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Wang H, Liu Y, Xu Q, Lin G, Shao L, Mo J, Li J, Chu Z, Ma X. Successive structural optimization of Ziritaxestat culminates in the discovery of orally bioavailable and in vivo potent imidazothiadiazole derivative for treating ATX-driven diseases. Eur J Med Chem 2025; 295:117769. [PMID: 40413987 DOI: 10.1016/j.ejmech.2025.117769] [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: 04/06/2025] [Revised: 05/12/2025] [Accepted: 05/14/2025] [Indexed: 05/27/2025]
Abstract
Herein, we communicate our medicinal chemistry campaign culminating in the discovery of imidazothiadiazole-based ATX inhibitor with oral bioavailability and potent in vivo efficacy. During our successive structural modification of Ziritaxestat, an ATX inhibitor advanced into phase III clinical trial, a total of 25 analogs have been designed and synthesized for improving its potency. Among them, 9 compounds exhibited single-digit nanomolar ATX inhibitory activity (IC50 = 2.54-9.01 nM), which was remarkably enhanced over Ziritaxestat (IC50 = 29.9 nM). In particular, compound 25, an imidazothiadiazole derivative that incorporated deuterated N-methyl for boosting metabolic stability, displayed an oral bioavailability of 27.1 %. In air pouch model of inflammation, it exerted superior in vivo efficacy to that of Ziritaxestat, as revealed by the more dramatic suppression of LPA secretion resulted from the treatment with 25. Moreover, 25 demonstrated promising therapeutic efficacy against bleomycin-induced systemic sclerosis in mice. Attributed to its attractive in vitro and in vivo performance in battling ATX-related diseases, 25 deserves further development as a potential candidate.
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Affiliation(s)
- Henian Wang
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China
| | - Yulei Liu
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China
| | - Qinlong Xu
- Hefei Institute of Pharmaceutical Industry Company, Ltd., Hefei, 230088, China
| | - Gaofeng Lin
- Hefei Institute of Pharmaceutical Industry Company, Ltd., Hefei, 230088, China
| | - Li Shao
- Hefei Institute of Pharmaceutical Industry Company, Ltd., Hefei, 230088, China
| | - Jiajia Mo
- Hefei Institute of Pharmaceutical Industry Company, Ltd., Hefei, 230088, China
| | - Jiaming Li
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China; Institute of Medicinal Chemistry, Anhui Academy of Chinese Medicine, Hefei, 230012, China; Anhui Province Key Laboratory of Bioactive Natural Products, Hefei, 230012, China.
| | - Zhaoxing Chu
- Hefei Institute of Pharmaceutical Industry Company, Ltd., Hefei, 230088, China.
| | - Xiaodong Ma
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China; Institute of Medicinal Chemistry, Anhui Academy of Chinese Medicine, Hefei, 230012, China; Anhui Province Key Laboratory of Bioactive Natural Products, Hefei, 230012, China.
