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Gabrielli F, Crepaldi E, Cavicchioli A, Rivi M, Costanzo AC, Cursaro C, Andreone P. Itching for Answers: A Comprehensive Review of Cholestatic Pruritus Treatments. Biomolecules 2024; 14:1227. [PMID: 39456160 PMCID: PMC11505983 DOI: 10.3390/biom14101227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 08/21/2024] [Accepted: 08/28/2024] [Indexed: 10/28/2024] Open
Abstract
Cholestasis is a clinical and laboratory syndrome indicating impaired bile production or excretion. One of the hallmark symptoms of cholestasis is pruritus. Itch can be severe and debilitating for patients, impacting their quality of life similarly to pain, and, in some cases, it can be refractory. Current therapies like anion exchange resins and rifampicin, offer partial relief but with side effects. Effective, well-tolerated treatments are urgently needed. This literature review examines existing options (bile acid sequestrants, antihistamines, opioid antagonists, sertraline, and rifampicin) and explores novel therapies (monoclonal antibodies, PPAR agonists, and bile-acid-based therapies). We analyze mechanisms, limitations, and adverse effects to aid clinicians and researchers. Novel approaches include monoclonal antibodies to inhibit bile recirculation and PPAR agonists targeting pruritus signaling. Despite the limited current options, ongoing research promises better treatments for cholestatic pruritus, addressing its distressing impact. In summary, cholestasis-associated pruritus poses a significant challenge with limited treatments. Advancements in understanding its pathophysiology offer hope for more effective therapies in the future.
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Affiliation(s)
- Filippo Gabrielli
- Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41126 Modena, Italy
- Internal and Metabolic Medicine, AOU of Modena-Baggiovara, 41126 Modena, Italy
| | - Eleonora Crepaldi
- Postgraduate School of Allergology and Clinical Immunology, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Alessia Cavicchioli
- Internal and Metabolic Medicine, AOU of Modena-Baggiovara, 41126 Modena, Italy
| | - Marco Rivi
- Postgraduate School of Allergology and Clinical Immunology, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Arianna Carmen Costanzo
- Department of Hepato-bilio-pancreatic Surgery and Liver Transplantation, Hautepierre Hospital, Avenue Molière, 67200 Strasbourg, France
| | - Carmela Cursaro
- Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Pietro Andreone
- Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41126 Modena, Italy
- Internal and Metabolic Medicine, AOU of Modena-Baggiovara, 41126 Modena, Italy
- Postgraduate School of Allergology and Clinical Immunology, University of Modena and Reggio Emilia, 41126 Modena, Italy
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Karatza E, Swift B, Carreño F, Mukherjee S, Casillas L, Lennie J, Fettiplace J, McLaughlin MM, Kremer AE. Serum bile acid change correlates with improvement in pruritus in patients with primary biliary cholangitis receiving linerixibat. Liver Int 2024; 44:2293-2302. [PMID: 38780109 DOI: 10.1111/liv.15982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 05/07/2024] [Accepted: 05/11/2024] [Indexed: 05/25/2024]
Abstract
BACKGROUND & AIMS Total serum bile acid (TSBA) levels are elevated in patients with primary biliary cholangitis (PBC) and may mediate cholestatic pruritus. Linerixibat, an ileal bile acid transporter inhibitor, improved pruritus in patients with PBC. We explored the relationship between linerixibat dose, TSBA concentration, and pruritus. METHODS Data from Phase 1/2 trials were used to develop a population kinetic-pharmacodynamic model to characterize the linerixibat dose-TSBA relationship. Individual Bayesian parameter estimates for participants in the GLIMMER study were used to derive the area under the TSBA concentration curve over 24 h (AUC0-24). Time-matched post hoc estimates of AUC0-24 were correlated with pruritus reported on a 0-10 numerical rating scale. Baseline TSBA concentration was correlated with change from baseline (ΔBL) in monthly itch score (MIS). ΔBL in model-estimated TSBA AUC0-24 was correlated with time-matched ΔBL in weekly itch score (WIS) or MIS. RESULTS Linerixibat dose dependently reduced TSBA AUC0-24, reaching steady state after 5 days. Baseline TSBA levels in GLIMMER did not correlate with ΔBL in MIS. ΔBL in TSBA AUC0-24 correlated with improved WIS over 12 weeks of treatment (r = 0.52, p < 0.0001). Of participants with a ≥30% decrease in TSBA AUC0-24, 60% were pruritus responders (≥2-point improvement in WIS from baseline). CONCLUSIONS Linerixibat treatment leads to rapid, dose-dependent TSBA reductions. Baseline TSBA levels do not correlate with on-treatment pruritus change, suggesting they do not predict linerixibat response. Change in TSBA AUC0-24 correlates significantly with, and can be predictive of, pruritus improvement in patients with PBC.
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Affiliation(s)
- Eleni Karatza
- The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | | | | | | | | | | | | | | | - Andreas E Kremer
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
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Levy C, Caldwell S, Mantry P, Luketic V, Landis CS, Huang J, Mena E, Maheshwari R, Rank K, Xu J, Malkov VA, Billin AN, Liu X, Lu X, Barchuk WT, Watkins TR, Chung C, Myers RP, Kowdley KV. Cilofexor in Patients With Compensated Cirrhosis Due to Primary Sclerosing Cholangitis: An Open-Label Phase 1B Study. Clin Transl Gastroenterol 2024; 15:e00744. [PMID: 38976363 PMCID: PMC11346858 DOI: 10.14309/ctg.0000000000000744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 06/13/2024] [Indexed: 07/10/2024] Open
Abstract
INTRODUCTION This proof-of-concept, open-label phase 1b study evaluated the safety and efficacy of cilofexor, a potent selective farnesoid X receptor agonist, in patients with compensated cirrhosis due to primary sclerosing cholangitis. METHODS Escalating doses of cilofexor (30 mg [weeks 1-4], 60 mg [weeks 5-8], 100 mg [weeks 9-12]) were administered orally once daily over 12 weeks. The primary endpoint was safety. Exploratory measures included cholestasis and fibrosis markers and pharmacodynamic biomarkers of bile acid homeostasis. RESULTS Eleven patients were enrolled (median age: 48 years; 55% men). The most common treatment-emergent adverse events (TEAEs) were pruritus (8/11 [72.7%]), fatigue, headache, nausea, and upper respiratory tract infection (2/11 [18.2%] each). Seven patients experienced a pruritus TEAE (one grade 3) considered drug-related. One patient temporarily discontinued cilofexor owing to peripheral edema. There were no deaths, serious TEAEs, or TEAEs leading to permanent discontinuation. Median changes (interquartile ranges) from baseline to week 12 (predose, fasting) were -24.8% (-35.7 to -7.4) for alanine transaminase, -13.0% (-21.9 to -8.6) for alkaline phosphatase, -43.5% (-52.1 to -30.8) for γ-glutamyl transferase, -12.7% (-25.0 to 0.0) for total bilirubin, and -21.2% (-40.0 to 0.0) for direct bilirubin. Least-squares mean percentage change (95% confidence interval) from baseline to week 12 at trough was -55.3% (-70.8 to -31.6) for C4 and -60.5% (-81.8 to -14.2) for cholic acid. Fasting fibroblast growth factor 19 levels transiently increased after cilofexor administration. DISCUSSION Escalating doses of cilofexor over 12 weeks were well tolerated and improved cholestasis markers in patients with compensated cirrhosis due to primary sclerosing cholangitis (NCT04060147).
