for "familial intrahepatic cholestasis" alone as well as in combination with other key words was performed considering primarily original studies and meta-analyses. RESULTS PFIC1 involves ATP8B1 gene encoding for aminophospholipid flippase FIC1. PFIC2 includes ABCB11 gene, encoding for protein functioning as bile salt export pump. PFIC3 is due to mutations of ABCB4 gene responsible for the synthesis of class III multidrug resistance P-glycoprotein flippase. PFIC4 and PFIC5 involve tight junction protein-2 gene and NR1H4 gene encoding for farnesoid X receptor. Benign Intrahepatic Cholestasis, Intrahepatic Cholestasis of Pregnancy and Low-phospholipid-associated cholelithiasis involve the same genes and are characterized by intermittent attacks of cholestasis, no progression to cirrhosis, reversible pregnancy-specific cholestasis and cholelithiasis in young people. Blood and liver tissue levels of bile-excreted drugs can be influenced by the presence of mutations in PFIC genes, causing drug-induced cholestasis. Mutations in PFIC genes might increase the risk of liver cancer. CONCLUSION There is a high proportion of unexplained cholestasis potentially caused by specific genetic pathophysiologic pathways. The use of next generation sequencing and whole-exome sequencing could improve the diagnostic process in this setting.
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Affiliation(s)
- Giovanni Vitale
- ITEC Unit, Department of Medical and Surgical Sciences, University of Bologna, Italy; Research Centre for the Study of Hepatitis, University of Bologna, Italy; End-stage Liver Disease Unit, Department of Medical and Surgical Sciences, Sant'Orsola-Malpighi Hospital, University of Bologna, Italy
| | - Stefano Gitto
- ITEC Unit, Department of Medical and Surgical Sciences, University of Bologna, Italy; Research Centre for the Study of Hepatitis, University of Bologna, Italy
| | - Ranka Vukotic
- ITEC Unit, Department of Medical and Surgical Sciences, University of Bologna, Italy; Research Centre for the Study of Hepatitis, University of Bologna, Italy
| | - Francesco Raimondi
- Bioquant Institute, Heidelberg University, Germany; Heidelberg University Biochemistry Center (BZH), Germany
| | - Pietro Andreone
- ITEC Unit, Department of Medical and Surgical Sciences, University of Bologna, Italy; Research Centre for the Study of Hepatitis, University of Bologna, Italy.
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Yeap SP, Harley H, Thompson R, Williamson KD, Bate J, Sethna F, Farrell G, Hague WB. Biliary transporter gene mutations in severe intrahepatic cholestasis of pregnancy: Diagnostic and management implications. J Gastroenterol Hepatol 2019; 34:425-435. [PMID: 29992621 DOI: 10.1111/jgh.14376] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Revised: 06/19/2018] [Accepted: 06/20/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Clinical syndromes associated with biallelic mutations of bile acid (BA) transporters usually present in childhood. Subtle mutations may underlie intrahepatic cholestasis of pregnancy (ICP) and oral contraceptive steroid (OCS) induced cholestasis. In five women with identified genetic mutations of such transporters, with eight observed pregnancies complicated by ICP, we examined relationships between transporter mutations, clinical phenotypes, and treatment outcomes. METHODS Gene mutation analysis for BA transporter deficiencies was performed using Next Generation/Sanger sequencing, with analysis for gene deletions/duplications. RESULTS Intrahepatic cholestasis of pregnancy was early-onset (9-32 weeks gestation) and severe (peak BA 74-370 μmol/L), with premature delivery (28+1 -370 weeks gestation) in 7/8 pregnancies, in utero passage of meconium in 4/8, but overall good perinatal outcomes, with no stillbirths. There was generally no response to ursodeoxycholic acid and variable responses to rifampicin and chelation therapies; naso-biliary drainage appeared effective in 2/2 episodes persisting post-partum in each of the two sisters. Episodic jaundice occurring spontaneously or provoked by non-specific infections, and OCS-induced cholestasis, had previously occurred in 3/5 women. Two cases showed biallelic heterozygosity for several ABCB11 mutations, one was homozygous for an ABCB4 mutation and a fourth case was heterozygous for another ABCB4 mutation. CONCLUSIONS Early-onset or recurrent ICP, especially with previous spontaneous or OCS-induced episodes of cholestasis and/or familial cholestasis, may be attributable to transporter mutations, including biallelic mutations of one or more transporters. Response to standard therapies for ICP is often incomplete; BA sequestering therapy or naso-biliary drainage may be effective. Optimized management can produce good outcomes despite premature birth and evidence of fetal compromise.
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Affiliation(s)
- Sze Pheh Yeap
- Liver Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia
| | - Hugh Harley
- Liver Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia.,Department of Medicine, University of Adelaide, Adelaide, South Australia, Australia
| | | | | | - John Bate
- Liver Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia
| | - Farah Sethna
- Department of Obstetrics and Gynaecology, Canberra Hospital, Canberra, Australian Capital Territory, Australia
| | - Geoffrey Farrell
- Liver Research Unit, Canberra Hospital, Canberra, Australian Capital Territory, Australia.,The Australian National University Medical School, Canberra, Australian Capital Territory, Australia
| | - William Bill Hague
- Obstetric Medicine, Women's and Children's Hospital, North Adelaide, South Australia, Australia.,Robinson Research Institute, University of Adelaide, North Adelaide, South Australia, Australia
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Chen HL, Wu SH, Hsu SH, Liou BY, Chen HL, Chang MH. Jaundice revisited: recent advances in the diagnosis and treatment of inherited cholestatic liver diseases. J Biomed Sci 2018; 25:75. [PMID: 30367658 PMCID: PMC6203212 DOI: 10.1186/s12929-018-0475-8] [Citation(s) in RCA: 85] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Accepted: 10/03/2018] [Indexed: 12/17/2022] Open
Abstract
Background Jaundice is a common symptom of inherited or acquired liver diseases or a manifestation of diseases involving red blood cell metabolism. Recent progress has elucidated the molecular mechanisms of bile metabolism, hepatocellular transport, bile ductular development, intestinal bile salt reabsorption, and the regulation of bile acids homeostasis. Main body The major genetic diseases causing jaundice involve disturbances of bile flow. The insufficiency of bile salts in the intestines leads to fat malabsorption and fat-soluble vitamin deficiencies. Accumulation of excessive bile acids and aberrant metabolites results in hepatocellular injury and biliary cirrhosis. Progressive familial intrahepatic cholestasis (PFIC) is the prototype of genetic liver diseases manifesting jaundice in early childhood, progressive liver fibrosis/cirrhosis, and failure to thrive. The first three types of PFICs identified (PFIC1, PFIC2, and PFIC3) represent defects in FIC1 (ATP8B1), BSEP (ABCB11), or MDR3 (ABCB4). In the last 5 years, new genetic disorders, such as TJP2, FXR, and MYO5B defects, have been demonstrated to cause a similar PFIC phenotype. Inborn errors of bile acid metabolism also cause progressive cholestatic liver injuries. Prompt differential diagnosis is important because oral primary bile acid replacement may effectively reverse liver failure and restore liver functions. DCDC2 is a newly identified genetic disorder causing neonatal sclerosing cholangitis. Other cholestatic genetic disorders may have extra-hepatic manifestations, such as developmental disorders causing ductal plate malformation (Alagille syndrome, polycystic liver/kidney diseases), mitochondrial hepatopathy, and endocrine or chromosomal disorders. The diagnosis of genetic liver diseases has evolved from direct sequencing of a single gene to panel-based next generation sequencing. Whole exome sequencing and whole genome sequencing have been actively investigated in research and clinical studies. Current treatment modalities include medical treatment (ursodeoxycholic acid, cholic acid or chenodeoxycholic acid), surgery (partial biliary diversion and liver transplantation), symptomatic treatment for pruritus, and nutritional therapy. New drug development based on gene-specific treatments, such as apical sodium-dependent bile acid transporter (ASBT) inhibitor, for BSEP defects are underway. Short conclusion Understanding the complex pathways of jaundice and cholestasis not only enhance insights into liver pathophysiology but also elucidate many causes of genetic liver diseases and promote the development of novel treatments.
