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1
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Ijichi H. Phase 3 Trials of Elafibranor and Seladelpar for Primary Biliary Cholangitis. N Engl J Med 2024; 390:1934. [PMID: 38810194 DOI: 10.1056/nejmc2403986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/31/2024]
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Marani M, Madan V, Le TK, Deng J, Lee KK, Ma EZ, Kwatra SG. Dysregulation of the Skin-Liver Axis in Prurigo Nodularis: An Integrated Genomic, Transcriptomic, and Population-Based Analysis. Genes (Basel) 2024; 15:146. [PMID: 38397136 PMCID: PMC10887737 DOI: 10.3390/genes15020146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 01/06/2024] [Accepted: 01/18/2024] [Indexed: 02/25/2024] Open
Abstract
Pruritus has long been linked to hepatic dysfunction; however, there are limited data characterizing the association between liver disease and prurigo nodularis (PN), a chronic inflammatory skin disease featuring severe pruritis. We thus conducted a cross-sectional analysis of hepatic comorbidities in PN patients using TriNetX, a large global health research network. This analysis revealed that PN patients had a higher risk (p < 0.001) of developing liver cirrhosis, acute and subacute hepatic failure, inflammatory liver disease, chronic hepatitis, nonalcoholic steatohepatitis, portal hypertension, fatty liver, chronic passive congestion of the liver, and hepatocellular carcinoma compared with healthy controls. The cumulative incidence of liver disease was about three times higher in PN patients compared with healthy controls. These findings provided the basis for translational studies to investigate a genetic mechanism for this association. Cutaneous transcriptomic analysis performed on PN patients revealed the dysregulation of genes related to hepatic failure in lesional PN compared with both nonlesional PN and control skin. Similarly, gene set variation analysis (GSVA) revealed a significantly increased (p < 0.05) activation of liver metabolism, chronic hepatic failure, acute hepatic failure, cholestatic liver disease, polycystic liver disease, and hepatocellular carcinoma pathways in lesional PN compared with control skin. A subsequent genome-wide association study (GWAS) identified shared single-nucleotide polymorphisms (SNPs) in the genes AR, EDIL3, MACROD2, PCSK5, RUNX1T1, TENM4, and ZEB2 between PN and liver disease from the FinnGen cohort. Significant dysregulation of the skin-liver axis in PN patients may explain the increased incidence and severity of hepatic comorbidities and help identify future therapeutic targets for PN.
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Affiliation(s)
| | | | | | | | | | | | - Shawn G. Kwatra
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Enhanced anxiolytic and analgesic effectiveness or a better safety profile of morphine and tramadol combination in cholestatic and addicted mice. Neuroreport 2022; 33:681-689. [DOI: 10.1097/wnr.0000000000001834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
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Cholestatic Itch: Our Current Understanding of Pathophysiology and Treatments. Am J Clin Dermatol 2022; 23:647-659. [PMID: 35900649 DOI: 10.1007/s40257-022-00710-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/23/2022] [Indexed: 11/01/2022]
Abstract
Hepatic pruritus is common in liver conditions, including cholestasis and nonalcoholic fatty liver disease. The pruritus can be severe enough to diminish sleep and decrease quality of life. The pathophysiology likely involves many molecules and receptors, including bile acids, bilirubin, lysophosphatidic acid (LPA), endogenous opioids, and serotonin. Recent advances suggest a significant role of Mas-related G protein-coupled receptor X4 (MRGPRX4) and autotaxin/LPA as key players in cholestatic pruritus. Further research is needed to develop increasingly targeted therapies with greater efficacy, especially given that many patients report itch refractory to various treatments. Cholestyramine was the only US FDA-approved drug for cholestatic pruritus until recent approval of ileal bile acid transporter (IBAT) inhibitors for use in the pediatric cholestatic conditions, progressive familial intrahepatic cholestasis and Alagille syndrome. Both medications decrease the bile acid pool. IBAT inhibitors are under investigation for broader use, and targeting LPA receptors and MRGPR4 are additional attractive options.
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Kremer AE, Mayo MJ, Hirschfield G, Levy C, Bowlus CL, Jones DE, Steinberg A, McWherter CA, Choi YJ. Seladelpar improved measures of pruritus, sleep, and fatigue and decreased serum bile acids in patients with primary biliary cholangitis. Liver Int 2022; 42:112-123. [PMID: 34403559 DOI: 10.1111/liv.15039] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 08/11/2021] [Accepted: 08/15/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Primary biliary cholangitis (PBC) can result in life-altering cholestatic pruritus and fatigue, but treatment options are limited. Seladelpar, a peroxisome proliferator-activated receptor-delta (PPARδ) agonist, has demonstrated potent anti-cholestatic effects in clinical studies. This open-label, uncontrolled phase 2 study in PBC patients evaluated the effects of 1-year of seladelpar treatment on measures of pruritus and quality of life. METHODS Self-reported experiences of 101 PBC patients were collected at baseline and after 1 year of seladelpar treatment using the pruritus visual analog scale (VAS), 5D-itch scale, and PBC-40 questionnaires along with bile acid profiles. RESULTS In patients with moderate-to-severe pruritus, substantial improvement in pruritus was seen in 58% and 93% of patients in 5/10 mg and 10 mg treatment groups, respectively. After 1 year, patients reporting improvement substantially outnumbered those who worsened in the total 5-D itch (including individual domains) and PBC-40 (itch and fatigue domains) questionnaires. Improvement in sleep disturbance at 1-year was reported in 81% (5/10 mg) and 78% (10 mg) of the patients with baseline itch-related sleep disturbance by 5-D itch score with similar results using the PBC-40 sleep questionnaire. Seladelpar-treated patients had significant reductions of 46% (5/10 mg) and 31% (10 mg) in the serum bile acid precursor C4 and reductions of up to 38% in serum bile acids. CONCLUSIONS Seladelpar treatment for 1 year led to consistent improvement in both symptom burden and biochemical response, suggesting its potential as a single agent to address two key unmet needs in PBC patients.