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Affiliation(s)
- Cynthia Levy
- Division of Digestive Health and Liver Diseases, University of Miami Miller School of Medicine, Miami, Florida, USA
- Schiff Center for Liver Diseases, University of Miami, Miami, Florida, USA;
| | - Stephen Caldwell
- University of Virginia School of Medicine, Charlottesville, Virginia, USA;
| | - Parvez Mantry
- Methodist Transplant Specialists, Dallas, Texas, USA;
| | - Velimir Luketic
- Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA;
| | - Charles S. Landis
- Univerisity of Washington School of Medicine, Seattle, Washington, USA;
| | - Jonathan Huang
- University of Rochester School of Medicine and Dentistry, Rochester, New York, USA;
| | - Edward Mena
- Pasadena Liver Center, Pasadena, California, USA;
| | | | - Kevin Rank
- MNGI Digestive Health, Minneapolis, Minnesota, USA;
| | - Jun Xu
- Gilead Sciences, Inc., Foster City, California, USA;
| | | | | | - Xiangyu Liu
- Gilead Sciences, Inc., Foster City, California, USA;
| | - Xiaomin Lu
- Gilead Sciences, Inc., Foster City, California, USA;
| | | | | | - Chuhan Chung
- Gilead Sciences, Inc., Foster City, California, USA;
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Gungabissoon U, Smith HT, von Maltzahn R, Logie J, Fairburn-Beech J, Ma L, P D, McGirr A, Hunnicutt JN, Rowe CL, Tierney M, Friedler HS. Pruritus in primary biliary cholangitis is under-recorded in patient medical records. BMJ Open Gastroenterol 2024; 11:e001287. [PMID: 38538090 PMCID: PMC10982897 DOI: 10.1136/bmjgast-2023-001287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Accepted: 01/26/2024] [Indexed: 04/04/2024] Open
Abstract
OBJECTIVE Cholestatic pruritus in primary biliary cholangitis (PBC) reduces patients' health-related quality of life (HRQoL). Despite this, existing research suggests that pruritus is under-recorded in patients' health records. This study assessed the extent to which pruritus was recorded in medical records of patients with PBC as compared with patient-reported pruritus, and whether patients reporting mild itch were less likely to have pruritus recorded. We also evaluated clinico-demographic characteristics and HRQoL of patients with medical record-documented and patient-reported pruritus. DESIGN This cross-sectional study used clinical information abstracted from medical records, together with patient-reported (PBC-40) data from patients with PBC in the USA enrolled in the PicnicHealth cohort. Medical record-documented pruritus was classified as 'recent' (at, or within 12 months prior to, enrolment) or 'ever' (at, or any point prior to, enrolment). Patient-reported pruritus (4-week recall) was assessed using the first PBC-40 questionnaire completed on/after enrolment; pruritus severity was classified by itch domain score (any severity: ≥1; clinically significant itch: ≥7). Patient clinico-demographic characteristics and PBC-40 domain scores were described in patients with medical record-documented and patient-reported pruritus; overlap between groups was evaluated. Descriptive statistics were reported. RESULTS Pruritus of any severity was self-reported by 200/225 (88.9%) patients enrolled; however, only 88/225 (39.1%) had recent medical record-documented pruritus. Clinically significant pruritus was self-reported by 120/225 (53.3%) patients; of these, 64/120 (53.3%) had recent medical record-documented pruritus. Patients reporting clinically significant pruritus appeared to have higher mean scores across PBC-40 domains (indicating reduced HRQoL), versus patients with no/mild patient-reported pruritus or medical-record documented pruritus. CONCLUSION Compared with patient-reported measures, pruritus in PBC is under-recorded in medical records and is associated with lower HRQoL. Research based only on medical records underestimates the true burden of pruritus, meaning physicians may be unaware of the extent and impact of pruritus, leading to potential undertreatment.
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Affiliation(s)
| | | | | | | | | | - Liyuan Ma
- GSK, Collegeville, Pennsylvania, USA
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Carreño F, Karatza E, Mehta R, Collins J, Austin D, Swift B. Population Dose-Response-Time Analysis of Itch Reduction and Patient-Reported Tolerability Supports Phase III Dose Selection for Linerixibat. Clin Pharmacol Ther 2024; 115:288-298. [PMID: 37953500 DOI: 10.1002/cpt.3103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 10/31/2023] [Indexed: 11/14/2023]
Abstract
Increase in serum bile acids (BAs) in patients with primary biliary cholangitis (PBC) may play a causal role in cholestatic pruritus (itch). Linerixibat is a selective small molecule inhibitor of the ileal bile acid transporter, which blocks re-absorption of BAs in the gastrointestinal tract thereby lowering BAs in the systemic circulation and reducing itch. One consequence is excess BAs in the colon, leading to diarrhea and abdominal pain. GLIMMER (NCT02966834) was a placebo-controlled phase IIb dose-ranging trial of linerixibat once (q.d.) or twice daily (b.i.d.) in adults with moderate to severe pruritus and PBC. To determine the optimal dose for maximum itch reduction while minimizing diarrhea, a kinetic-pharmacodynamic (k-PD) model was developed using data from GLIMMER. The PD end point modeled was worst daily itch, derived from itch score reported by patients b.i.d. A proportional odds model was developed post hoc to indicate the probability of diarrhea occurrence, a patient-reported outcome (GI-5) recorded weekly. The final k-PD model successfully described the effects of linerixibat and placebo on itch. Model simulations were consistent with the observed dose-dependent increase in the average number of itch responders (patients with a ≥ 2-point improvement in itch). This was paralleled by a dose-dependent increase in the probability of higher diarrhea frequency scores. The b.i.d. dosing regimens led to a modest increase in the number of itch responders as compared with q.d. dosing. This quantitative framework highlights the trade-off between benefit and tolerability and supported the selection of 40 mg b.i.d. in the phase III GLISTEN trial (NCT04950127).