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Affiliation(s)
- Huey-Ling Chen
- Departments of Pediatrics, National Taiwan University College of Medicine and Children's Hospital, 17F, No. 8, Chung Shan S. Rd, Taipei, 100, Taiwan. .,Department of Medical Education and Bioethics, National Taiwan University College of Medicine, No. 1, Jen Ai Rd Section 1, Taipei, 100, Taiwan. .,Hepatitis Research Center, National Taiwan University Hospital, Changde St. No.1, Zhongzhen Dist., Taipei 100, Taiwan.
| | - Shang-Hsin Wu
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, No. 7 Chung Shan S. Rd, Taipei 100, Taiwan
| | - Shu-Hao Hsu
- Graduate Institute of Anatomy and Cell Biology, Nationatl Taiwan University College of Medicine, No. 1 Jen Ai Rd Section 1, Taipei 100, Taiwan
| | - Bang-Yu Liou
- Departments of Pediatrics, National Taiwan University College of Medicine and Children's Hospital, 17F, No. 8, Chung Shan S. Rd, Taipei, 100, Taiwan
| | - Hui-Ling Chen
- Hepatitis Research Center, National Taiwan University Hospital, Changde St. No.1, Zhongzhen Dist., Taipei 100, Taiwan
| | - Mei-Hwei Chang
- Departments of Pediatrics, National Taiwan University College of Medicine and Children's Hospital, 17F, No. 8, Chung Shan S. Rd, Taipei, 100, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, Changde St. No.1, Zhongzhen Dist., Taipei 100, Taiwan
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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: 44] [Impact Index Per Article: 6.3] [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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19
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Chkheidze R, Joseph R, Burner J, Matevosyan K. Plasma exchange for the management of refractory pruritus of cholestasis: A report of three cases and review of literature. J Clin Apher 2018; 33:412-418. [PMID: 28792089 DOI: 10.1002/jca.21573] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2017] [Revised: 07/17/2017] [Accepted: 07/21/2017] [Indexed: 01/06/2025]
Abstract
BACKGROUND Intractable pruritus of cholestasis leads to significant morbidity. Therapeutic plasma exchange (TPE) has been shown to be an effective alternative in the setting of refractory pruritus associated with cholestatic liver disease based on several individual reports. Due to rarity of this approach to intractable pruritus, the literature is sparse and therefore TPE, as a treatment for refractory pruritus is currently not in the apheresis guidelines. We present three additional patients with severe intractable pruritus of cholestasis successfully treated with plasma exchange to add to the mounting literature showing this as an effective and safe adjunctive therapy. METHODS Three patients underwent serial plasma exchange procedures to control pruritus. Frequency of plasma exchange was three times a week, with slow taper upon improvement of pruritus. Total bile acid levels were assessed before procedures. RESULTS All three patients had an intractable pruritus with different underlying etiologies of cholestasis. All three patients showed significant improvement in pruritus, with none or minimal pruritus in one patient with primary biliary cirrhosis. Pre procedure bile acids levels were decreased initially, but showed rebound increase upon tapering of plasma exchange, without increased pruritus. No serious side effects or complications were observed. CONCLUSION Our results in conjunction with the published literature show that severe and intractable pruritus associated with cholestasis could be successfully treated with TPE, irrespective of the underlying disease, and can be done safely.
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Affiliation(s)
- Rati Chkheidze
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, 75390
| | - Ranjit Joseph
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, 75390
| | - James Burner
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, 75390
| | - Karen Matevosyan
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, 75390
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21
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Long-term challenges and perspectives of pre-adolescent liver disease. Lancet Gastroenterol Hepatol 2017; 2:435-445. [DOI: 10.1016/s2468-1253(16)30160-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Revised: 09/13/2016] [Accepted: 09/22/2016] [Indexed: 12/11/2022]
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22
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Choudhury A, Kulkarni AV, Sahoo B, Bihari C. Endoscopic nasobiliary drainage: an effective treatment option for benign recurrent intrahepatic cholestasis (BRIC). BMJ Case Rep 2017; 2017:bcr2016218874. [PMID: 28476903 PMCID: PMC5612549 DOI: 10.1136/bcr-2016-218874] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/19/2017] [Indexed: 11/03/2022] Open
Abstract
Benign recurrent intrahepatic cholestasis (BRIC) is characterised by recurrent episodes of jaundice, severe pruritus and low or normal serum γ-glutamyltransferase activity lasting from several weeks to months. BRIC is an autosomal recessive disorder caused by the mutation in either of the two hepatic transporter genes-ATP8B1 or ABCB11 gene. The disease is very well known for episodic flare of jaundice with cholestatic symptoms that are spontaneous or perpetuated by acute insults, followed by self-recovery. There is no proven medical therapy and rarely does it progress to progressive familial intrahepatic cholestasis (PFIC) or biliary cirrhosis. BRIC may be associated with nephrolithiasis, diabetes or pancreatitis. Here, we report a case of BRIC with spontaneous flare and further complicated by drug-induced liver injury with disabling cholestastic symptoms, who underwent endoscopic nasobiliary drainage and was completely relieved of the distressing symptoms.
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Affiliation(s)
- Ashok Choudhury
- Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Anand V Kulkarni
- Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Bishnupriya Sahoo
- Pediatrics, Shree Guru Gobind Singh Tricentenary University Faculty of Medicine and Health Sciences, Gurgaon, India
| | - Chhagan Bihari
- Institute of Liver and Biliary Sciences, New Delhi, India
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23
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Joshi D, Gupta N, Samyn M, Deheragoda M, Dobbels F, Heneghan MA. The management of childhood liver diseases in adulthood. J Hepatol 2017; 66:631-644. [PMID: 27914924 DOI: 10.1016/j.jhep.2016.11.013] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Revised: 11/20/2016] [Accepted: 11/21/2016] [Indexed: 12/12/2022]
Abstract
An increasing number of patients with childhood liver disease survive into adulthood. These young adults are now entering adult services and require ongoing management. Aetiologies can be divided into liver diseases that develop in young adults which present to adult hepatologists i.e., biliary atresia and Alagille syndrome or liver diseases that occur in children/adolescents and adults i.e., autoimmune hepatitis or Wilson's disease. To successfully manage these young adults, a dynamic and responsive transition service is essential. In this review, we aim to describe the successful components of a transition service highlighting the importance of self-management support and a multi-disciplinary approach. We will also review some of the liver specific aetiologies which are unique to young adults, offering an update on pathogenesis, management and outcomes.