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Younossi ZM, Estep MJ, Felix S, Lam B, Mukherjee S, Swift B, Casillas L, de Souza AR, Hunnicutt J, McLaughlin MM, Racila A, Nader F, Stepanova M. Serum Bile Acid Elevation is an Independently Associated With Pruritus in Patients With At-risk Metabolic Dysfunction-associated Steatotic Liver Disease. J Clin Exp Hepatol 2025; 15:102549. [PMID: 40256443 PMCID: PMC12008524 DOI: 10.1016/j.jceh.2025.102549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Accepted: 03/13/2025] [Indexed: 04/22/2025] Open
Abstract
Background and aims Elevated serum bile acids are associated with pruritus in cholestatic liver diseases. We assessed the association of serum bile acids and other putative biomarkers of cholestatic pruritus (autotaxin and interleukin-31 (IL-31) with pruritus in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Methods We used serum from patients with MASLD and metabolic dysfunction-associated steatohepatitis (MASH), viral hepatitis B, viral hepatitis C, and healthy blood donors to measure the levels of bile acids, autotaxin, and IL-31. Clinically significant pruritus was defined from the Chronic Liver Disease Questionnaire. Results Six hundred fifty-one subjects were included [MASLD (N = 497, 88 MASH), viral hepatitis B and C (VH, N = 98), healthy controls (N = 56)]. Post hoc definitions of high biomarker levels associated with the presence of clinically significant pruritus were as follows: high bile acids ≥5.9 μmol/L, high autotaxin ≥220 ng/mL, and high IL-31 ≥ 25 pg/mL. The VH patients had the highest bile acids levels and lowest levels were in healthy controls (P < 0.0001). The highest autotaxin levels were seen in hepatitis C, while the highest IL-31 levels in MASH. MASH patients had higher levels of all three biomarkers than non-MASH-MASLD. Also, at-risk MASLD or MASLD with advanced fibrosis (AF) had higher bile acids and autotaxin (all P < 0.01) but not IL-31 (P > 0.05). MASLD patients with high bile acids had more pruritus (all MASLD: 25% vs. 17%; MASH 30% vs. 13%; at-risk MASLD: 33% vs. 12%; AF: 41% vs. 8%). In multivariable logistic regressions, having high bile acids was an independent predictor of pruritus in at-risk MASLD [odds ratio (OR) (95% CI) = 4.4 (1.6-12.1)] and MASLD with advanced fibrosis [OR = 7.5 (2.0-29.0)]; but not autotaxin or IL-31 (all P > 0.05). Conclusions High serum bile acid level is independently associated with pruritus in at-risk MASLD.
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Affiliation(s)
- Zobair M. Younossi
- The Global NASH Council, Washington DC, USA
- Beatty Liver and Obesity Research Program, Inova Health System, Falls Church, VA, USA
| | - Michael J. Estep
- The Global NASH Council, Washington DC, USA
- Beatty Liver and Obesity Research Program, Inova Health System, Falls Church, VA, USA
| | - Sean Felix
- Beatty Liver and Obesity Research Program, Inova Health System, Falls Church, VA, USA
| | - Brian Lam
- The Global NASH Council, Washington DC, USA
- Beatty Liver and Obesity Research Program, Inova Health System, Falls Church, VA, USA
| | | | | | | | | | | | | | - Andrei Racila
- The Global NASH Council, Washington DC, USA
- Beatty Liver and Obesity Research Program, Inova Health System, Falls Church, VA, USA
| | - Fatema Nader
- The Global NASH Council, Washington DC, USA
- Beatty Liver and Obesity Research Program, Inova Health System, Falls Church, VA, USA
- Center for Outcomes Research in Liver Diseases, Washington DC, USA
| | - Maria Stepanova
- The Global NASH Council, Washington DC, USA
- Beatty Liver and Obesity Research Program, Inova Health System, Falls Church, VA, USA
- Center for Outcomes Research in Liver Diseases, Washington DC, USA
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Narayanan S, Sneller L, Mathur P. To be or not to be: the non-antimicrobial properties of common antimicrobials. J Antimicrob Chemother 2025:dkaf150. [PMID: 40376834 DOI: 10.1093/jac/dkaf150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/18/2025] Open
Abstract
Antibiotics are diverse in their utility in clinical care. They are widely prescribed for their antimicrobial effect and used as modulators, although rarely, of non-infectious conditions, to influence immune responses, to decrease morbidity and improve quality of life. This review provides a concise summary of different classes of antibiotics and their unique properties that allow them to be used in the treatment of non-infectious conditions.