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Affiliation(s)
- Fernando Carreño
- UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- GSK, Collegeville, Pennsylvania, USA
| | - Eleni Karatza
- UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- GSK, Durham, North Carolina, USA
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Smith HT, de Souza AR, Thompson AH, McLaughlin MM, Dever JJ, Myers JA, Chen JV. Cholestatic Pruritus Treatments in Primary Biliary Cholangitis and Primary Sclerosing Cholangitis: A Systematic Literature Review. Dig Dis Sci 2023; 68:2710-2730. [PMID: 36933112 PMCID: PMC10024020 DOI: 10.1007/s10620-023-07862-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 01/30/2023] [Indexed: 03/19/2023]
Abstract
BACKGROUND AND AIMS We conducted a systematic literature review to understand the evidence supporting treatment decisions for cholestatic pruritus associated with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). METHODS Studies that enrolled ≥ 75% participants with PBC or PSC and reported ≥ 1 endpoint(s) related to efficacy, safety, health-related quality of life (HRQoL) or other patient-reported outcomes were included. Bias was assessed using the Cochrane risk of bias tool for randomised controlled trials (RCTs) and the Quality of Cohort studies tool for non-RCTs. RESULTS Thirty-nine publications were identified, covering 42 studies and six treatment classes (including investigational and approved products): anion-exchange resins, antibiotics (rifampicin/derivatives), opiates, selective serotonin reuptake inhibitors, fibrates, ileal bile acid transporter inhibitors and other agents not categorised in these six classes. Across studies, median sample size was small (n = 18), 20 studies were over 20 years old, 25 followed patients for ≤ 6 weeks, only 25 were RCTs. Pruritus was assessed using several different tools, with inconsistencies in their application. Cholestyramine, considered first-line therapy for moderate-severe cholestatic pruritus, was assessed in six studies (two RCTs) including 56 patients with PBC and 2 with PSC, with evidence of efficacy demonstrated in only three studies, among which, two RCTs were assessed as having a high risk of bias. Findings were similar for other drug classes. CONCLUSIONS There is a lack of consistent and reproducible evidence available on efficacy, impact on HRQoL, and safety of cholestatic pruritus treatments, leaving physicians to rely on clinical experience rather than evidence-based medicine for treatment selection.
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Affiliation(s)
- Helen T Smith
- Value Evidence, GSK, 980 Great West Road, Brentford, TW8 9GS, Middlesex, UK.
| | | | - April H Thompson
- Specialty Medicines, Global Medical Affairs, GSK, Research Triangle Park, Durham, NC, 27701, USA
| | - Megan M McLaughlin
- Medicine Development, GSK, 1250 S Collegeville Rd, Collegeville, PA, 19426, USA
| | - John J Dever
- Statistics and Evidence Synthesis, Medical Decision Modeling Inc., 3500 Depauw Blvd, Suite #1037, Indianapolis, IN, 46268, USA
| | - Julie A Myers
- Statistics and Evidence Synthesis, Medical Decision Modeling Inc., 3500 Depauw Blvd, Suite #1037, Indianapolis, IN, 46268, USA
| | - Jing Voon Chen
- Modeling and Analytics, Medical Decision Modeling Inc., 3500 Depauw Blvd, Suite #1037, Indianapolis, IN, 46268, USA
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Jones D, Carbone M, Invernizzi P, Little N, Nevens F, Swain MG, Wiesel P, Levy C. Impact of setanaxib on quality of life outcomes in primary biliary cholangitis in a phase 2 randomized controlled trial. Hepatol Commun 2023; 7:e0057. [PMID: 36809195 PMCID: PMC9949832 DOI: 10.1097/hc9.0000000000000057] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 12/04/2022] [Indexed: 02/23/2023] Open
Abstract
BACKGROUND There is a real unmet need for primary biliary cholangitis (PBC) treatments that can improve quality of life impacting symptoms. In this post hoc analysis, we evaluated potential effects of the NADP oxidase 1/4 inhibitor, setanaxib, on patient-reported quality of life from a phase 2 trial in PBC. PATIENTS AND METHODS The underpinning double-blind, randomized, placebo-controlled trial (NCT03226067) recruited 111 patients with PBC and inadequate response/intolerance to ursodeoxycholic acid. Patients self-administered oral placebo (n=37), setanaxib 400 mg once daily (OD; n=38), or setanaxib 400 mg twice daily (BID; n=36), in addition to ursodeoxycholic acid for 24 weeks. Quality of life outcomes were assessed using the validated PBC-40 questionnaire. Patients were stratified post hoc by baseline fatigue severity. RESULTS At week 24, patients treated with setanaxib 400 mg BID reported greater mean (SE) absolute reductions from baseline in PBC-40 fatigue domain score [-3.6 (1.3)] versus those receiving setanaxib 400 mg OD [-0.8 (1.0)]) or placebo [0.6 (0.9)]. Similar observations were made across all PBC-40 domains except itch. In the setanaxib 400 mg BID arm, patients with moderate-to-severe fatigue at baseline had a greater reduction in mean fatigue score at week 24 [-5.8 (2.1)] versus those with mild fatigue [-0.6 (0.9)]; results were similar across all domains. Reduced fatigue was correlated with emotional, social, symptom, and cognitive improvements. CONCLUSIONS These results support further investigation of setanaxib as a treatment for patients with PBC, particularly for those with clinically significant fatigue.
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Affiliation(s)
- David Jones
- Newcastle University Medical School, Newcastle Upon Tyne, UK
| | - Marco Carbone
- Division of Gastroenterology, Department of Medicine and Surgery, Centre for Autoimmune Liver Diseases, University of Milano-Bicocca, Monza, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology, Department of Medicine and Surgery, Centre for Autoimmune Liver Diseases, University of Milano-Bicocca, Monza, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | | | - Frederik Nevens
- Department of Gastroenterology and Hepatology, University Hospital KU Leuven, Health Care Provider of the ERN RARE-LIVER, Leuven, Belgium
| | - Mark G. Swain
- University of Calgary Liver Unit, Calgary, Alberta, Canada
| | | | - Cynthia Levy
- Schiff Center for Liver Diseases, University of Miami, Florida, USA
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Nietsche TR, Dotta G, Barcaui CB, Ferraz MLCG. Cholestatic pruritus: a knowledge update. An Bras Dermatol 2022; 97:332-337. [PMID: 35279351 PMCID: PMC9133300 DOI: 10.1016/j.abd.2021.06.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 06/20/2021] [Accepted: 06/22/2021] [Indexed: 12/01/2022] Open
Abstract
This review is focused on updating knowledge about cholestatic pruritus. It summarizes clinical-epidemiological characteristics, pathophysiology, diagnostic approach, and evidence-based therapeutic recommendations regarding this form of pruritus. Pruritus is a frequent symptom that accompanies several liver diseases, particularly cholestatic ones. The symptom may be mild and tolerable, but it can also dramatically reduce the quality of life. Although the exact pathophysiology of this form of pruritus remains unclear, current evidence supports a mixed origin. It is extremely important for dermatologists to have knowledge about cholestatic pruritus since they are usually the first physicians to be sought by the patient when they experience the symptom. In the absence of specific dermatological alterations, cholestasis must always be considered as a possible cause of pruritus. In addition to allowing an adequate diagnosis, a better pathophysiological understanding of hepatic pruritus provides the identification of new therapeutic targets and, consequently, optimization of the approach in patients with this condition.