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Affiliation(s)
- Andreas E Kremer
- Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland.,Department of Medicine 1, University Hospital Erlangen and Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany
| | - Marlyn J Mayo
- Division of Digestive and Liver Diseases, University of Texas SW Medical Center, Dallas, TX, USA
| | - Gideon Hirschfield
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
| | - Cynthia Levy
- Division of Digestive Health and Liver Diseases, University of Miami Miller School of Medicine. Miami, Florida, USA
| | - Christopher L Bowlus
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of California Davis, Sacramento, CA, USA
| | - David E Jones
- Clinical and Translation Research Institute, Newcastle University, Newcastle upon Tyne, UK
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Abstract
Abstract
Purpose of Review
Chronic pruritus represents a burdensome symptom in cholestatic liver disease. This review recommends a stepwise therapeutic approach, alongside with providing information on epidemiology, pathophysiology, and novel drug targets.
Recent Findings
Current epidemiological data emphasize chronic itch as a major symptom in immune-mediated liver diseases such as primary biliary cholangitis affecting up to 70% of patients with a significant number suffering from long-lasting and severe pruritus. κ-opioid receptor (KOR) agonists, PPAR agonists, and ileal bile acid transporter (IBAT) inhibitors are currently investigated for their anti-pruritic efficacy in clinical trials. Future therapies may target the autotaxin-lysophosphatidic acid-axis or the Mas-related GPCR MRGPRX4.
Summary
Cholestatic pruritus still remains a challenging symptom for patients and physicians. Using a stepwise approach including cholestyramine, rifampicin, bezafibrate, naltrexone, and sertraline, pruritus is often adequately manageable. KOR agonists and IBAT inhibitors are currently the most promising anti-pruritic drugs for cholestatic pruritus in development.
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Abstract
Chronic pruritus is a symptom of various internal disorders. In contrast to dermatological diseases, pruritus does not present with primary skin alterations in these patients. However, intense scratching my cause secondary skin changes such as abrasion, excoriation, prurigo nodularis, or in rare cases even scarring. The most common internal causes for chronic pruritus are chronic kidney disease, hepatobiliary, and hematological disorders as well as adverse drug reactions. Pruritus is less commonly seen in patients with endocrine or metabolic diseases, malabsorption syndromes, infectious diseases, and solid tumors. The pathogenesis of pruritus in these disorders remains largely elusive, albeit first insights have been gained for uremic and cholestatic pruritus. Antipruritic treatment is therefore symptomatic in most cases and may represent a clinical challenge. The calcium channel blockers gabapentin and pregabalin have the best proven efficacy in chronic kidney disease associated pruritus. In Japan, nalfurafine, a κ-opioid receptor agonist, has been licensed for this indication. UVB light may also attenuate uremic symptoms. In patients suffering from hepatobiliary disorders the sequestrant cholestyramine and the enzyme inducer rifampicin are effective. Furthermore, bezafibrate, the μ‑opioid receptor antagonists and, in Japan, nalfurafine may be used to ameliorate cholestatic pruritus. So far, no randomized controlled trials have been performed for chronic itch in other internal disorders. Antipruritic treatment is symptom-based with a focus on the effective therapy of the underlying disease.
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Abstract
PURPOSE OF REVIEW Pruritus is a common extrahepatic symptom in various liver disorders, in particularly those with cholestatic features. This review summarizes epidemiology, pathophysiology, evidence-based therapeutic recommendations and currently investigated drugs for pruritus in hepatobiliary disorders. RECENT FINDINGS Recent epidemiological data suggest pruritus as a common and relevant symptom in immune-mediated liver diseases, i.e., primary biliary cholangitis (PBC) with over 70% affected patients, up to 56% suffering from chronic pruritus. The better pathophysiological understanding of hepatic pruritus has led to the identification of novel therapeutic targets, addressed in drug trials using KOR agonists, PPAR agonists, and ileal bile acid transporter inhibitors. Hepatic itch remains among the most agonizing symptoms for affected patients and a clinical challenge for physicians. Therapeutic recommendations include a guideline-based stepwise approach starting with cholestyramine, followed by rifampicin, naltrexone, and sertraline. Bezafibrate and ileal bile acid transporter inhibitors represent promising future anti-pruritic treatment options.
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Affiliation(s)
- Miriam M Düll
- Department of Medicine 1, Gastroenterology, Hepatology, Pneumology and Endocrinology, Friedrich-Alexander-University Erlangen-Nürnberg, Ulmenweg 18, D-91054, Erlangen, Germany
| | - Andreas E Kremer
- Department of Medicine 1, Gastroenterology, Hepatology, Pneumology and Endocrinology, Friedrich-Alexander-University Erlangen-Nürnberg, Ulmenweg 18, D-91054, Erlangen, Germany.
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Jafferany M, Davari ME. Itch and psyche: psychiatric aspects of pruritus. Int J Dermatol 2018; 58:3-23. [PMID: 29917231 DOI: 10.1111/ijd.14081] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Revised: 04/07/2018] [Accepted: 05/16/2018] [Indexed: 01/02/2023]
Abstract
Itch, also referred to as pruritus, is an unpleasant cutaneous sensation provoking the desire to scratch. It is often an uncomfortable, subjective sensation responsible for decreased quality of life in a variety of psychodermatological conditions. Comorbid psychiatric conditions, including depression and anxiety, are frequently associated with itch and scratch cycle. The reciprocal and intricate relationship between the psyche and itch has been widely studied. The neurobiology of itch involves the complexity of specific mediators, itch-related neuronal pathways, and central processing of itch. The connection between itch and the psyche can be grouped under three headings: pruritic diseases with psychosocial sequelae, pruritic diseases aggravated by psychosocial factors, and psychiatric disorders causing pruritus. Itch and pain modulation go together in most circumstances and involve various substances including histamine, interleukins, protease-activated receptors, transient receptor potential receptors, opioids, and cannabinoids. The close interaction between keratinocytes and nerve endings modulating pain and itch also play a major role. Management of itch associated with its psychosomatic components is directed at an underlying cause and adopting a holistic approach to address not only dermatologic and somatosensory aspects, but also the cognitive, emotional, and psychosocial components. An integrated multidisciplinary team consisting of a dermatologist, psychiatrist, psychologist, and social worker is vital in addressing the multifaceted aspects of pruritus.