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Affiliation(s)
- Deepak Joshi
- Institute of Liver Studies, King's College Hospital, London, UK.
| | - Nitika Gupta
- Division of Paediatric Gastroenterology, Emory University School of Medicine, Atlanta, USA
| | - Marianne Samyn
- Institute of Liver Studies, King's College Hospital, London, UK
| | | | - Fabienne Dobbels
- Academic Centre for Nursing and Midwifery, Katholieke Universiteit Leuven, Belgium
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van der Woerd WL, Houwen RHJ, van de Graaf SFJ. Current and future therapies for inherited cholestatic liver diseases. World J Gastroenterol 2017; 23:763-775. [PMID: 28223721 PMCID: PMC5296193 DOI: 10.3748/wjg.v23.i5.763] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Revised: 11/16/2016] [Accepted: 01/11/2017] [Indexed: 02/06/2023] Open
Abstract
Familial intrahepatic cholestasis (FIC) comprises a group of rare cholestatic liver diseases associated with canalicular transport defects resulting predominantly from mutations in ATP8B1, ABCB11 and ABCB4. Phenotypes range from benign recurrent intrahepatic cholestasis (BRIC), associated with recurrent cholestatic attacks, to progressive FIC (PFIC). Patients often suffer from severe pruritus and eventually progressive cholestasis results in liver failure. Currently, first-line treatment includes ursodeoxycholic acid in patients with ABCB4 deficiency (PFIC3) and partial biliary diversion in patients with ATP8B1 or ABCB11 deficiency (PFIC1 and PFIC2). When treatment fails, liver transplantation is needed which is associated with complications like rejection, post-transplant hepatic steatosis and recurrence of disease. Therefore, the need for more and better therapies for this group of chronic diseases remains. Here, we discuss new symptomatic treatment options like total biliary diversion, pharmacological diversion of bile acids and hepatocyte transplantation. Furthermore, we focus on emerging mutation-targeted therapeutic strategies, providing an outlook for future personalized treatment for inherited cholestatic liver diseases.
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Kumar P, Charaniya R, Ahuja A, Mittal S, Sahoo R. Benign Recurrent Intrahepatic Cholestasis in a Young Adult. J Clin Diagn Res 2016; 10:OD01-2. [PMID: 27504332 DOI: 10.7860/jcdr/2016/18917.7924] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2016] [Accepted: 02/25/2016] [Indexed: 11/24/2022]
Abstract
Benign Recurrent Intrahepatic Cholestasis (BRIC) is a rare genetic disorder characterized by recurrent episodes of cholestatic jaundice. The initial episode of jaundice generally occurs before second decade of life and can persist for several weeks to months before resolving spontaneously. It is a benign disease and even after repeated episodes of jaundice, fibrosis of liver cell does not occur. We had a young adult patient who was having recurrent episodes of cholestatic jaundice with intervening symptom free period for last 20 years. He had first episode of jaundice at the age of eight and since then had several similar episodes. Diagnosis was made by classical clinical presentation and histopathological findings. We intend to report this case due to rarity of this disease in India.
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Affiliation(s)
- Prabhat Kumar
- Senior Resident, Department of Medicine, PGIMER & Dr RML Hospital , New Delhi, India
| | - Riyaz Charaniya
- Postgraduate Resident, Department of Medicine, PGIMER & Dr RML Hospital , New Delhi, India
| | - Arvind Ahuja
- Associate Professor, Department of Pathology, PGIMER & Dr RML Hospital , New Delhi, India
| | - Sakshi Mittal
- Senior Resident, Department of Medicine, PGIMER & Dr RML Hospital , New Delhi, India
| | - Ratnakar Sahoo
- Professor, Department of Medicine, PGIMER & Dr RML Hospital , New Delhi, India
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Hegade VS, Bolier R, Oude Elferink RPJ, Beuers U, Kendrick S, Jones DEJ. A systematic approach to the management of cholestatic pruritus in primary biliary cirrhosis. Frontline Gastroenterol 2016; 7:158-166. [PMID: 28839853 PMCID: PMC5369477 DOI: 10.1136/flgastro-2015-100618] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2015] [Revised: 07/24/2015] [Accepted: 08/04/2015] [Indexed: 02/04/2023] Open
Abstract
Pruritus (itch) is an important symptom of primary biliary cirrhosis (PBC), an archetypal cholestatic liver disease. Cholestatic pruritus can be a debilitating symptom causing significant deterioration in patients' quality of life. Effective management of pruritus in PBC involves awareness among clinicians to adequately assess its severity, and treatment with specific drug therapies in line with current practice guidelines. In PBC, antipruritic drugs are not universally effective and/or have significant side effects, and despite best efforts with various combinations of drugs, some patients remain significantly symptomatic, eventually opting for invasive or experimental treatments. Therefore, there is a clear unmet need for better alternative treatments for patients with refractory or intractable cholestatic pruritus. Recent advances in the understanding of pathogenesis of cholestatic pruritus and bile acid physiology have raised hopes for novel therapies, some of which are currently under trial. In this review, we aim to provide a practical guide to the management of this important and complex problem, discussing current knowledge and recent advances in the pathogenesis, summarise the evidence base for available therapeutic approaches and update potential novel future therapies for the management of pruritus in PBC.