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Affiliation(s)
| | - Gabriel Dotta
- Hospital São Paulo, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - Carlos Baptista Barcaui
- Hospital Universitário Pedro Ernesto, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
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Dervout C, Boulais N, Barnetche T, Nousbaum JB, Brenaut E, Misery L. Efficacy of Treatments for Cholestatic Pruritus: A Systemic Review and Meta-analysis. Acta Derm Venereol 2022; 102:adv00653. [PMID: 35088869 PMCID: PMC9609979 DOI: 10.2340/actadv.v102.310] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Cholestatic itch is a disabling symptom that may be secondary to liver or biliary diseases. Management of cholestatic pruritus is complex. A systematic review and meta-analysis on the efficacy of treatments for cholestatic pruritus were performed. PubMed and Cochrane Library were searched using the algorithm “(hepatitis OR cholestatic OR liver) AND (pruritus OR itch) AND (management OR treatment OR treatments)” for 1975–2019. Of the 2,264 articles identified, 93 were included in a systematic review and 15 in a meta-analysis (studies evaluating pruritus with a visual analogue scale). Some treatments act by reducing levels of pruritogens in the enterohepatic cycle, others modify the metabolism or secretion of these pruritogens, or act on pruritus pathways. A further possible treatment is albumin dialysis. However, due to many heterogeneities in the reviewed studies it is difficult to identify and recommend an optimum treatment. Only 15 studies were included in the meta-analysis, due to the small number of randomized studies using a visual analogue scale.
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Affiliation(s)
| | | | | | | | - Emilie Brenaut
- Department of Dermatology, University Hospital, FR-29609 Brest, France.
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Chovatiya R, Brieva J, Hung A. Dupilumab treatment for cholestatic pruritus. Dermatol Ther 2022; 35:e15296. [PMID: 34981593 PMCID: PMC10120610 DOI: 10.1111/dth.15296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/21/2021] [Accepted: 12/30/2021] [Indexed: 11/03/2022]
Affiliation(s)
- Raj Chovatiya
- Department of Dermatology, Feinberg School of Medicine at Northwestern University, Chicago, Illinois, USA
| | - Joaquin Brieva
- Department of Dermatology, Feinberg School of Medicine at Northwestern University, Chicago, Illinois, USA
| | - Adelina Hung
- Department of Gastroenterology and Hepatology, Sinai Health System, Chicago, Illinois, USA
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Zamek-Gliszczynski MJ, Kenworthy D, Bershas DA, Sanghvi M, Pereira AI, Mudunuru J, Crossman L, Pirhalla JL, Thorpe KM, Dennison JMTJ, McLaughlin MM, Allinder M, Swift B, O'Connor-Semmes RL, Young GC. Pharmacokinetics and ADME Characterization of Intravenous and Oral [ 14C]-Linerixibat in Healthy Male Volunteers. Drug Metab Dispos 2021; 49:1109-1117. [PMID: 34625435 DOI: 10.1124/dmd.121.000595] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 09/24/2021] [Indexed: 12/14/2022] Open
Abstract
Linerixibat, an oral small-molecule ileal bile acid transporter inhibitor under development for cholestatic pruritus in primary biliary cholangitis, was designed for minimal absorption from the intestine (site of pharmacological action). This study characterized the pharmacokinetics, absorption, metabolism, and excretion of [14C]-linerixibat in humans after an intravenous microtracer concomitant with unlabeled oral tablets and [14C]-linerixibat oral solution. Linerixibat exhibited absorption-limited flip-flop kinetics: longer oral versus intravenous half-life (6-7 hours vs. 0.8 hours). The short intravenous half-life was consistent with high systemic clearance (61.9 l/h) and low volume of distribution (16.3 l). In vitro studies predicted rapid hepatic clearance via cytochrome P450 3A4 metabolism, which predicted human hepatic clearance within 1.5-fold. However, linerixibat was minimally metabolized in humans after intravenous administration: ∼80% elimination via biliary/fecal excretion (>90%-97% as unchanged parent) and ∼20% renal elimination by glomerular filtration (>97% as unchanged parent). Absolute oral bioavailability of linerixibat was exceedingly low (0.05%), primarily because of a very low fraction absorbed (0.167%; fraction escaping first-pass gut metabolism (fg) ∼100%), with high hepatic extraction ratio (77.0%) acting as a secondary barrier to systemic exposure. Oral linerixibat was almost entirely excreted (>99% recovered radioactivity) in feces as unchanged and unabsorbed linerixibat. Consistent with the low oral fraction absorbed and ∼20% renal recovery of intravenous [14C]-linerixibat, urinary elimination of orally administered radioactivity was negligible (<0.04% of dose). Linerixibat unequivocally exhibited minimal gastrointestinal absorption and oral systemic exposure. Linerixibat represents a unique example of high CYP3A4 clearance in vitro but nearly complete excretion as unchanged parent drug via the biliary/fecal route. SIGNIFICANCE STATEMENT: This study conclusively established minimal absorption and systemic exposure to orally administered linerixibat in humans. The small amount of linerixibat absorbed was eliminated efficiently as unchanged parent drug via the biliary/fecal route. The hepatic clearance mechanism was mispredicted to be mediated via cytochrome P450 3A4 metabolism in vitro rather than biliary excretion of unchanged linerixibat in vivo.