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Tajiri K, Shimizu Y. Recent advances in the management of pruritus in chronic liver diseases. World J Gastroenterol 2017; 23:3418-3426. [PMID: 28596678 PMCID: PMC5442078 DOI: 10.3748/wjg.v23.i19.3418] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Revised: 03/13/2017] [Accepted: 05/04/2017] [Indexed: 02/06/2023] Open
Abstract
Pruritus is a symptom found in patients with chronic liver diseases, especially cholestatic liver diseases such as primary biliary cholangitis. This symptom impairs patient quality of life by disturbing sleep and may lead to consideration of liver transplantation. Mechanisms implicated in pruritus have been associated with the peripheral and central nervous systems, leading to the development of various therapeutic options. Little evidence for the efficacy of most of these treatments is currently available, indicating a need for further investigations.
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Saffioti F, Gurusamy KS, Eusebi LH, Tsochatzis E, Davidson BR, Thorburn D. Pharmacological interventions for primary biliary cholangitis: an attempted network meta-analysis. Cochrane Database Syst Rev 2017; 3:CD011648. [PMID: 28350426 PMCID: PMC6464661 DOI: 10.1002/14651858.cd011648.pub2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
BACKGROUND Primary biliary cholangitis (previously primary biliary cirrhosis) is a chronic liver disease caused by the destruction of small intra-hepatic bile ducts resulting in stasis of bile (cholestasis), liver fibrosis, and liver cirrhosis. The optimal pharmacological treatment of primary biliary cholangitis remains uncertain. OBJECTIVES To assess the comparative benefits and harms of different pharmacological interventions in the treatment of primary biliary cholangitis through a network meta-analysis and to generate rankings of the available pharmacological interventions according to their safety and efficacy. However, it was not possible to assess whether the potential effect modifiers were similar across different comparisons. Therefore, we did not perform the network meta-analysis, and instead, assessed the comparative benefits and harms of different interventions using standard Cochrane methodology. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 2), MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and randomised controlled trials registers to February 2017 to identify randomised clinical trials on pharmacological interventions for primary biliary cholangitis. SELECTION CRITERIA We included only randomised clinical trials (irrespective of language, blinding, or publication status) in participants with primary biliary cholangitis. We excluded trials which included participants who had previously undergone liver transplantation. We considered any of the various pharmacological interventions compared with each other or with placebo or no intervention. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane. We calculated the odds ratio (OR) and rate ratio with 95% confidence intervals (CI) using both fixed-effect and random-effects models based on available-participant analysis with Review Manager 5. We assessed risk of bias according to Cochrane, controlled risk of random errors with Trial Sequential Analysis, and assessed the quality of the evidence using GRADE. MAIN RESULTS We identified 74 trials including 5902 participants that met the inclusion criteria of this review. A total of 46 trials (4274 participants) provided information for one or more outcomes. All the trials were at high risk of bias in one or more domains. Overall, all the evidence was low or very low quality. The proportion of participants with symptoms varied from 19.9% to 100% in the trials that reported this information. The proportion of participants who were antimitochondrial antibody (AMA) positive ranged from 80.8% to 100% in the trials that reported this information. It appeared that most trials included participants who had not received previous treatments or included participants regardless of the previous treatments received. The follow-up in the trials ranged from 1 to 96 months.The proportion of people with mortality (maximal follow-up) was higher in the methotrexate group versus the no intervention group (OR 8.83, 95% CI 1.01 to 76.96; 60 participants; 1 trial; low quality evidence). The proportion of people with mortality (maximal follow-up) was lower in the azathioprine group versus the no intervention group (OR 0.56, 95% CI 0.32 to 0.98; 224 participants; 2 trials; I2 = 0%; low quality evidence). However, it has to be noted that a large proportion of participants (25%) was excluded from the trial that contributed most participants to this analysis and the results were not reliable. There was no evidence of a difference in any of the remaining comparisons. The proportion of people with serious adverse events was higher in the D-penicillamine versus no intervention group (OR 28.77, 95% CI 1.57 to 526.67; 52 participants; 1 trial; low quality evidence). The proportion of people with serious adverse events was higher in the obeticholic acid plus ursodeoxycholic acid (UDCA) group versus the UDCA group (OR 3.58, 95% CI 1.02 to 12.51; 216 participants; 1 trial; low quality evidence). There was no evidence of a difference in any of the remaining comparisons for serious adverse events (proportion) or serious adverse events (number of events). None of the trials reported health-related quality of life at any time point. FUNDING nine trials had no special funding or were funded by hospital or charities; 31 trials were funded by pharmaceutical companies; and 34 trials provided no information on source of funding. AUTHORS' CONCLUSIONS Based on very low quality evidence, there is currently no evidence that any intervention is beneficial for primary biliary cholangitis. However, the follow-up periods in the trials were short and there is significant uncertainty in this issue. Further well-designed randomised clinical trials are necessary. Future randomised clinical trials ought to be adequately powered; performed in people who are generally seen in the clinic rather than in highly selected participants; employ blinding; avoid post-randomisation dropouts or planned cross-overs; should have sufficient follow-up period (e.g. five or 10 years or more); and use clinically important outcomes such as mortality, health-related quality of life, cirrhosis, decompensated cirrhosis, and liver transplantation. Alternatively, very large groups of participants should be randomised to facilitate shorter trial duration.