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Affiliation(s)
- Vinod S Hegade
- Faculty of Medical Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
| | - Ruth Bolier
- Tytgat Institute for Liver and Intestinal Research, Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Ronald PJ Oude Elferink
- Tytgat Institute for Liver and Intestinal Research, Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Ulrich Beuers
- Tytgat Institute for Liver and Intestinal Research, Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Stuart Kendrick
- GlaxoSmithKline Research and Development, Medicines Research Centre, Stevenage, Hertfordshire, UK
| | - David EJ Jones
- Faculty of Medical Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
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Hayashi H, Naoi S, Hirose Y, Matsuzaka Y, Tanikawa K, Igarashi K, Nagasaka H, Kage M, Inui A, Kusuhara H. Successful treatment with 4-phenylbutyrate in a patient with benign recurrent intrahepatic cholestasis type 2 refractory to biliary drainage and bilirubin absorption. Hepatol Res 2016; 46:192-200. [PMID: 26223708 DOI: 10.1111/hepr.12561] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2015] [Revised: 07/10/2015] [Accepted: 07/21/2015] [Indexed: 12/15/2022]
Abstract
AIM Benign recurrent intrahepatic cholestasis type 2 (BRIC2) is caused by mutations in ABCB11, a gene encoding the bile salt export pump (BSEP) that mediates biliary bile salt secretion, and presents with repeated intermittent cholestasis with refractory itching. Currently, no effective medical therapy has been established. We previously provided experimental and clinical evidence suggesting the therapeutic potential of 4-phenylbutyrate (4PB) for the cholestatic attacks of BRIC2. METHODS After examining the potential therapeutic use of 4PB treatment by in vitro studies, a patient with BRIC2 was treated p.o. with 4PB at gradually increasing doses (200, 350, and 500 mg/kg per day) for 4 months. Biochemical, histological and clinical data were collected. RESULTS The patient was diagnosed with BRIC2 because he had non-synonymous mutations (c.1211A>G [p.D404G] and 1331T>C [p.V444A]) in ABCB11, reduced hepatocanalicular expression of BSEP and low biliary bile salt concentrations. In vitro analysis showed that 4PB treatment partially restored the decreased expression of BSEP caused by p.D404G mutation. During the first 2 months of 4PB therapy at 200 and 350 mg/kg per day, the patient had no relief from his symptoms. No beneficial effect was observed after additional treatment with bilirubin absorption and endoscopic nasobiliary drainage. However, after starting treatment at a dose of 500 mg/kg per day, the patient's liver function tests and intractable itching were markedly improved. No apparent side-effects were observed during or after 4PB therapy. The symptoms relapsed within 1.5 months after cessation of 4PB therapy. CONCLUSION 4PB therapy would have a therapeutic effect on the cholestatic attacks of BRIC2.
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Affiliation(s)
- Hisamitsu Hayashi
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
| | - Sotaro Naoi
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
| | - Yu Hirose
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
| | - Yusuke Matsuzaka
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
| | - Ken Tanikawa
- Department of Diagnostic Pathology, Kurume University Hospital, Kurume, Japan
| | - Koji Igarashi
- Bioscience Division, Reagent Development Department, TOSOH, Ayase, Japan
| | - Hironori Nagasaka
- Department of Pediatrics, Takarazuka City Hospital, Takarazuka, Japan
| | - Masayoshi Kage
- Department of Diagnostic Pathology, Kurume University Hospital, Kurume, Japan
| | - Ayano Inui
- Department of Pediatric Hepatology and Gastroenterology, Saiseikai Yokohamashi Tobu Hospital, Yokohama, Japan
| | - Hiroyuki Kusuhara
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
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Hegade VS, Krawczyk M, Kremer AE, Kuczka J, Gaouar F, Kuiper EMM, van Buuren HR, Lammert F, Corpechot C, Jones DEJ. The safety and efficacy of nasobiliary drainage in the treatment of refractory cholestatic pruritus: a multicentre European study. Aliment Pharmacol Ther 2016; 43:294-302. [PMID: 26526892 DOI: 10.1111/apt.13449] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2015] [Revised: 09/08/2015] [Accepted: 10/07/2015] [Indexed: 01/05/2023]
Abstract
BACKGROUND Pruritus is a common symptom associated with cholestatic liver diseases. To date only small single centre case series have suggested efficacy of nasobiliary drainage in relieving cholestatic pruritus. AIM To perform a multicentre study to evaluate the safety and efficacy of nasobiliary drainage in cholestatic pruritus. METHODS This was a retrospective study of all patients treated with nasobiliary drainage for refractory cholestatic pruritus between 2006 and 2015 at five European centres. Pruritus was quantified using a visual analogue scale (VAS) and liver enzymes, serum bilirubin and total serum bile salts (TBS) were measured before (pre-NBD) and after nasobiliary drainage (post-NBD). We analysed the duration of treatment response and associated complications. RESULTS In total, 27 patients (59% females) underwent 29 nasobiliary drainage procedures. The median duration of NBD was 7 days. NBD decreased pruritus in 89.6% of cases (VAS from 10.0 to 0.3, P < 0.0001). The median percentage decline in pruritus VAS was 94% and 33% of patients were free of pruritus within 24 h of starting drainage. The duration of treatment response was independent of duration of drainage (P = 0.12) and bile output. Significant improvements were seen in the median levels of serum alkaline phosphatase (P = 0.001) and serum bilirubin (P = 0.03) but not in serum TBS (P = 0.07). Mild post-endoscopic retrograde cholangiopancreatography pancreatitis (31%) was the most frequent complication. CONCLUSIONS Nasobiliary drainage is effective in relieving cholestatic pruritus in most patients and has favourable effect on biomarkers of cholestasis. Nasobiliary drainage may be associated with high risk of adverse events, especially pancreatitis. Prospective studies are needed to confirm our findings.
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Affiliation(s)
- V S Hegade
- Freeman Hospital, The Newcastle upon Tyne NHS Foundation Trust and Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
| | - M Krawczyk
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany.,Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - A E Kremer
- Department of Medicine I, Friedrich-Alexander-University of Erlangen, Erlangen, Germany
| | - J Kuczka
- Department of Medicine I, Friedrich-Alexander-University of Erlangen, Erlangen, Germany
| | - F Gaouar
- Service d'Hépatologie, Centre de référence des Maladies Inflammatoires des voies biliaires, Hôpital Saint-Antoine, Paris, France
| | - E M M Kuiper
- Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, The Netherlands
| | - H R van Buuren
- Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, The Netherlands
| | - F Lammert
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - C Corpechot
- Service d'Hépatologie, Centre de référence des Maladies Inflammatoires des voies biliaires, Hôpital Saint-Antoine, Paris, France
| | - D E J Jones
- Freeman Hospital, The Newcastle upon Tyne NHS Foundation Trust and Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
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Appleby VJ, Hutchinson JM, Davies MH. Safety and efficacy of long-term nasobiliary drainage to treat intractable pruritus in cholestatic liver disease. Frontline Gastroenterol 2015; 6:252-254. [PMID: 28839819 PMCID: PMC5369582 DOI: 10.1136/flgastro-2014-100489] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2014] [Revised: 08/05/2014] [Accepted: 08/18/2014] [Indexed: 02/04/2023] Open
Abstract
INTRODUCTION Cholestasis related pruritus, secondary to intrahepatic and/or extrahepatic biliary obstruction is a common manifestation in chronic liver disease. Pruritus is difficult to treat, and results are often suboptimal. A stepwise medical approach is usually employed, followed by a trial molecular adsorbents recirculation system in medication resistant cases. Pruritus resulting in reduced quality of life is a variant syndrome eligible for liver transplantation in the setting of preserved synthetic function. AIM This case series describes the use of long-term (LT) nasobiliary drainage (NBD) in three patients with intractable pruritus. This case series tests the hypothesis that LT-NBD could be successfully used to alleviate cholestasis related pruritus, and prevent or delay the need for liver transplantation. METHOD LT-NBD was carried out in three female patients (mean age 43 years) with intractable pruritus secondary to primary biliary cirrhosis (PBC) (n=2), and benign recurrent intrahepatic cholestasis (n=1). NBD was carried out through the endoscopic placement of a 6 French Cook Medical nasobiliary catheter into the common bile duct. RESULTS Symptomatic relief of pruritus was described by all three cases within 24 h of NBD placement. LT-NBD was stopped in the patient with benign recurrent intrahepatic cholestasis after 8 weeks due to complete resolution of pruritus. In one patient with PBC, LT-NBD was undertaken over 12 months, with complete resolution of pruritus. In the second patient with PBC, LT-NBD was carried out over 14 months, with complete resolution of pruritus. DISCUSSION This case series supports the efficacy of LT-NBD in the treatment of intractable pruritus. We propose that NBD offers an accessible modality for the treatment of intractable pruritus in liver disease, potentially avoiding the need for liver transplantation.