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Affiliation(s)
- Maciej J Zamek-Gliszczynski
- Drug Metabolism and Disposition (M.J.Z.-G., D.A.B., J.M., J.L.P.), Medicine Development (M.M.M.), and Development Biostatistics (M.A.), GlaxoSmithKline, Collegeville, Pennsylvania; Drug Metabolism and Disposition (D.K., G.C.Y.), and Bioanalysis, Immunogenicity and Biomarkers (A.I.P.), GlaxoSmithKline, Ware, United Kingdom; Pharmaron ABS Inc., Germantown, Maryland (M.S.); Covance, Harrogate, United Kingdom (L.C.); Global Clinical Development, GlaxoSmithKline, Brentford, United Kingdom (K.M.T.); Hammersmith Medicines Research, London, United Kingdom (J.M.T.J.D.); Clinical Pharmacology, Modeling and Simulation, GlaxoSmithKline, RTP, North Carolina (B.S.); and Clinical Pharmacology, Modeling and Simulation, Parexel, Durham, North Carolina (R.L.O.-S.)
| | - David Kenworthy
- Drug Metabolism and Disposition (M.J.Z.-G., D.A.B., J.M., J.L.P.), Medicine Development (M.M.M.), and Development Biostatistics (M.A.), GlaxoSmithKline, Collegeville, Pennsylvania; Drug Metabolism and Disposition (D.K., G.C.Y.), and Bioanalysis, Immunogenicity and Biomarkers (A.I.P.), GlaxoSmithKline, Ware, United Kingdom; Pharmaron ABS Inc., Germantown, Maryland (M.S.); Covance, Harrogate, United Kingdom (L.C.); Global Clinical Development, GlaxoSmithKline, Brentford, United Kingdom (K.M.T.); Hammersmith Medicines Research, London, United Kingdom (J.M.T.J.D.); Clinical Pharmacology, Modeling and Simulation, GlaxoSmithKline, RTP, North Carolina (B.S.); and Clinical Pharmacology, Modeling and Simulation, Parexel, Durham, North Carolina (R.L.O.-S.)
| | - David A Bershas
- Drug Metabolism and Disposition (M.J.Z.-G., D.A.B., J.M., J.L.P.), Medicine Development (M.M.M.), and Development Biostatistics (M.A.), GlaxoSmithKline, Collegeville, Pennsylvania; Drug Metabolism and Disposition (D.K., G.C.Y.), and Bioanalysis, Immunogenicity and Biomarkers (A.I.P.), GlaxoSmithKline, Ware, United Kingdom; Pharmaron ABS Inc., Germantown, Maryland (M.S.); Covance, Harrogate, United Kingdom (L.C.); Global Clinical Development, GlaxoSmithKline, Brentford, United Kingdom (K.M.T.); Hammersmith Medicines Research, London, United Kingdom (J.M.T.J.D.); Clinical Pharmacology, Modeling and Simulation, GlaxoSmithKline, RTP, North Carolina (B.S.); and Clinical Pharmacology, Modeling and Simulation, Parexel, Durham, North Carolina (R.L.O.-S.)
| | - Mitesh Sanghvi
- Drug Metabolism and Disposition (M.J.Z.-G., D.A.B., J.M., J.L.P.), Medicine Development (M.M.M.), and Development Biostatistics (M.A.), GlaxoSmithKline, Collegeville, Pennsylvania; Drug Metabolism and Disposition (D.K., G.C.Y.), and Bioanalysis, Immunogenicity and Biomarkers (A.I.P.), GlaxoSmithKline, Ware, United Kingdom; Pharmaron ABS Inc., Germantown, Maryland (M.S.); Covance, Harrogate, United Kingdom (L.C.); Global Clinical Development, GlaxoSmithKline, Brentford, United Kingdom (K.M.T.); Hammersmith Medicines Research, London, United Kingdom (J.M.T.J.D.); Clinical Pharmacology, Modeling and Simulation, GlaxoSmithKline, RTP, North Carolina (B.S.); and Clinical Pharmacology, Modeling and Simulation, Parexel, Durham, North Carolina (R.L.O.-S.)
| | - Adrian I Pereira
- Drug Metabolism and Disposition (M.J.Z.-G., D.A.B., J.M., J.L.P.), Medicine Development (M.M.M.), and Development Biostatistics (M.A.), GlaxoSmithKline, Collegeville, Pennsylvania; Drug Metabolism and Disposition (D.K., G.C.Y.), and Bioanalysis, Immunogenicity and Biomarkers (A.I.P.), GlaxoSmithKline, Ware, United Kingdom; Pharmaron ABS Inc., Germantown, Maryland (M.S.); Covance, Harrogate, United Kingdom (L.C.); Global Clinical Development, GlaxoSmithKline, Brentford, United Kingdom (K.M.T.); Hammersmith Medicines Research, London, United Kingdom (J.M.T.J.D.); Clinical Pharmacology, Modeling and Simulation, GlaxoSmithKline, RTP, North Carolina (B.S.); and Clinical Pharmacology, Modeling and Simulation, Parexel, Durham, North Carolina (R.L.O.-S.)
| | - Jennypher Mudunuru
- Drug Metabolism and Disposition (M.J.Z.-G., D.A.B., J.M., J.L.P.), Medicine Development (M.M.M.), and Development Biostatistics (M.A.), GlaxoSmithKline, Collegeville, Pennsylvania; Drug Metabolism and Disposition (D.K., G.C.Y.), and Bioanalysis, Immunogenicity and Biomarkers (A.I.P.), GlaxoSmithKline, Ware, United Kingdom; Pharmaron ABS Inc., Germantown, Maryland (M.S.); Covance, Harrogate, United Kingdom (L.C.); Global Clinical Development, GlaxoSmithKline, Brentford, United Kingdom (K.M.T.); Hammersmith Medicines Research, London, United Kingdom (J.M.T.J.D.); Clinical Pharmacology, Modeling and Simulation, GlaxoSmithKline, RTP, North Carolina (B.S.); and Clinical Pharmacology, Modeling and Simulation, Parexel, Durham, North Carolina (R.L.O.-S.)
| | - Lee Crossman
- Drug Metabolism and Disposition (M.J.Z.-G., D.A.B., J.M., J.L.P.), Medicine Development (M.M.M.), and Development Biostatistics (M.A.), GlaxoSmithKline, Collegeville, Pennsylvania; Drug Metabolism and Disposition (D.K., G.C.Y.), and Bioanalysis, Immunogenicity and Biomarkers (A.I.P.), GlaxoSmithKline, Ware, United Kingdom; Pharmaron ABS Inc., Germantown, Maryland (M.S.); Covance, Harrogate, United Kingdom (L.C.); Global Clinical Development, GlaxoSmithKline, Brentford, United Kingdom (K.M.T.); Hammersmith Medicines Research, London, United Kingdom (J.M.T.J.D.); Clinical Pharmacology, Modeling and Simulation, GlaxoSmithKline, RTP, North Carolina (B.S.); and Clinical Pharmacology, Modeling and Simulation, Parexel, Durham, North Carolina (R.L.O.-S.)