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Affiliation(s)
- Francesca Saffioti
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentrePond StreetHampsteadLondonUKNW3 2QG
- University of MessinaDepartment of Clinical and Experimental Medicine, Division of Clinical and Molecular HepatologyVia Consolare Valeria, 1MessinaMessinaItaly98125
| | - Kurinchi Selvan Gurusamy
- Royal Free Campus, UCL Medical SchoolDepartment of SurgeryRoyal Free HospitalRowland Hill StreetLondonUKNW3 2PF
| | - Leonardo Henry Eusebi
- Royal Free Hampstead NHS Foundation Trust and UCL Institute of Liver and Digestive HealthThe Royal Free Sheila Sherlock Liver CentreLondonUK
- University of BolognaDepartment of Medical and Surgical Sciences (DIMEC)BolognaItaly
| | - Emmanuel Tsochatzis
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentrePond StreetHampsteadLondonUKNW3 2QG
| | - Brian R Davidson
- Royal Free Campus, UCL Medical SchoolDepartment of SurgeryRoyal Free HospitalRowland Hill StreetLondonUKNW3 2PF
| | - Douglas Thorburn
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentrePond StreetHampsteadLondonUKNW3 2QG
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Abstract
Chronic pruritus is a symptom of various internal disorders. In contrast to dermatological diseases, pruritus does not present with primary skin alterations in these patients. However, intense scratching may cause secondary skin changes such as abrasion, excoriation, prurigo nodularis, or in rare cases even scaring. The most common internal medicine causes for chronic pruritus are chronic kidney disease, hepatobiliary and hematological disorders as well as adverse drug reactions. Pruritus is less commonly seen in patients with endocrine or metabolic diseases, malabsorption syndromes, infectious diseases and solid tumors. The pathogenesis of pruritus in these disorders remains largely elusive, albeit preliminary insights have been gained for uremic and cholestatic pruritus. Antipruritic treatment is therefore symptomatic in most cases and may represent a clinical challenge. The calcium channel blockers gabapentin and pregabalin have the best proven efficacy in chronic kidney disease-associated pruritus. In Japan nalfurafine, a κ-opioid receptor agonist, has been licensed for this indication. UVB light may also attenuate uremic symptoms. In patients suffering from hepatobiliary disorders the sequestrant cholestyramine and the enzyme inducer rifampicin are effective. Furthermore, μ‑opioid receptor antagonists and sertraline may be used to ameliorate cholestatic pruritus. So far, no randomized controlled trials have been performed for chronic itch in other internal medicine disorders. Antipruritic treatment is mainly based on effective therapy of the underlying disease.
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Affiliation(s)
- A E Kremer
- Medizinische Klinik 1, Friedrich-Alexander Universität Erlangen-Nürnberg, Ulmenweg 18, 91054, Erlangen, Deutschland.
| | - T Mettang
- DKD Helios Kliniken Wiesbaden, Aukammallee 33, 65191, Wiesbaden, Deutschland
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Rajagopalan M, Saraswat A, Godse K, Shankar DSK, Kandhari S, Shenoi SD, Tahiliani S, Zawar VV. Diagnosis and Management of Chronic Pruritus: An Expert Consensus Review. Indian J Dermatol 2017; 62:7-17. [PMID: 28216719 PMCID: PMC5286757 DOI: 10.4103/0019-5154.198036] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
The aim of this study is to formulate the best clinical practice in the diagnosis and management of chronic pruritus (CP). We searched PubMed, EMBASE, Scopus, Web of Science, and the WHO's regional databases, for studies on "Diagnosis and management of chronic pruritus" from January 1, 2014, to July 31, 2015. We included programmatic reports and hand-searched references of published reviews and articles. Two independent reviewers screened articles and extracted data. We screened 87 of 95 studies that contained qualitative data. Avoid: Dry climate, heat, alcohol compress, ice packs, frequent bathing and washing, intake of very hot and spicy food, intake of alcohol, contact with irritant substances, excitement, strain and stress, and allergens. Using: Mild nonalkaline soaps, moisturizers, bathing oils, lukewarm water while bathing, soft cotton clothing and night creams/lotions, relaxation therapy, autogenic training, psychosocial education, educating patients to cope with itching and scratching, and educational programs. Especially use of moisturizers is considered important. In addition, symptomatic treatment options include systemic H1 antihistamines and topical corticosteroids. Symptomatic therapy directed toward the cause (hepatic, renal, atopic, polycythemia, etc.). If refractory or cause is unknown, consider capsaicin, calcineurin inhibitors for localized pruritus and naltrexone, pregabalin, ultraviolet therapy, Cyclosporine for generalized itching. CP is quite frequent finding associated with skin and systemic diseases in the overall population. It is known to significantly affect quality life score of an individual and also adds burden on the health-care cost. A specific recommendation for treatment of CP is difficult as a result of varied and diverse possibility of underlying diseases associated with CP.
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Affiliation(s)
| | - Abir Saraswat
- Indushree Skin Clinic, Lucknow, Uttar Pradesh, India
| | - Kiran Godse
- Department of Dermatology, D. Y. Patil Hospital and School of Medicine, Navi Mumbai, Maharashtra, India
| | | | - Sanjiv Kandhari
- Dermatiologist, Dr. Kandhari's Skin Clinic, New Delhi, India
| | - Shrutakirthi D Shenoi
- Department of Dermatology, Kasturba Medical College and Hospital, Manipal, Karnataka, India
| | - Sushil Tahiliani
- Department of Dermatology, Hinduja Healthcare Surgical Hospital, Mumbai, Maharashtra, India
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15
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Jin XY, Khan TM. Quality of life among patients suffering from cholestatic liver disease-induced pruritus: A systematic review. J Formos Med Assoc 2016; 115:689-702. [PMID: 27431691 DOI: 10.1016/j.jfma.2016.05.006] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2015] [Revised: 03/31/2016] [Accepted: 05/05/2016] [Indexed: 12/14/2022] Open
Abstract
A systematic assessment of literature was done to estimate the impact of pruritus on health-related quality of life among patients with cholestatic liver disease (CLD). All the articles were reviewed manually for study design, population, outcomes, and study quality. A qualitative approach was used to analyze and extract data from included studies. A total of eight studies were retrieved, of which one was a cohort study and the other seven were cross-sectional studies. Overall, it appears that the incidence of pruritus was a common complication reported by most of the studies. Among patients with CLD incidence of pruritus was 29%. Pruritus was found to have a substantial impact on patients' health-related quality of life. Greater health-related quality of life impairment was observed with increased severity of pruritus. Pruritus was found to have a significant association (p<0.05) in quality-of-life instrument domains such as role limitation-physical, role limitation-emotional, bodily pain, vitality, energy, and physical mobility. Evidence suggests that pruritus has a substantial impact on health-related quality of life among patients with CLD. More research is required to support the evidence.