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Affiliation(s)
- Shivakumar Narayanan
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Laura Sneller
- Drexel University College of Medicine, Philadelphia, PA, USA
| | - Poonam Mathur
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA
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Chen Y, Chen R, Li H, Shuai Z. Clinical management of autoimmune liver diseases: juncture, opportunities, and challenges ahead. Immunol Res 2025; 73:67. [PMID: 40195209 PMCID: PMC11976385 DOI: 10.1007/s12026-025-09622-9] [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: 11/27/2024] [Accepted: 03/14/2025] [Indexed: 04/09/2025]
Abstract
The three major autoimmune liver diseases are autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC).These conditions are assumed to result from a breakdown in immunological tolerance, which leads to an inflammatory process that causes liver damage.The self-attack is started by T-helper cell-mediated identification of liver autoantigens and B-cell production of autoantibodies,and it is maintained by a reduction in the number and activity of regulatory T-cells.Infections and environmental factors have been explored as triggering factors for these conditions, in addition to a genetic predisposition.Allelic mutations in the HLA locus have been linked to vulnerability, as have relationships with single nucleotide polymorphisms in non-HLA genes.Despite the advances in the management of these diseases, there is no curative treatment for these disorders, and a significant number of patients eventually progress to an end-stage liver disease requiring liver transplantation.In this line, tailored immune-therapeutics have emerged as possible treatments to control the disease.In addition, early diagnosis and treatment are pivotal for reducing the long-lasting effects of these conditions and their burden on quality of life.Herein we present a review of the etiology, clinical presentation, diagnosis, and challenges on ALDs and the feasible solutions for these complex diseases.
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MESH Headings
- Humans
- Hepatitis, Autoimmune/therapy
- Hepatitis, Autoimmune/diagnosis
- Hepatitis, Autoimmune/immunology
- Hepatitis, Autoimmune/etiology
- Cholangitis, Sclerosing/therapy
- Cholangitis, Sclerosing/diagnosis
- Cholangitis, Sclerosing/immunology
- Liver Cirrhosis, Biliary/therapy
- Liver Cirrhosis, Biliary/diagnosis
- Liver Cirrhosis, Biliary/immunology
- Animals
- Immunotherapy/methods
- Autoimmune Diseases/therapy
- Autoimmune Diseases/diagnosis
- Disease Management
- Genetic Predisposition to Disease
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Affiliation(s)
- Yangfan Chen
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Ruofei Chen
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Haiyan Li
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Zongwen Shuai
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, 230032, China.
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Heyerick L, Dhondt A, Van Vlierberghe H, Verhelst X, Raevens S, Geerts A. Early plasmapheresis in type 2 benign recurrent intrahepatic cholestasis: A case report and review of literature. World J Hepatol 2025; 17:102375. [PMID: 40027565 PMCID: PMC11866144 DOI: 10.4254/wjh.v17.i2.102375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 12/06/2024] [Accepted: 01/07/2025] [Indexed: 02/20/2025] Open
Abstract
BACKGROUND Benign recurrent intrahepatic cholestasis (BRIC) is a rare autosomal recessive liver disease, causing episodic cholestasis with intense pruritus. This case report highlights the effectiveness of early plasmapheresis as a therapeutic option for BRIC type 2, offering rapid symptom relief and early termination of cholestatic episodes. It contributes to the limited evidence supporting plasmapheresis as a treatment for BRIC flares resistant to conventional therapies. CASE SUMMARY A 43-year-old male with BRIC type 2 presented with fatigue, jaundice, and severe pruritus, triggered by a recent mild severe acute respiratory syndrome coronavirus 2 infection. Laboratory results confirmed cholestasis with elevated bilirubin and alkaline phosphatase. First-line pharmacological treatments, including cholestyramine and rifampicin, failed. Endoscopic nasobiliary drainage was ineffective, prompting initiation of plasmapheresis. This intervention rapidly relieved pruritus, with complete biochemical normalisation after 11 sessions. Two years later, a similar episode occurred, and early reinitiation of plasmapheresis led to symptom resolution within two sessions and biochemical recovery within two weeks. The patient tolerated the procedure well, with no adverse effects observed. Follow-up showed no signs of cholestasis recurrence. CONCLUSION Plasmapheresis is a safe and effective option for therapy-refractory BRIC type 2, particularly when initiated early in cholestasis.