| | - Jill L Pirhalla
- Drug Metabolism and Disposition (M.J.Z.-G., D.A.B., J.M., J.L.P.), Medicine Development (M.M.M.), and Development Biostatistics (M.A.), GlaxoSmithKline, Collegeville, Pennsylvania; Drug Metabolism and Disposition (D.K., G.C.Y.), and Bioanalysis, Immunogenicity and Biomarkers (A.I.P.), GlaxoSmithKline, Ware, United Kingdom; Pharmaron ABS Inc., Germantown, Maryland (M.S.); Covance, Harrogate, United Kingdom (L.C.); Global Clinical Development, GlaxoSmithKline, Brentford, United Kingdom (K.M.T.); Hammersmith Medicines Research, London, United Kingdom (J.M.T.J.D.); Clinical Pharmacology, Modeling and Simulation, GlaxoSmithKline, RTP, North Carolina (B.S.); and Clinical Pharmacology, Modeling and Simulation, Parexel, Durham, North Carolina (R.L.O.-S.)
| | - Karl M Thorpe
- Drug Metabolism and Disposition (M.J.Z.-G., D.A.B., J.M., J.L.P.), Medicine Development (M.M.M.), and Development Biostatistics (M.A.), GlaxoSmithKline, Collegeville, Pennsylvania; Drug Metabolism and Disposition (D.K., G.C.Y.), and Bioanalysis, Immunogenicity and Biomarkers (A.I.P.), GlaxoSmithKline, Ware, United Kingdom; Pharmaron ABS Inc., Germantown, Maryland (M.S.); Covance, Harrogate, United Kingdom (L.C.); Global Clinical Development, GlaxoSmithKline, Brentford, United Kingdom (K.M.T.); Hammersmith Medicines Research, London, United Kingdom (J.M.T.J.D.); Clinical Pharmacology, Modeling and Simulation, GlaxoSmithKline, RTP, North Carolina (B.S.); and Clinical Pharmacology, Modeling and Simulation, Parexel, Durham, North Carolina (R.L.O.-S.)
| | - Jeremy M T J Dennison
- Drug Metabolism and Disposition (M.J.Z.-G., D.A.B., J.M., J.L.P.), Medicine Development (M.M.M.), and Development Biostatistics (M.A.), GlaxoSmithKline, Collegeville, Pennsylvania; Drug Metabolism and Disposition (D.K., G.C.Y.), and Bioanalysis, Immunogenicity and Biomarkers (A.I.P.), GlaxoSmithKline, Ware, United Kingdom; Pharmaron ABS Inc., Germantown, Maryland (M.S.); Covance, Harrogate, United Kingdom (L.C.); Global Clinical Development, GlaxoSmithKline, Brentford, United Kingdom (K.M.T.); Hammersmith Medicines Research, London, United Kingdom (J.M.T.J.D.); Clinical Pharmacology, Modeling and Simulation, GlaxoSmithKline, RTP, North Carolina (B.S.); and Clinical Pharmacology, Modeling and Simulation, Parexel, Durham, North Carolina (R.L.O.-S.)
| | - Megan M McLaughlin
- Drug Metabolism and Disposition (M.J.Z.-G., D.A.B., J.M., J.L.P.), Medicine Development (M.M.M.), and Development Biostatistics (M.A.), GlaxoSmithKline, Collegeville, Pennsylvania; Drug Metabolism and Disposition (D.K., G.C.Y.), and Bioanalysis, Immunogenicity and Biomarkers (A.I.P.), GlaxoSmithKline, Ware, United Kingdom; Pharmaron ABS Inc., Germantown, Maryland (M.S.); Covance, Harrogate, United Kingdom (L.C.); Global Clinical Development, GlaxoSmithKline, Brentford, United Kingdom (K.M.T.); Hammersmith Medicines Research, London, United Kingdom (J.M.T.J.D.); Clinical Pharmacology, Modeling and Simulation, GlaxoSmithKline, RTP, North Carolina (B.S.); and Clinical Pharmacology, Modeling and Simulation, Parexel, Durham, North Carolina (R.L.O.-S.)
| | - Matthew Allinder
- Drug Metabolism and Disposition (M.J.Z.-G., D.A.B., J.M., J.L.P.), Medicine Development (M.M.M.), and Development Biostatistics (M.A.), GlaxoSmithKline, Collegeville, Pennsylvania; Drug Metabolism and Disposition (D.K., G.C.Y.), and Bioanalysis, Immunogenicity and Biomarkers (A.I.P.), GlaxoSmithKline, Ware, United Kingdom; Pharmaron ABS Inc., Germantown, Maryland (M.S.); Covance, Harrogate, United Kingdom (L.C.); Global Clinical Development, GlaxoSmithKline, Brentford, United Kingdom (K.M.T.); Hammersmith Medicines Research, London, United Kingdom (J.M.T.J.D.); Clinical Pharmacology, Modeling and Simulation, GlaxoSmithKline, RTP, North Carolina (B.S.); and Clinical Pharmacology, Modeling and Simulation, Parexel, Durham, North Carolina (R.L.O.-S.)
| | - Brandon Swift
- Drug Metabolism and Disposition (M.J.Z.-G., D.A.B., J.M., J.L.P.), Medicine Development (M.M.M.), and Development Biostatistics (M.A.), GlaxoSmithKline, Collegeville, Pennsylvania; Drug Metabolism and Disposition (D.K., G.C.Y.), and Bioanalysis, Immunogenicity and Biomarkers (A.I.P.), GlaxoSmithKline, Ware, United Kingdom; Pharmaron ABS Inc., Germantown, Maryland (M.S.); Covance, Harrogate, United Kingdom (L.C.); Global Clinical Development, GlaxoSmithKline, Brentford, United Kingdom (K.M.T.); Hammersmith Medicines Research, London, United Kingdom (J.M.T.J.D.); Clinical Pharmacology, Modeling and Simulation, GlaxoSmithKline, RTP, North Carolina (B.S.); and Clinical Pharmacology, Modeling and Simulation, Parexel, Durham, North Carolina (R.L.O.-S.)
| | - Robin L O'Connor-Semmes
- Drug Metabolism and Disposition (M.J.Z.-G., D.A.B., J.M., J.L.P.), Medicine Development (M.M.M.), and Development Biostatistics (M.A.), GlaxoSmithKline, Collegeville, Pennsylvania; Drug Metabolism and Disposition (D.K., G.C.Y.), and Bioanalysis, Immunogenicity and Biomarkers (A.I.P.), GlaxoSmithKline, Ware, United Kingdom; Pharmaron ABS Inc., Germantown, Maryland (M.S.); Covance, Harrogate, United Kingdom (L.C.); Global Clinical Development, GlaxoSmithKline, Brentford, United Kingdom (K.M.T.); Hammersmith Medicines Research, London, United Kingdom (J.M.T.J.D.); Clinical Pharmacology, Modeling and Simulation, GlaxoSmithKline, RTP, North Carolina (B.S.); and Clinical Pharmacology, Modeling and Simulation, Parexel, Durham, North Carolina (R.L.O.-S.)
| | - Graeme C Young
- Drug Metabolism and Disposition (M.J.Z.-G., D.A.B., J.M., J.L.P.), Medicine Development (M.M.M.), and Development Biostatistics (M.A.), GlaxoSmithKline, Collegeville, Pennsylvania; Drug Metabolism and Disposition (D.K., G.C.Y.), and Bioanalysis, Immunogenicity and Biomarkers (A.I.P.), GlaxoSmithKline, Ware, United Kingdom; Pharmaron ABS Inc., Germantown, Maryland (M.S.); Covance, Harrogate, United Kingdom (L.C.); Global Clinical Development, GlaxoSmithKline, Brentford, United Kingdom (K.M.T.); Hammersmith Medicines Research, London, United Kingdom (J.M.T.J.D.); Clinical Pharmacology, Modeling and Simulation, GlaxoSmithKline, RTP, North Carolina (B.S.); and Clinical Pharmacology, Modeling and Simulation, Parexel, Durham, North Carolina (R.L.O.-S.)