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Affiliation(s)
- Xin Yee Jin
- School of Pharmacy, Monash University, Bandar Sunway, 45700, Selangor, Malaysia
| | - Tahir Mehmood Khan
- School of Pharmacy, Monash University, Bandar Sunway, 45700, Selangor, Malaysia.
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Abstract
The burden of chronic pruritus is increasingly recognized as significant worldwide. As wet-laboratory researchers investigate the pathophysiology of chronic pruritus, epidemiologists and health services researchers are quantifying the impact of pruritus by incidence, prevalence, and quality of life measures. Outcomes researchers are also investigating factors that may predict chronic pruritus incidence and severity. Such efforts will direct resources for research, public health intervention, and clinical care.
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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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Kremer AE, Bolier R, van Dijk R, Oude Elferink RPJ, Beuers U. Advances in pathogenesis and management of pruritus in cholestasis. Dig Dis 2014; 32:637-45. [PMID: 25034299 DOI: 10.1159/000360518] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Chronic pruritus is a burdensome feature of numerous hepatobiliary disorders such as primary biliary cirrhosis, primary sclerosing cholangitis, cholangiocarcinoma, inherited forms of cholestasis and intrahepatic cholestasis of pregnancy. Bile salts, μ-opioids, serotonin, histamine and steroids have been controversially discussed in the pathogenesis of cholestatic pruritus. However, for these substances neither a correlation with itch severity nor a causative link has ever been established. Recent findings indicate that the potent neuronal activator lysophosphatidic acid and autotaxin, the enzyme forming lysophosphatidic acid, may play a key element in the pathogenesis of cholestatic pruritus. Serum activity of autotaxin correlated with itch intensity and response to antipruritic treatment in patients with cholestatic pruritus, but not other forms of pruritus. Autotaxin activity thereby represents the first biomarker for pruritus and had a positive predictive value of 70% in differentiating cholestatic pruritus from other forms of pruritus. Treatment options for patients with cholestatic pruritus include the anion exchange resin colestyramine, the PXR agonist rifampicin, the μ-opioid antagonist naltrexone, and the serotonin reuptake inhibitor sertraline. These drugs are recommended by evidence-based guidelines as a stepwise therapeutic approach. Patients unresponsive to these drugs should be referred to specialized centers to receive experimental approaches such as UVB phototherapy, albumin dialysis, plasmapheresis or nasobiliary drainage. This review discusses pruritogen candidates in cholestasis, gives novel insights into the neuronal signaling pathway of pruritus and summarizes evidence-based treatment options for patients suffering from pruritus in cholestasis.
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Affiliation(s)
- Andreas E Kremer
- Department of Medicine 1, Friedrich Alexander University of Erlangen-Nuremberg, Erlangen, Germany
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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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Abstract
The care of the patient with cholestasis hinges on identifying the etiology, treating reversible causes, and managing chronic cholestatic processes. PBC and PSC are important causes of chronic cholestasis, and are the most common causes of cholestatic liver disease. Effective therapy is available for patients with PBC, whereas none exists for patients with PSC. Awareness of the complications that may be associated with cholestasis and implementing the appropriate management are essential.
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Affiliation(s)
- Andrea A Gossard
- Cholestatic Liver Disease Study Group, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN, USA.
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Abstract
Cholestasis is defined as impairment of bile formation or bile flow. Care of the patient with cholestatic features is dependent on identifying the cause of the cholestasis, initiating appropriate treatment of reversible conditions, and the recognition and management of cholestasis-specific complications. Cholestasis may include extrahepatic ducts and intrahepatic bile ducts, or may be limited to one or the other. Jaundice and pruritus are the hallmarks of cholestasis clinically but biochemical evidence may, and often does, precede the clinical manifestations.
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Affiliation(s)
- Andrea A Gossard
- Cholestatic Liver Disease Study Group, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55901, USA.
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Belghiti M, Estévez-Herrera J, Giménez-Garzó C, González-Usano A, Montoliu C, Ferrer-Montiel A, Felipo V, Planells-Cases R. Potentiation of the transient receptor potential vanilloid 1 channel contributes to pruritogenesis in a rat model of liver disease. J Biol Chem 2013; 288:9675-9685. [PMID: 23408423 DOI: 10.1074/jbc.m113.455162] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
Persistent pruritus is a common disabling dermatologic symptom associated with different etiologic factors. These include primary skin conditions, as well as neuropathic, psychogenic, or systemic disorders like chronic liver disease. Defective clearance of potential pruritogenic substances that activate itch-specific neurons innervating the skin is thought to contribute to cholestatic pruritus. However, because the underlying disease-specific pruritogens and itch-specific neuronal pathways and mechanism(s) are unknown, symptomatic therapeutic intervention often leads to no or only limited success. In the current study, we aimed to first validate rats with bile duct ligation (BDL) as a model for hepatic pruritus and then to evaluate the contribution of inflammation, peripheral neuronal sensitization, and specific signaling pathways and subpopulations of itch-responsive neurons to scratching behavior and thermal hypersensitivity. Chronic BDL rats displayed enhanced scratching behavior and thermal hyperalgesia indicative of peripheral neuroinflammation. BDL-induced itch and hypersensitivity involved a minor contribution of histaminergic/serotonergic receptors, but significant activation of protein-activated receptor 2 (PAR2) receptors, prostaglandin PGE2 formation, and potentiation of transient receptor potential vanilloid 1 (TRPV1) channel activity. The sensitization of dorsal root ganglion nociceptors in BDL rats was associated with increased surface expression of PAR2 and TRPV1 proteins and an increase in the number of PAR2- and TRPV1-expressing peptidergic neurons together with a shift of TRPV1 receptor expression to medium sized dorsal root ganglion neurons. These results suggest that pruritus and hyperalgesia in chronic cholestatic BDL rats are associated with neuroinflammation and involve PAR2-induced TRPV1 sensitization. Thus, pharmacological modulation of PAR2 and/or TRPV1 may be a valuable therapeutic approach for patients with chronic liver pruritus refractory to conventional treatments.