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Affiliation(s)
- V J Appleby
- Department of Hepatology, St James University Hosptial, Leeds, UK
| | - J M Hutchinson
- Department of Hepatology, St James University Hosptial, Leeds, UK
| | - M H Davies
- Department of Hepatology, St James University Hosptial, Leeds, UK
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Bassari R, Koea JB. Jaundice associated pruritis: A review of pathophysiology and treatment. World J Gastroenterol 2015; 21:1404-1413. [PMID: 25663760 PMCID: PMC4316083 DOI: 10.3748/wjg.v21.i5.1404] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2014] [Revised: 10/19/2014] [Accepted: 11/19/2014] [Indexed: 02/06/2023] Open
Abstract
To review the underlying pathophysiology and currently available treatments for pruritis associated with jaundice. English language literature was reviewed using MEDLINE, PubMed, EMBASE and clinicaltrials.gov for papers and trails addressing the pathophysiology and potential treatments for pruritis associated with jaundice. Recent advances in the understanding of the peripheral anatomy of itch transmission have defined a histamine stimulated pathway and a cowhage stimulated pathway with sensation conveyed centrally via the contralateral spinothalamic tract. Centrally, cowhage and histamine stimulated neurons terminate widely within the thalamus and sensorimotor cortex. The causative factors for itch in jaundice have not been clarified although endogenous opioids, serotonin, steroid and lysophosphatidic acid all play a role. Current guidelines for the treatment of itching in jaundice recommend initial management with biliary drainage where possible and medical management with ursodeoxycholic acid, followed by cholestyramine, rifampicin, naltrexone and sertraline. Other than biliary drainage no single treatment has proved universally effective. Pruritis associated with jaundice is a common but poorly understood condition for which biliary drainage is the most effective therapy. Pharmacological therapy has advanced but remains variably effective.
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Ołdakowska-Jedynak U, Jankowska I, Hartleb M, Jirsa M, Pawłowska J, Czubkowski P, Krawczyk M. Treatment of pruritus with Prometheus dialysis and absorption system in a patient with benign recurrent intrahepatic cholestasis. Hepatol Res 2014; 44:E304-E308. [PMID: 24164717 DOI: 10.1111/hepr.12262] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2013] [Revised: 10/10/2013] [Accepted: 10/21/2013] [Indexed: 02/08/2023]
Abstract
Benign recurrent intrahepatic cholestasis (BRIC) is an autosomal recessive liver disorder characterized by recurrent episodes of jaundice and itching. Episodes of cholestasis last variously from 1 week to several months, may start at any age and usually resolve spontaneously. No effective treatment has been found as yet. We report a case of genetically proven BRIC in a male patient who developed three episodes of pruritus and jaundice at the age of 14, 16 and 19 years. During the third episode, he did not respond to pharmacological medical therapy, and fractionated plasma separation and absorption (FPSA, Prometheus) was performed to manage intractable pruritus. The treatment immediately alleviated pruritus, lowered serum bilirubin concentration and induced sustained remission in the 5-year follow up. FPSA seems to be a safe and effective way of treatment for BRIC in patients with severe pruritus and prolonged jaundice.
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34
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Receptors, cells and circuits involved in pruritus of systemic disorders. Biochim Biophys Acta Mol Basis Dis 2014; 1842:869-92. [DOI: 10.1016/j.bbadis.2014.02.007] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2013] [Revised: 02/16/2014] [Accepted: 02/18/2014] [Indexed: 12/12/2022]
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Srivastava A. Progressive familial intrahepatic cholestasis. J Clin Exp Hepatol 2014; 4:25-36. [PMID: 25755532 PMCID: PMC4017198 DOI: 10.1016/j.jceh.2013.10.005] [Citation(s) in RCA: 179] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2013] [Accepted: 10/31/2013] [Indexed: 12/12/2022] Open
Abstract
Progressive familial intrahepatic cholestasis (PFIC) is a group of rare disorders which are caused by defect in bile secretion and present with intrahepatic cholestasis, usually in infancy and childhood. These are autosomal recessive in inheritance. The estimated incidence is about 1 per 50,000 to 1 per 100,000 births, although exact prevalence is not known. These diseases affect both the genders equally and have been reported from all geographical areas. Based on clinical presentation, laboratory findings, liver histology and genetic defect, these are broadly divided into three types-PFIC type 1, PFIC type 2 and PFIC type 3. The defect is in ATP8B1 gene encoding the FIC1 protein, ABCB 11 gene encoding BSEP protein and ABCB4 gene encoding MDR3 protein in PFIC1, 2 and 3 respectively. The basic defect is impaired bile salt secretion in PFIC1/2 whereas in PFIC3, it is reduced biliary phospholipid secretion. The main clinical presentation is in the form of cholestatic jaundice and pruritus. Serum gamma glutamyl transpeptidase (GGT) is normal in patients with PFIC1/2 while it is raised in patients with PFIC3. Treatment includes nutritional support (adequate calories, supplementation of fat soluble vitamins and medium chain triglycerides) and use of medications to relieve pruritus as initial therapy followed by biliary diversion procedures in selected patients. Ultimately liver transplantation is needed in most patients as they develop progressive liver fibrosis, cirrhosis and end stage liver disease. Due to the high risk of developing liver tumors in PFIC2 patients, monitoring is recommended from infancy. Mutation targeted pharmacotherapy, gene therapy and hepatocyte transplantation are being explored as future therapeutic options.
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Key Words
- ABC, ATP binding cassette
- ASBT, apical sodium bile salt transporter
- ATP, adenosine triphosphate
- ATPase, adenosine triphosphatase
- BRIC, benign recurrent intrahepatic cholestasis
- BSEP, bile salt exporter protein
- CFTR, cystic fibrosis transmembrane conductance regulator
- CYP, cytochrome P
- DNA, deoxyribonucleic acid
- ERAD, endoplasmic reticulum associated degradation
- ESLD, end stage liver disease
- FIC1, familial intrahepatic cholestasis protein 1
- FXR, farnesoid X receptor
- HCC, hepatocellular carcinoma
- IB, ileal bypass
- ICP, intrahepatic cholestasis of pregnancy
- LT, liver transplant
- MARS, Molecular Adsorbent Recirculating System
- MDR, multidrug resistance protein
- MRCP, magnetic resonance cholangiopancreaticography
- PBD, partial biliary drainage
- PEBD, partial external biliary drainage
- PFIC, progressive familial intrahepatic cholestasis
- PIBD, partial internal biliary drainage
- PPAR, peroxisome proliferator activator receptor
- UDCA, ursodeoxycholic acid
- bile secretion
- children
- cholestasis
- familial
- mRNA, messenger ribonucleic acid
- pGp, p-glycoprotein
- pruritus
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Affiliation(s)
- Anshu Srivastava
- Address for correspondence: Anshu Srivastava, Associate Professor, Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh 226014, India. Tel.: +91 522 2495212, +91 9935219497 (mobile); fax: +91 522 2668017.