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Affiliation(s)
- Lander Heyerick
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent 9000, Belgium.
| | - Annemieke Dhondt
- Department of Nephrology, Ghent University Hospital, Ghent 9000, Belgium
| | - Hans Van Vlierberghe
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent 9000, Belgium
| | - Xavier Verhelst
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent 9000, Belgium
| | - Sarah Raevens
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent 9000, Belgium
| | - Anja Geerts
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent 9000, Belgium
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Kanda T, Sasaki-Tanaka R, Kimura N, Abe H, Yoshida T, Hayashi K, Sakamaki A, Yokoo T, Kamimura H, Tsuchiya A, Kamimura K, Terai S. Pruritus in Chronic Cholestatic Liver Diseases, Especially in Primary Biliary Cholangitis: A Narrative Review. Int J Mol Sci 2025; 26:1883. [PMID: 40076514 PMCID: PMC11900276 DOI: 10.3390/ijms26051883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Revised: 02/18/2025] [Accepted: 02/20/2025] [Indexed: 03/14/2025] Open
Abstract
Patients with chronic cholestatic liver diseases often experience itch and struggle with this symptom. We discuss the mechanism of itch in patients with chronic cholestatic liver diseases, such as primary biliary cholangitis (PBC) and others, and their therapies, including ileal bile acid transporter (IBAT) inhibitors. In patients with PBC, there are high serum/plasma concentrations of multiple factors, including bile salts, bilirubin, endogenous opioids, lysophosphatidic acid (LPA), autotaxin, and histamine. Bile salts, bilirubin, LPA, and autotaxin affect itch mediators in the skin and sensory nerves, while the endogenous opioid balance affects mediators in the spinal cord. Itch is sensitized by both the peripheral and central nervous systems. Both mechanisms are involved in itch in patients with chronic cholestatic liver disease. Although IBAT inhibitors have been approved for use in pediatric cholestatic conditions, such as progressive familial intrahepatic cholestasis and Alagille syndrome, IBAT inhibition seems to be a promising treatment for chronic refractory itch in patients with PBC. A traditional non-systematic review results in this narrative review. Multidisciplinary cooperation, involving hepatologists, dermatologists, and pharmacists, could provide better treatment for PBC patients suffering from refractory itch. In conclusion, we summarized the existing knowledge on itch caused by chronic cholestatic liver diseases, especially in PBC with a focus on the mechanisms and therapies. This narrative review provides the mechanisms and therapeutic options for itch in patients with chronic cholestatic liver diseases.
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Affiliation(s)
- Tatsuo Kanda
- Division of Gastroenterology and Hepatology, Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Uonuma Kikan Hospital, Minamiuonuma 949-7302, Japan
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-9510, Japan (K.H.); (A.S.)
| | - Reina Sasaki-Tanaka
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-9510, Japan (K.H.); (A.S.)
| | - Naruhiro Kimura
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-9510, Japan (K.H.); (A.S.)
| | - Hiroyuki Abe
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-9510, Japan (K.H.); (A.S.)
| | - Tomoaki Yoshida
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-9510, Japan (K.H.); (A.S.)
| | - Kazunao Hayashi
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-9510, Japan (K.H.); (A.S.)
| | - Akira Sakamaki
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-9510, Japan (K.H.); (A.S.)
| | - Takeshi Yokoo
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-9510, Japan (K.H.); (A.S.)
| | - Hiroteru Kamimura
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-9510, Japan (K.H.); (A.S.)
| | - Atsunori Tsuchiya
- Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Yamanashi, Chuo 409-3898, Japan;
| | - Kenya Kamimura
- Department of General Medicine, Niigata University School of Medicine, Niigata 951-9510, Japan;
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-9510, Japan (K.H.); (A.S.)