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Affiliation(s)
| | | | | | | | - Carmina Montoliu
- Fundación Investigación Hospital Clínico de Valencia, INCLIVA, 46010 Valencia, Spain
| | - Antonio Ferrer-Montiel
- Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, 03202 Elche, Spain
| | - Vicente Felipo
- Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain
| | - Rosa Planells-Cases
- Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain; Leibniz-Institut für Molekulare Pharmakologie (FMP) and Max-Delbrück-Centrum für Molekulare Medizin (MDC), 13125 Berlin, Germany.
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Neonatale Cholestase. PÄDIATRISCHE GASTROENTEROLOGIE, HEPATOLOGIE UND ERNÄHRUNG 2013. [PMCID: PMC7498771 DOI: 10.1007/978-3-642-24710-1_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Die Inzidenz der NC wird auf 1 : 2500 Neugeborene geschätzt. Dies entspricht jährlich ca. 300 Erkrankungsfällen in Deutschland.
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Kremer AE, Oude Elferink RPJ, Beuers U. [Cholestatic pruritus : new insights into pathophysiology and current treatment]. Hautarzt 2012; 63:532-8. [PMID: 22733242 DOI: 10.1007/s00105-011-2321-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Pruritus is a common symptom of hepatobiliary disorders and may considerably diminish quality of life. Cholestatic pruritus exerts a circadian rhythm and is typically most severe in the evening hours and early at night. Itching is reported often to be most intense at the palms and the soles, but may also be generalized. The pathophysiological mechanisms of cholestatic pruritus have not been completely clarified. In the past, bile salts, histamine, progesterone metabolites and opioids have been discussed as potential causal substances; a correlation with itch intensity could never be proven. The enzyme autotaxin, which releases lysophosphatidic acid, has recently been identified as potential cholestatic pruritogen. Treatment aims to bind pruritogens in the gut lumen by resins such as cholestyramine, to modulate pruritogen metabolism by rifampicin and to influence central itch signaling by µ-opioid antagonists and selective serotonin re-uptake inhibitors. In cases of refractory pruritus experimental treatment options such as UV-therapy, extracorporeal albumin dialysis and nasobiliary drainage may be considered.
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Affiliation(s)
- A E Kremer
- Medizinische Klinik, Gastroenterologie, Hepatologie, Pneumologie und Endokrinologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Deutschland.
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Imam MH, Gossard AA, Sinakos E, Lindor KD. Pathogenesis and management of pruritus in cholestatic liver disease. J Gastroenterol Hepatol 2012; 27:1150-8. [PMID: 22413872 DOI: 10.1111/j.1440-1746.2012.07109.x] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Patients with cholestatic liver diseases such as primary biliary cirrhosis, primary sclerosing cholangitis and intrahepatic cholestasis of pregnancy commonly complain of pruritus. The underlying pathogenesis remains obscure with several mediators possibly playing an important role; these include lysophosphatidic acid, bile salts, opioids, histamine and progesterone metabolites. We describe in this review novel insights into the pathogenesis and management of pruritus in patients with cholestasis.
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Affiliation(s)
- Mohamad H Imam
- Division of Gastroenterology and Hepatology, Mayo Clinic Rochester, Rochester, MN 55905, USA
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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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Selmi C, Affronti A, Ferrari L, Invernizzi P. Immune-mediated bile duct injury: The case of primary biliary cirrhosis. World J Gastrointest Pathophysiol 2010; 1:118-28. [PMID: 21607152 PMCID: PMC3097954 DOI: 10.4291/wjgp.v1.i4.118] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2010] [Revised: 08/08/2010] [Accepted: 08/15/2010] [Indexed: 02/07/2023] Open
Abstract
Autoimmune cholangitis would be the appropriate name to define the immune-mediated bile duct injury following the breakdown of tolerance to mitochondrial proteins and the appearance of serum autoantibodies and autoreactive T cells. Nevertheless, the condition is universally named primary biliary cirrhosis (PBC). The disease etiology and pathogenesis remain largely unknown despite the proposed lines of evidence. One twin study and numerous epidemiology reports suggest that both a susceptible genetic background and environmental factors determine disease onset while a recent genome-wide association study proposed highly significant associations with several common genetic polymorphisms in subgroups of patients. Specific infectious agents and chemicals may contribute to the disease onset and perpetuation in a genetically susceptible host, possibly through molecular mimicry. Importantly, several murine models have been proposed and include strains in which PBC is genetically determined or induced by immunization with chemicals and bacteria. From a pathogenetic standpoint, new exciting data have demonstrated the unique apoptotic features of bile duct cells that allow the mitochondrial autoantigens to be taken up in their intact form within apoptotic blebs. We are convinced that the application of the most recent molecular techniques will soon provide developments in PBC etiology and pathogenesis with likely implications in diagnostics and therapeutics.
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Abstract
Pruritus remains a significant problem facing dermatologists and can be associated with various dermatoses and systemic derangements. At times, one can treat the underlying cutaneous or systemic process to alleviate itch. However, it is frequently challenging to identify the cause of a patient's itch and, in this situation, even more difficult to manage the symptom effectively. In this article, the authors discuss the approach to a patient with generalized pruritus without clinically obvious dermatoses. They also addresses mechanisms and management modalities of itch in common systemic diseases, including cholestasis, uremia, and neuropathic dysfunction.