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Bolier R, Oude Elferink RPJ, Beuers U. Advances in pathogenesis and treatment of pruritus. Clin Liver Dis 2013; 17:319-29. [PMID: 23540505 DOI: 10.1016/j.cld.2012.11.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The pathogenesis of itch during cholestasis is largely unknown and treatment options are limited. Lysophosphatidate, female steroid hormones, and endogenous opioids are among the agents discussed as potential pruritogens in cholestasis. The itch-alleviating action of guideline-based therapeutic interventions with anion exchanger resins, rifampicin, opioid antagonists, and serotonin reuptake inhibitors are studied to unravel the molecular pathogenesis of itch. Still, a considerable part of the patients is in need of alternative experimental therapeutic approaches (eg, UV-B phototherapy, extracorporeal albumin dialysis, nasobiliary drainage), providing additional information about the enigmatic pathophysiology of cholestatic pruritus.
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Affiliation(s)
- Ruth Bolier
- Tytgat Institute for Liver and Intestinal Research, Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, G4-216, PO Box 22600, Amsterdam NL-1100 DD, The Netherlands
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Wakui N, Fujita M, Oba N, Yamauchi Y, Takeda Y, Ueki N, Otsuka T, Nishinakagawa S, Shiono S, Kojima T. Endoscopic nasobiliary drainage improves jaundice attack symptoms in benign recurrent intrahepatic cholestasis: A case report. Exp Ther Med 2012; 5:389-394. [PMID: 23403701 PMCID: PMC3570127 DOI: 10.3892/etm.2012.814] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2012] [Accepted: 11/13/2012] [Indexed: 11/15/2022] Open
Abstract
A 66-year-old male with unbearable pruritus and jaundice was admitted for detailed examination. Blood tests on admission showed increased bilirubin with a dominant direct fraction. Ultrasonography and computed tomography performed subsequent to admission showed no narrowing or distension of the bile ducts. As the jaundice symptoms were not improved by the oral administration of ursodeoxycholic acid (300 mg/day) that had been started immediately after admission, endoscopic retrograde cholangiopancreatography (ERCP) was performed on hospital day 14. This also showed no abnormalities of the bile ducts. After considerating its potential effects for improving jaundice, endoscopic nasobiliary drainage (ENBD) was performed on the same day and was followed by immediate improvements in pruritus and jaundice. Detailed examinations were performed to identify the cause of the jaundice, which was suspected to be viral hepatitis, autoimmune hepatitis or drug-induced liver injury, however, there were no findings suggestive of any of these conditions. Following a further increase in bilirubin levels, confirmed by additional blood tests, a liver biopsy was performed. Histological findings were consistent with the histological features of benign recurrent intrahepatic cholestasis (BRIC). Although ursodeoxycholic acid is used as a first-line treatment in most cases of BRIC, ENBD should also be considered for patients not responding to this treatment.
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Affiliation(s)
- Noritaka Wakui
- Departments of Internal Gastroenterology, Tokyo Rosai Hospital, Tokyo 143-0013, Japan
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38
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Kremer AE, van Dijk R, Leckie P, Schaap FG, Kuiper EMM, Mettang T, Reiners KS, Raap U, van Buuren HR, van Erpecum KJ, Davies NA, Rust C, Engert A, Jalan R, Oude Elferink RPJ, Beuers U. Serum autotaxin is increased in pruritus of cholestasis, but not of other origin, and responds to therapeutic interventions. Hepatology 2012; 56:1391-400. [PMID: 22473838 DOI: 10.1002/hep.25748] [Citation(s) in RCA: 184] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
UNLABELLED Pruritus is a seriously disabling symptom accompanying many cholestatic liver disorders. Recent experimental evidence implicated the lysophospholipase, autotaxin (ATX), and its product, lysophosphatidic acid (LPA), as potential mediators of cholestatic pruritus. In this study, we highlight that increased serum ATX levels are specific for pruritus of cholestasis, but not pruritus of uremia, Hodgkin's disease, or atopic dermatitis. Treatment of patients with cholestasis with the bile salt sequestrant, colesevelam, but not placebo, effectively reduced total serum bile salts and fibroblast growth factor 19 levels, but only marginally altered pruritus intensity and ATX activity. Rifampicin (RMP) significantly reduced itch intensity and ATX activity in patients with pruritus not responding to bile salt sequestrants. In vitro, RMP inhibited ATX expression in human HepG2 hepatoma cells and hepatoma cells overexpressing the pregnane X receptor (PXR), but not in hepatoma cells in which PXR was knocked down. Treatment of severe, refractory pruritus by the molecular adsorbents recirculation system or nasobiliary drainage improved itch intensity, which, again, correlated with the reduction of ATX levels. Upon reoccurrence of pruritus, ATX activity returned to pretreatment values. CONCLUSION Serum ATX activity is specifically increased in patients with cholestatic, but not other forms of, systemic pruritus and closely correlates with the effectiveness of therapeutic interventions. The beneficial antipruritic action of RMP may be explained, at least partly, by the PXR-dependent transcriptional inhibition of ATX expression. Thus, ATX likely represents a novel therapeutic target for pruritus of cholestasis.
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Affiliation(s)
- Andreas E Kremer
- Tytgat Institute for Liver and Intestinal Research, Department of gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
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Abstract
Progressive familial intrahepatic cholestasis (PFIC) refers to a heterogeneous group of autosomal-recessive disorders of childhood that disrupt bile formation and present with cholestasis of hepatocellular origin. The exact prevalence remains unknown, but the estimated incidence varies between 1/50,000 and 1/100,000 births. Three types of PFIC have been identified and associated with mutations in hepatocellular transport-system genes involved in bile formation. PFIC1 and PFIC2 usually appear in the first months of life, whereas onset of PFIC3 may arise later in infancy, in childhood or even during young adulthood. The main clinical manifestations include cholestasis, pruritus and jaundice. PFIC patients usually develop fibrosis and end-stage liver disease before adulthood. Serum gamma-glutamyltransferase (GGT) activity is normal in PFIC1 and PFIC2 patients, but is elevated in PFIC3 patients. Both PFIC1 and PFIC2 are caused by impaired bile salt secretion due to defects in ATP8B1 encoding the FIC1 protein and in ABCB11 encoding bile salt export pump (BSEP) protein, respectively. Defects in ABCB4, encoding multidrug resistance 3 protein (MDR3), impair biliary phospholipid secretion, resulting in PFIC3. Diagnosis is based on clinical manifestations, liver ultrasonography, cholangiography and liver histology, as well as on specific tests to exclude other causes of childhood cholestasis. MDR3 and BSEP liver immunostaining, and analysis of biliary lipid composition should help to select PFIC candidates for whom genotyping could be proposed to confirm the diagnosis. Antenatal diagnosis may be proposed for affected families in which a mutation has been identified. Ursodeoxycholic acid (UDCA) therapy should be initiated in all patients to prevent liver damage. In some PFIC1 and PFIC2 patients, biliary diversion may also relieve pruritus and slow disease progression. However, most PFIC patients are ultimately candidates for liver transplantation. Monitoring of liver tumors, especially in PFIC2 patients, should be offered from the first year of life. Hepatocyte transplantation, gene therapy and specific targeted pharmacotherapy may represent alternative treatments in the future.