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12
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Marcus E, Stone P, Krooupa AM, Thorburn D, Vivat B. Quality of life in primary sclerosing cholangitis: a systematic review. Health Qual Life Outcomes 2021; 19:100. [PMID: 33743710 PMCID: PMC7981996 DOI: 10.1186/s12955-021-01739-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 03/09/2021] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Primary sclerosing cholangitis (PSC) is a rare bile duct and liver disease which can considerably impact quality of life (QoL). As part of a project developing a measure of QoL for people with PSC, we conducted a systematic review with four review questions. The first of these questions overlaps with a recently published systematic review, so this paper reports on the last three of our initial four questions: (A) How does QoL in PSC compare with other groups?, (B) Which attributes/factors are associated with impaired QoL in PSC?, (C) Which interventions are effective in improving QoL in people with PSC?. METHODS We systematically searched five databases from inception to 1 November 2020 and assessed the methodological quality of included studies using standard checklists. RESULTS We identified 28 studies: 17 for (A), ten for (B), and nine for (C). Limited evidence was found for all review questions, with few studies included in each comparison, and small sample sizes. The limited evidence available indicated poorer QoL for people with PSC compared with healthy controls, but findings were mixed for comparisons with the general population. QoL outcomes in PSC were comparable to other chronic conditions. Itch, pain, jaundice, severity of inflammatory bowel disease, liver cirrhosis, and large-duct PSC were all associated with impaired QoL. No associations were found between QoL and PSC severity measured with surrogate markers of disease progression or one of three prognostic scoring systems. No interventions were found to improve QoL outcomes. CONCLUSION The limited findings from included studies suggest that markers of disease progression used in clinical trials may not reflect the experiences of people with PSC. This highlights the importance for clinical research studies to assess QoL alongside clinical and laboratory-based outcomes. A valid and responsive PSC-specific measure of QoL, to adequately capture all issues of importance to people with PSC, would therefore be helpful for clinical research studies.
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Affiliation(s)
- Elena Marcus
- Marie Curie Palliative Care Research Department, Division of Psychiatry, University College London, 6th Floor, Maple House, 149 Tottenham Court Road, London, W1T 7NF, UK.
- University College London Institute of Liver and Digestive Health, UCL Royal Free Campus, Royal Free Hospital, London, UK.
| | - Paddy Stone
- Marie Curie Palliative Care Research Department, Division of Psychiatry, University College London, 6th Floor, Maple House, 149 Tottenham Court Road, London, W1T 7NF, UK
| | - Anna-Maria Krooupa
- Marie Curie Palliative Care Research Department, Division of Psychiatry, University College London, 6th Floor, Maple House, 149 Tottenham Court Road, London, W1T 7NF, UK
| | - Douglas Thorburn
- University College London Institute of Liver and Digestive Health, UCL Royal Free Campus, Royal Free Hospital, London, UK
- Sheila Sherlock Liver Unit, Royal Free Hospital, London, UK
| | - Bella Vivat
- Marie Curie Palliative Care Research Department, Division of Psychiatry, University College London, 6th Floor, Maple House, 149 Tottenham Court Road, London, W1T 7NF, UK
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13
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Archer S, Davies K. Biological basis of child health 9: development of the liver and clinical features of childhood liver disease. Nurs Child Young People 2021; 33:34-42. [PMID: 33682393 DOI: 10.7748/ncyp.2021.e1258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/10/2020] [Indexed: 11/09/2022]
Abstract
This article is the ninth in a series on the biological basis of child health and follows on from the previous article, which discussed the gastrointestinal system. The liver is the largest solid organ in the body and has more than 500 functions. These functions include: producing bile, which serves as a vehicle for waste products and as an aid for the digestion of dietary fat; synthesising most coagulation factors, needed in the clotting cascade; and transforming glycogen into glucose for use as energy in cell metabolism. While most liver conditions seen in children are rare, it is important that children's nurses can identify the clinical features of childhood liver disease. This article provides an overview of the embryological development of the liver, its anatomy and functions, liver function tests in children, and the clinical features and pathophysiology of childhood liver disease.
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Affiliation(s)
- Sam Archer
- child health, King's College Hospital NHS Foundation Trust, London, England
| | - Kate Davies
- London South Bank University and honorary research fellow in paediatric endocrinology, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, England
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14
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Abstract
Given the visibility of cutaneous findings, skin manifestations are often a presenting symptom of underlying systemic disease, including chronic liver disease. Many cutaneous signs and symptoms that correlate with chronic liver disease are common physical examination findings in patients with no history of liver disease. It is nonetheless important to be aware that these cutaneous findings may be an indication of underlying liver disease and often occur in the setting of such hepatic dysfunction. This article covers general cutaneous signs that may correlate with various liver diseases and describes specific cutaneous signs as they relate to more specific liver diseases.
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Affiliation(s)
- Ashaki D Patel
- Department of Dermatology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
| | - Kimberly Katz
- Department of Dermatology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
| | - Kenneth B Gordon
- Department of Dermatology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
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15
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Pedersen MR, Mayo MJ. Managing the Symptoms and Complications of Cholestasis. Clin Liver Dis (Hoboken) 2020; 15:120-124. [PMID: 32257123 PMCID: PMC7128033 DOI: 10.1002/cld.901] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Accepted: 10/23/2019] [Indexed: 02/04/2023] Open
Abstract
http://aasldpubs.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)2046-2484/video/15-3-reading-mayo a video presentation of this article http://aasldpubs.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)2046-2484/video/15-3-interview-mayo an interview with the author https://www.wileyhealthlearning.com/Activity/7058616/disclaimerspopup.aspx questions and earn CME.