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Affiliation(s)
- Jamison D Feramisco
- Department of Dermatology, University of California at San Francisco, 1701 Divisadero Street, 3rd floor, San Francisco, CA 94115, USA
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Wang H, Yosipovitch G. New insights into the pathophysiology and treatment of chronic itch in patients with end-stage renal disease, chronic liver disease, and lymphoma. Int J Dermatol 2010; 49:1-11. [PMID: 20465602 DOI: 10.1111/j.1365-4632.2009.04249.x] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Affiliation(s)
- Hui Wang
- Department of Dermatology, Wake Forest University Health Sciences, Winston-Salem, NC 27157, USA
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Abstract
Chronic pruritus, one of the main symptoms in dermatologic diseases, is often intractable and has a high impact on a patient´s quality of life. In addition to dermatologic disorders, chronic pruritus is associated with systemic and neurologic, as well as psychologic, diseases. Aging skin is considered to be more susceptible to pruritic disorders. Thus, owing to demographic changes, pruritus is becoming more prevalent. The elderly are often afflicted with comorbidities and polypharmacy, which can complicate diagnosis and therapy. In this review we present a rational work-up adapted to the special premises and needs of geriatric patients. This may facilitate the choice of suitable therapeutic regimens.
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Affiliation(s)
- Sonja A Grundmann
- Neurodermatology & Competence Center Pruritus, Department of Dermatology, University of Münster, Germany
| | - Sonja Ständer
- Neurodermatology & Competence Center Pruritus, Department of Dermatology, University of Münster, Germany
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Kremer AE, Beuers U, Oude-Elferink RPJ, Pusl T. Pathogenesis and treatment of pruritus in cholestasis. Drugs 2009; 68:2163-82. [PMID: 18840005 DOI: 10.2165/00003495-200868150-00006] [Citation(s) in RCA: 77] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Pruritus is an enigmatic, seriously disabling symptom accompanying cholestatic liver diseases and a broad range of other disorders. Most recently, novel itch-specific neuronal pathways, itch mediators and their relevant receptors have been identified. In addition, new antipruritic therapeutic strategies have been developed and/or are under evaluation. This review highlights recent experimental and clinical findings focusing on the pathogenesis and actual treatment of pruritus in cholestatic liver disease. Evidence-based therapeutic recommendations, including the use of anion exchange resins cholestyramine, colestipol and colesevelam, the microsomal enzyme inducer rifampicin, the opioid receptor antagonists naltrexone and naloxone, and the serotonin reuptake inhibitor sertraline, are provided.
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Affiliation(s)
- Andreas E Kremer
- Liver Center, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
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Kumagi T, Heathcote EJ. Successfully treated intractable pruritus with rifampin in a case of benign recurrent intrahepatic cholestasis. Clin J Gastroenterol 2008; 1:160-163. [DOI: 10.1007/s12328-008-0027-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2008] [Accepted: 07/25/2008] [Indexed: 11/28/2022]
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Tandon P, Rowe BH, Vandermeer B, Bain VG. The efficacy and safety of bile Acid binding agents, opioid antagonists, or rifampin in the treatment of cholestasis-associated pruritus. Am J Gastroenterol 2007; 102:1528-36. [PMID: 17403073 DOI: 10.1111/j.1572-0241.2007.01200.x] [Citation(s) in RCA: 101] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES The objective of this review was to evaluate the efficacy and safety of rifampin, opioid antagonists, or bile acid binding agents in the treatment of cholestasis-related pruritus (CAP) from available randomized controlled trial evidence. METHODS In addition to a comprehensive gray literature search, the Cochrane Library, MEDLINE, EMBASE, PubMed, and Web of Science were searched. Only full-text RCTs in participants (>75% adult) with CAP on at least one of the three medications were included. The primary outcome was change in pruritus score, recorded as a continuous or dichotomous outcome. Two independent reviewers performed trial selection and quality assessment. RESULTS From 487 citations, 12 RCTs were included. Rifampin (standardized mean difference [SMD]-1.62, 95% CI -3.05 to -0.18) and opioid antagonists (SMD -0.68, 95% CI -1.19 to -0.17) significantly reduced CAP. The two cholestyramine studies were too heterogeneous to pool. Although cholestyramine (P= 0.35) and rifampin (P= 0.96) were not associated with greater side effects compared with placebo, opioid antagonists were (number needed to harm = 2.6, 95% CI 1.4-25). CONCLUSIONS The available RCTs are small, few in number, and use varying scales for measuring pruritus. Although both opioid antagonists and rifampin demonstrated a reduction in pruritus, there were insufficient data to judge the efficacy of cholestyramine. Opioid antagonists were associated with transient side effects in a significant proportion of patients. A longer well-designed randomized controlled trial is needed to confirm the efficacy of bile acid binding agents and accurately assess adverse events.
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Affiliation(s)
- Puneeta Tandon
- Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada
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Pusl T, Beuers U. Extrahepatic manifestations of cholestatic liver diseases: pathogenesis and therapy. Clin Rev Allergy Immunol 2006. [PMID: 15879620 DOI: 10.1385/criai:] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Pruritus, fatigue, and metabolic bone disease are frequent complications of cholestatic liver diseases, which can be quite distressing for the patient and can considerably reduce the quality of life. The molecular pathogenesis of these extrahepatic manifestations of cholestasis is poorly understood, and hypotheses to explain these symptoms are being discussed. This article provides treatment recommendations for the complications of cholestasis based on putative pathomechanisms and summarizes recent experimental and clinical data involving management options.
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Affiliation(s)
- Thomas Pusl
- Department of Medicine II, Klinikum of the University of Munich-Grosshadern, Munich, Germany
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Pusl T, Beuers U. Extrahepatic manifestations of cholestatic liver diseases: pathogenesis and therapy. Clin Rev Allergy Immunol 2006; 28:147-57. [PMID: 15879620 DOI: 10.1385/criai:28:2:147] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Pruritus, fatigue, and metabolic bone disease are frequent complications of cholestatic liver diseases, which can be quite distressing for the patient and can considerably reduce the quality of life. The molecular pathogenesis of these extrahepatic manifestations of cholestasis is poorly understood, and hypotheses to explain these symptoms are being discussed. This article provides treatment recommendations for the complications of cholestasis based on putative pathomechanisms and summarizes recent experimental and clinical data involving management options.