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Affiliation(s)
- Emmanuel Jacquemin
- Pediatric Hepatology and Liver Transplantation Unit, and Reference Centre for Rare Liver Diseases, Bicêtre Hospital, AP-HP, 78 rue du général Leclerc, 94275 Le Kremlin-Bicêtre cedex, France.
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40
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Nasobiliary drainage in an episode of intrahepatic cholestasis in a child with mild ABCB11 disease. J Pediatr Gastroenterol Nutr 2012; 55:88-90. [PMID: 21822150 DOI: 10.1097/mpg.0b013e31822f2bda] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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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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42
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Chandra Dhar S, Kumar Ghosh C, Kumar Saha S, Chandra Nath N, Uddin H, Wareshuzzaman M, Omar Faruk M. A Female with Benign Recurrent Intrahepatic Cholestasis. Euroasian J Hepatogastroenterol 2012. [DOI: 10.5005/jp-journals-10018-1047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
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Nicolaou M, Andress EJ, Zolnerciks JK, Dixon PH, Williamson C, Linton KJ. Canalicular ABC transporters and liver disease. J Pathol 2011; 226:300-15. [DOI: 10.1002/path.3019] [Citation(s) in RCA: 94] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
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Dogra S, Jindal R. Cutaneous manifestations of common liver diseases. J Clin Exp Hepatol 2011; 1:177-84. [PMID: 25755383 PMCID: PMC3940632 DOI: 10.1016/s0973-6883(11)60235-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2011] [Accepted: 11/25/2011] [Indexed: 02/06/2023] Open
Abstract
Skin functions as a window to our overall health and a number of systemic diseases result in various cutaneous changes. Knowledge of these manifestations helps in suspecting an underlying systemic illness. Cutaneous abnormalities are quite common in patients with liver diseases and this article aims to focus on these dermatoses. Cutaneous manifestations seen in patients with liver disease though common are nonspecific. They can also be seen in patients without liver diseases and generally do not indicate about a specific underlying hepatic disorder. The presence of a constellation of signs and symptoms is more useful in pointing toward an underlying hepatobiliary condition. The commonest symptom in patients with liver disease is pruritus which is often protracted and disabling. Other common features include spider angiomas, palmar erythema, paper money skin, xanthelasmas, pigmentary changes, and nutritional deficiencies. In this article, first the common cutaneous manifestations that may be associated with liver disorders are discussed and then common liver diseases with their specific cutaneous findings are discussed. Cutaneous abnormalities may be the first clue to the underlying liver disease. Identifying them is crucial for early diagnosis and better management.
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Affiliation(s)
- Sunil Dogra
- Address for correspondence: Sunil Dogra, Associate Professor, Department of Dermatology, Venereology and Leprology, Postgraduate Institute of Medical Education and Research, Chandigarh - 160012, India
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Hori T, Egawa H, Takada Y, Ueda M, Oike F, Ogura Y, Sakamoto S, Kasahara M, Ogawa K, Miyagawa-Hayashino A, Yonekawa Y, Yorifuji T, Watanabe KI, Doi H, Nguyen JH, Chen F, Baine AMT, Gardner LB, Uemoto S. Progressive familial intrahepatic cholestasis: a single-center experience of living-donor liver transplantation during two decades in Japan. Clin Transplant 2011; 25:776-785. [PMID: 21158920 DOI: 10.1111/j.1399-0012.2010.01368.x] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Progressive familial intrahepatic cholestasis (PFIC) results in liver cirrhosis. Therefore, some PFIC patients require liver transplantation (LT). Although three types of PFIC have been identified, their etiologies include unknown mechanisms. PATIENTS A total of 717 recipients who underwent living-donor LT (LDLT) at <20 yr old were enrolled in this study. Among these recipients, 14 PFIC recipients comprising 11 PFIC type 1 (PFIC1) and three PFIC type 2 (PFIC2) were evaluated. RESULTS Three of 11 PFIC1 recipients died, while all three PFIC2 recipients survived. Eight of 11 PFIC1 recipients showed steatosis after LDLT. Among the eight steatosis-positive PFIC1 recipients, seven showed severe steatosis and seven were complicated with steatohepatitis. Nine of 11 PFIC1 recipients showed fibrosis after LDLT, and eight of the nine fibrosis-positive PFIC1 recipients showed severe fibrosis. In contrast to the PFIC1 recipients, the PFIC2 recipients did not show any steatosis or fibrosis after LDLT. CONCLUSIONS The clinical courses and outcomes of PFIC1 recipients after LDLT are still not sufficient owing to steatosis/fibrosis, unlike the case for PFIC2 recipients. As PFIC1 patients will require LT during the long-term progression of the disease, further strategy improvements are required for PFIC1 patients.
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Affiliation(s)
- Tomohide Hori
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University Hospital, Sakyo-ku, Kyoto, Japan.
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Oude Elferink RPJ, Kremer AE, Martens JJWW, Beuers UH. The molecular mechanism of cholestatic pruritus. Dig Dis 2011; 29:66-71. [PMID: 21691108 DOI: 10.1159/000324131] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Pruritus is a frequent symptom in patients with cholestatic liver diseases. Pruritus can be excruciating and, in rare cases, become a primary indication for liver transplantation. The molecular mechanism of itch signal transduction is largely unclear. It was our hypothesis that compounds which accumulate in the circulation during cholestasis act as direct or indirect pruritogens by affecting signaling in itch fibers. To test this, we screened plasma samples of a large group of patients with various cholestatic conditions for their capacity to activate neuroblastoma cells. Quite strikingly, we found that samples from itchy cholestatic patients caused a significantly higher activation than samples from non-itchy cholestatic patients and healthy controls. Purification revealed lysophosphatidic acid (LPA) as the active compound. LPA is a very potent signaling lipid that can activate cells through various LPA receptors. Subsequently, we could demonstrate that cholestatic patients with pruritus have highly elevated levels of serum autotaxin (ATX), the enzyme that converts lysophosphatidylcholine into LPA. This is a striking finding as ATX has never been connected to itch perception thus far. We have also shown that LPA, when injected intradermally, causes itching in mice. On the basis of our results, we hypothesize that during cholestasis, expression of ATX is induced and gives rise to increased local formation of LPA near unmyelinated nerve endings of itch fibers. LPA then activates these neurons through one of the LPA receptors, which in turn potentiates action potentials along itch fibers.