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Affiliation(s)
- Mark R. Pedersen
- Division of Digestive and Liver DiseaseDepartment of Internal MedicineThe University of Texas Southwestern Medical CenterDallasTX
| | - Marlyn J. Mayo
- Division of Digestive and Liver DiseaseDepartment of Internal MedicineThe University of Texas Southwestern Medical CenterDallasTX
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16
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Hegade VS, Mells GF, Fisher H, Kendrick S, DiBello J, Gilchrist K, Alexander GJ, Hirschfield GM, Sandford RN, Jones DEJ. Pruritus Is Common and Undertreated in Patients With Primary Biliary Cholangitis in the United Kingdom. Clin Gastroenterol Hepatol 2019; 17:1379-1387.e3. [PMID: 30557739 DOI: 10.1016/j.cgh.2018.12.007] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2018] [Revised: 11/13/2018] [Accepted: 12/06/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS Little is known about the prevalence or treatment of pruritus associated with primary biliary cholangitis (PBC). We analyzed data from patients with PBC recruited from all clinical centers in the United Kingdom (UK) to characterize the prevalence, severity, progression, and treatment of pruritus. METHODS We performed cross-sectional and longitudinal studies of patients in the UK-PBC cohort to assess trajectories of pruritus. Data on pruritus frequency, severity, and therapy were collected via paper questionnaires completed by 2194 patients at their initial assessment in 2011 and then again in 2014 and 2017. Self-reported treatment data were validated against the prescription record of PBC cohort in the Clinical Practice Research Datalink, a primary care database. We defined persistent pruritus as itch that occurs frequently or all the time and severe pruritus as PBC-40 pruritus domain scores of 12 or more, throughout their disease course. Latent class mixed models were used to study pruritus trajectories and identify factors associated with high pruritus. RESULTS At initial assessment, 1613 (73.5%) patients had experienced pruritus at some point since their development of PBC-persistent pruritus was reported by 34.5% of the patients and severe pruritus by 11.7%. Only 37.4% of patients with persistent pruritus and 50% with severe pruritus reported ever receiving cholestyramine. Frequencies of rifampicin use were 11% in patients with persistent pruritus and 23% in patients with severe pruritus. Comparison of 2011 and 2014 surveys (comprising 1423 patients) showed consistent self-reported data on pruritus. Proportions of patients in the UK-PBC cohort treated with cholestyramine or naltrexone (37.4% and 4.4%) did not differ significantly from proportions treated in the Clinical Practice Research Datalink cohort (30.4% and 4.4%) (P = .07 for cholestyramine and P = .32 for naltrexone). Latent class mixed models (n = 1753) identified 3 different groups of pruritus. Multivariable analysis identified younger age at diagnosis and higher level of alkaline phosphatase at 12 months after diagnosis as factors significantly associated with persistent high pruritus. CONCLUSIONS In a large national cohort study of patients with PBC, we found a high prevalence of pruritus and inadequate guideline-recommended therapy. Patient-reported data used to determine pruritus prevalence and treatment are reliable. Younger age and levels of higher alkaline phosphatase were associated with persistent pruritus. We need to increase awareness and management of pruritus in PBC in the UK.
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Affiliation(s)
- Vinod S Hegade
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom; National Institute for Health Research Newcastle Biomedical Research Centre, Newcastle University, Newcastle upon Tyne, United Kingdom.
| | - George F Mells
- Department of Hepatology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom; Academic Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom
| | - Holly Fisher
- Institute of Health and Society, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Stuart Kendrick
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom; GlaxoSmithKline, Stevenage, United Kingdom
| | - Julia DiBello
- GlaxoSmithKline Research and Development, Collegeville, Pennsylvania
| | - Kim Gilchrist
- GlaxoSmithKline Research and Development, Collegeville, Pennsylvania
| | - Graeme J Alexander
- Department of Hepatology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom; Academic Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom
| | - Gideon M Hirschfield
- Centre for Liver Research, National Institute for Health Research Biomedical Research Unit, University of Birmingham, Birmingham, United Kingdom
| | - Richard N Sandford
- Academic Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom
| | - David E J Jones
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom; National Institute for Health Research Newcastle Biomedical Research Centre, Newcastle University, Newcastle upon Tyne, United Kingdom
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17
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Yoh K, Nishikawa H, Enomoto H, Iwata Y, Ishii A, Yuri Y, Ishii N, Miyamoto Y, Hasegawa K, Nakano C, Takata R, Nishimura T, Aizawa N, Sakai Y, Ikeda N, Takashima T, Iijima H, Nishiguchi S. Effect of nalfurafine hydrochloride in patients with chronic liver disease with refractory pruritus on sleep disorders: a study protocol for single-arm, prospective, interventional study. BMJ Open Gastroenterol 2017; 4:e000177. [PMID: 29104757 PMCID: PMC5659178 DOI: 10.1136/bmjgast-2017-000177] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2017] [Revised: 09/17/2017] [Accepted: 09/20/2017] [Indexed: 02/06/2023] Open
Abstract
Introduction Chronic liver disease (CLD)-related pruritus manifests as cholestasis symptoms, which can cause severe itches in the whole body and significantly decrease quality of daily activities and sleep. The actigram, which documents movement by means of an accelerometer, has been demonstrated to be useful for assessing sleep quality. Nalfurafine hydrochloride, which is a selective κ-opioid receptor agonist, exerts its antipruritic efficacies through a novel mechanism. We aimed to prospectively examine the effect of nalfurafine hydrochloride on sleep quality for patients with CLD with pruritus utilising actigram. Methods and analysis This study will be a single-centre, prospective, interventional, single-arm study. Our study participants are subjects whose pruritus was confirmed to be uncontrollable by antihistamines or antiallergics within 6 months before informed consent (IC). Evaluation time points using actigram will be (1) before administration of testing drug; (2) after 1 week; (3) after 4 weeks (primary endpoint); and (4) every 4 weeks thereafter. The follow-up period will be 6 months. We will prospectively assess and compare changes in sleep quality in patients with CLD with pruritus undergoing nalfurafine hydrochloride therapy using actigram. Quantitative variables will be compared by paired t-test. Ethics and dissemination This study has received approval from the Institutional Review Board at Hyogo College of Medicine (approval no 2325). The study protocol, IC form and other documents were reviewed and approved. Final data will be publicly disseminated regardless of the results. A report releasing study results will be submitted in an appropriate journal. Trial registration number UMIN000028161; Pre-results.
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Affiliation(s)
- Kazunori Yoh
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Hiroki Nishikawa
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Hirayuki Enomoto
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Yoshinori Iwata
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Akio Ishii
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Yukihisa Yuri
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Noriko Ishii
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Yuho Miyamoto
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Kunihiro Hasegawa
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Chikage Nakano
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Ryo Takata
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Takashi Nishimura
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Nobuhiro Aizawa
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Yoshiyuki Sakai
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Naoto Ikeda
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Tomoyuki Takashima
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Hiroko Iijima
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Shuhei Nishiguchi
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
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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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