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Affiliation(s)
- Thomas Pusl
- Department of Medicine II, Klinikum of the University of Munich-Grosshadern, Munich, Germany
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Bergasa NV, Mehlman J, Bir K. Aerobic exercise: a potential therapeutic intervention for patients with liver disease. Med Hypotheses 2004; 62:935-41. [PMID: 15142652 DOI: 10.1016/j.mehy.2003.12.041] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2003] [Accepted: 12/05/2003] [Indexed: 12/31/2022]
Abstract
Fatigue is a symptom of liver disease. Indirect evidence suggests that this type of fatigue is centrally mediated. Non-alcoholic steatohepatitis (NASH), which may lead to cirrhosis, is associated with insulin resistance. An activated hypothalamic pituitary adrenal axis results in increased secretion of cortisol releasing hormone, cortisol and catecholamines. Prolonged exposure to high levels of cortisol is associated with insulin resistance, as exemplified by the metabolic syndrome. Accumulation in visceral fat is an independent factor associated with insulin resistance. Central (visceral) fat is less sensitive to insulin than the rest of body fat and the central nervous system and not peripheral insulin, appears to regulate lipolysis in visceral fat by, at least in part, adrenergic mechanisms. Aerobic training has documented beneficial effects on mental health and fatigue secondary to chronic illness. In addition, aerobic training increases insulin sensitivity. Thus, aerobic training may decrease fatigue in liver disease and improve NASH.
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Affiliation(s)
- Nora V Bergasa
- Columbia University College of Physicians and Surgeons, 630 W 168 Street, P&S 10-508 New York, NY 10032, USA.
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Abstract
Primary biliary cirrhosis is a chronic cholestatic liver disease of adults. This disorder is characterised histologically by chronic non-suppurative destruction of interlobular bile ducts leading to advanced fibrosis, cirrhosis, and liver failure. The precise aetiopathogenesis of primary biliary cirrhosis remains unknown, although dysregulation of the immune system and genetic susceptibility both seem to be important. Affected patients are typically middle-aged women with abnormal serum concentrations of alkaline phosphatase. Presence of antimitochondrial antibody in serum is almost diagnostic of the disorder. Identification of primary biliary cirrhosis is important, because effective treatment with ursodeoxycholic acid has been shown to halt disease progression and improve survival without need for liver transplantation. However, therapeutic options for disease-related complications-including fatigue and metabolic bone disease-remain unavailable. Mathematical models have been developed that accurately predict the natural history of primary biliary cirrhosis in individuals. Despite advances in understanding of the disease, it remains one of the major indications for liver transplantation worldwide.
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Affiliation(s)
- Jayant A Talwalkar
- Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, MN 55905, USA
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Ständer S, Weisshaar E, Steinhof M, Luger TA, Metze D. Pruritus - Pathophysiologie, Klinik und Therapie - Eine Ubersicht. Pruritus - pathophysiology, clinical features and therapy - an overview. J Dtsch Dermatol Ges 2003; 1:105-18. [PMID: 16285178 DOI: 10.1046/j.1610-0387.2003.02023.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Pruritus is an unpleasant sensory perception of the skin associated with the desire to scratch. As a physiological nociception, pruritus leads to the removal of harmful agents such as parasites and plants from the skin surface. More often, pruritus occurs as a severe and therapy-refractory symptom of various underlying dermatological and systemic diseases. Comparable to chronic pain, chronic pruritus worsens the general condition and may lead to physical and psychological exhaustion. Until the 1990s, pruritus had been regarded as an incomplete pain sensation. Only recently, itch was defined as a separate, pain-independent sensation with its own mediators, spinal neurons and cortical areas. These observations led to the development of new therapeutic modalities. This paper gives an overview of itch pathophysiology, clinical types and therapies.
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Abstract
Pruritus, fatigue and metabolic bone disease represent three major extrahepatic manifestations of chronic cholestatic liver disease that considerably affect the patient's quality of life. The present article reviews pathogenetic aspects of and current therapeutic approaches to extrahepatic manifestations of cholestatic liver disease. Pathogenesis of pruritus of cholestasis remains poorly understood. The involvement of putative peripherally acting pruritogens, such as bile acids or endogenous opioids, is being discussed. More recently, central mechanisms, including an increased central opioidergic tone and pertubations in the serotonergic system have been proposed. Treatment of the underlying disease is beneficial also for the control of cholestasis-associated pruritus. Current therapeutic recommendations include ursodeoxycholic acid, cholestyramine, rifampicin and opioid antagonists. Liver transplantation may be indicated when severe pruritus is refractory to medical treatment. Fatigue is being recognized as the most frequent and one of the most disabling complaints in chronic cholestasis. Fatigue is presumably of central origin and its association with other neuropsychiatric disorders (e.g. depression, obsessive-compulsive disorders) is consistent with defective central neurotransmission. No specific therapies are currently available and a healthy lifestyle, regular sleep and avoidance of unnecessary stress and other precipiting factors are recommended. Antidepressant therapy may be warranted in selected patients. Osteopenia and osteoporosis are common in chronic cholestatic liver disease, whereas osteomalacia is rare. The pathophysiology of cholestasis-associated metabolic bone disease is regarded as multifactorial. Therapeutic recommendations include regular exercise, calcium and vitamin D supplementation in late stage disease, hormone replacement therapy in postmenopausal women and bisphosphonates.
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Affiliation(s)
- Helena Glasova
- Department of Medicine II, Klinikum of the University of Munich-Grosshadern, Munich, Germany
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Abstract
Fatigue is an important symptom and a quality of life determinant in patients with cholestatic liver disease. The pathogenesis of fatigue is obscure, although alterations in central neurotransmission and peripheral muscle dysfunction have been incriminated. No effective treatment is available at present. The available literature on fatigue in cholestatic liver disease is reviewed.
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Affiliation(s)
- D Kumar
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
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Shawcross DL, Jalan R. Delayed opioid withdrawal-like reaction in primary biliary cirrhosis following naloxone therapy. Gastroenterology 2001; 121:743-4. [PMID: 11547785 DOI: 10.1053/gast.2001.27714] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
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