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Affiliation(s)
- Ronald P J Oude Elferink
- Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.
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Abstract
PURPOSE OF REVIEW Pruritus is a frequent symptom in patients with cholestatic liver diseases. Itching may be excruciating, may seriously impair quality of life and even induce suicidal ideation in the most severe cases. RECENT FINDINGS The molecular mechanism of itch signal transduction in cholestasis is largely unclear. It may be caused or potentiated by compounds that accumulate in the circulation during cholestasis, which either directly or indirectly affect signalling in itch fibres. In the past, bile salts and endogenous opioids have been proposed but never been proven to be key factors in itch perception during cholestasis. We have performed a screen for compounds in plasma from patients with various cholestatic conditions for their capacity to activate neuronal cell lines. In these sera, we could identify a potent neuronal activator as lysophosphatidic acid (LPA). LPA is a very potent signalling phospholipid that can activate cells through various LPA receptors. Quite strikingly, samples from itchy cholestatic patients contained higher amounts of LPA. These increased levels of LPA turned out to be caused by elevated levels of serum autotaxin, the enzyme that converts lysophosphatidylcholine into LPA. This is a striking finding, as autotaxin has never been connected to itch perception thus far. We have also shown that LPA, when injected intradermally, caused scratching behaviour in mice. SUMMARY On the basis of our results, we hypothesize that during cholestasis expression of autotaxin is induced, which gives rise to increased local formation of LPA near unmyelinated nerve endings of itch fibres. LPA activates these neurons through one of the LPA receptors, which in turn potentiates action potentials along itch fibres leading to the perception of pruritus.
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Kremer AE, Oude Elferink RPJ, Beuers U. Pathophysiology and current management of pruritus in liver disease. Clin Res Hepatol Gastroenterol 2011; 35:89-97. [PMID: 21809485 DOI: 10.1016/j.clinre.2010.10.007] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Pruritus is frequently reported by patients with cholestatic hepatobiliary diseases such as primary biliary cirrhosis, primary sclerosing cholangitis, intrahepatic cholestasis of pregnancy and hereditary cholestatic syndromes, but may accompany almost any other liver disease. Increased concentrations of bile salts, histamine, progesterone metabolites or endogenous opioids have been controversially discussed as potential pruritogens in cholestasis in the past. Most recently, novel insights unravelled lysophosphatidic acid (LPA), a potent neuronal activator, as a potential pruritogen in pruritus of cholestasis. Nevertheless, the pathogenesis of pruritus in cholestasis is still not clearly defined and current antipruritic treatment strategies provide relief only in a part of the affected patients. Based on recent experimental and clinical findings, this review outlines the actual insight in pathogenesis of pruritus in cholestasis and summarizes evidence-based and experimental therapeutic interventions for cholestatic patients suffering from itch.
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Affiliation(s)
- Andreas E Kremer
- Tytgat Institute for liver and intestinal research, Department of gastroenterology and hepatology, Academic Medical Center, S1-164, University of Amsterdam, Meibergdreef 69-71, NL-1105 BK Amsterdam, The Netherlands.
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Abstract
BACKGROUND The discovery of genetic mutations in children with inherited syndromes of intrahepatic cholestasis allows for diagnostic specificity despite similar clinical phenotypes. Here, we aimed to determine whether mutation screening of target genes could assign a molecular diagnosis in children with idiopathic cholestasis. PATIENTS AND METHODS DNA samples were obtained from 51 subjects with cholestasis of undefined etiology and surveyed for mutations in the genes SERPINA1, JAG1, ATP8B1, ABCB11, and ABCB4 by a high-throughput gene chip. Then, the sequence readouts for all 5 genes were analyzed for mutations and correlated with clinical phenotypes. Healthy subjects served as controls. RESULTS Sequence analysis of the genes identified 14 (or 27%) subjects with missense, nonsense, deletion, and splice site variants associated with disease phenotypes based on the type of mutation and/or biallelic involvement in the JAG1, ATP8B1, ABCB11, or ABCB4 genes. These patients had no syndromic features and could not be differentiated by biochemical markers or histopathology. Among the remaining subjects, 10 (or ∼20%) had sequence variants in ATP8B1 or ABCB11 that involved only 1 allele, 8 had variants not likely to be associated with disease phenotypes, and 19 had no variants that changed amino acid composition. CONCLUSIONS Gene sequence analysis assigned a molecular diagnosis in 27% of subjects with idiopathic cholestasis based on the presence of variants likely to cause disease phenotypes.
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Kuiper EMM, van Erpecum KJ, Beuers U, Hansen BE, Thio HB, de Man RA, Janssen HLA, van Buuren HR. The potent bile acid sequestrant colesevelam is not effective in cholestatic pruritus: results of a double-blind, randomized, placebo-controlled trial. Hepatology 2010; 52:1334-40. [PMID: 20683930 DOI: 10.1002/hep.23821] [Citation(s) in RCA: 90] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
UNLABELLED Colesevelam is an anion-exchange resin with a 7-fold higher bile acid-binding capacity and fewer side effects than cholestyramine, the current first-line treatment option for cholestatic pruritus. The aim of this trial was to compare the effects of colesevelam and a placebo in patients with cholestatic pruritus. In a randomized, double-blind, investigator-initiated, multicenter trial, patients with cholestatic pruritus, both treatment-naive and previously treated, received 1875 mg of colesevelam or an identical placebo twice daily for 3 weeks. The effect on pruritus was assessed with daily visual analogue scales, quality-of-life scores, and evaluations of cutaneous scratch lesions. The predefined primary endpoint was the proportion of patients with at least a 40% reduction in pruritus visual analogue scale scores. Thirty-eight patients were included, and 35 were evaluable: 17 took colesevelam, 18 took the placebo, 22 were female, 8 were treatment-naive, 14 had primary biliary cirrhosis, and 14 had primary sclerosing cholangitis. The mean serum bile acid levels were comparable between the groups before treatment (P = 0.74), but they were significantly different after treatment (P = 0.01) in favor of patients treated with colesevelam. Thirty-six percent of patients in the colesevelam group reached the primary endpoint versus 35% in the placebo group (P = 1.0). There were no significant differences between the groups with respect to pruritus scores, quality-of-life scores, and severity of cutaneous scratch lesions. Mild side effects occurred in one colesevelam-treated patient and four placebo-treated patients. CONCLUSION Although colesevelam significantly decreased serum bile acid levels, this trial was unable to demonstrate that it was more effective than a placebo in alleviating the severity of pruritus of cholestasis.
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Affiliation(s)
- Edith M M Kuiper
- Department of Gastroenterology and Hepatology, Erasmus University Medical Centre, Rotterdam, the Netherlands
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