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Iwadare T, Kimura T, Yamashita Y, Okumura T, Wakabayashi SI, Kobayashi H, Sugiura A, Yamazaki T, Shimamoto S, Igarashi K, Joshita S, Umemura T. Serum Autotaxin Levels Predict Liver-Related Events in Patients With Primary Biliary Cholangitis: A Long-Term Multicenter Observational Study. Clin Transl Gastroenterol 2024; 15:e00779. [PMID: 39466702 PMCID: PMC11671064 DOI: 10.14309/ctg.0000000000000779] [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: 07/29/2024] [Accepted: 10/04/2024] [Indexed: 10/30/2024] Open
Abstract
INTRODUCTION A straightforward, reliable, and noninvasive method for predicting the development of liver-related events (LRE) in primary biliary cholangitis (PBC) has not been attained thus far. This study investigated whether serum autotaxin (ATX) could predict LRE in patients with PBC. METHODS This retrospective multicenter investigation included 190 biopsy-proven untreated patients with PBC. All subjects were followed for at least 1 year, during which time the prevalence of LRE, including newly developing hepatocellular carcinoma, esophagogastric varices, ascites, and hepatic encephalopathy, was investigated in relation with ATX levels at the time of liver biopsy. RESULTS During the median follow-up period of 9.7 years, LRE were observed in 22 patients (11.6%). The area under the receiver operating characteristic curve and cutoff value of serum ATX for predicting LRE were 0.80 and 1.086 mg/L, respectively. Patients with serum ATX ≥1.086 had a significantly higher cumulative incidence of LRE compared with patients with ATX < 1.086 (33.3% vs 3.6%, P < 0.00001). Notably, the predictive capability of ATX for LRE in patients with PBC surpassed that of FIB-4, ALBI, APRI, and Mac-2-binding protein glycan isomer. A multivariate Cox proportional hazards model revealed ATX as an independent associated factor for LRE (hazard ratio 6.24, 95% confidence interval 1.87-20.80, P = 0.003) along with Nakanuma stage (hazard ratio 2.75, 95% confidence interval 1.52-4.99, P < 0.001). These results were closely replicated in a serologically diagnosed PBC validation cohort (n = 32). DISCUSSION Serum ATX levels may serve as a predictive marker for LRE in patients with PBC.
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Affiliation(s)
- Takanobu Iwadare
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan;
| | - Takefumi Kimura
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan;
- Consultation Center for Liver Diseases, Shinshu University Hospital, Matsumoto, Japan;
| | - Yuki Yamashita
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan;
- Consultation Center for Liver Diseases, Shinshu University Hospital, Matsumoto, Japan;
| | - Taiki Okumura
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan;
| | - Shun-ichi Wakabayashi
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan;
| | - Hiroyuki Kobayashi
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan;
| | - Ayumi Sugiura
- Department of Internal Medicine, Sato Hospital, Nakano, Japan;
| | - Tomoo Yamazaki
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan;
- Department of Medicine, University of California San Diego, La Jolla, USA;
| | | | - Koji Igarashi
- Bioscience Division, TOSOH Corporation, Ayase, Japan;
| | - Satoru Joshita
- Department of Medicine, Yodakubo Hospital, Nagawa, Japan.
| | - Takeji Umemura
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan;
- Consultation Center for Liver Diseases, Shinshu University Hospital, Matsumoto, Japan;
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Kim JH, Lee R, Hwang SH, Choi SH, Kim JH, Cho IH, Lee JI, Nah SY. Ginseng and ginseng byproducts for skincare and skin health. J Ginseng Res 2024; 48:525-534. [PMID: 39583168 PMCID: PMC11583465 DOI: 10.1016/j.jgr.2024.09.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 08/21/2024] [Accepted: 09/20/2024] [Indexed: 11/26/2024] Open
Abstract
Ginseng is a traditional herbal medicine with a long history of use for the prevention and/or treatment of various diseases. Ginseng is used worldwide as a functional food to maintain human health. In addition, ginseng has been used as a raw ingredient in cosmetics with various applications, ranging from skin toning to anti-aging. Some cosmetic products contain ginseng extracts from Korea and other countries, as it is thought that ginseng can also exert beneficial effects on human skin. However, it remains unclear which ginseng component(s) could be the main active compound that directly contributes to skin health and/or prevents skin aging. It is also important to understand the mechanisms by which the ginseng component(s) exert their effects on the skin and skin health. This review describes recent in vitro and in vivo studies involving ginseng extracts, ginseng ingredients, and ginseng byproducts for skincare and skin health and discusses emerging evidence that ginsenosides, gintonin, and ginseng byproducts could be novel candidates for skincare and skin health applications ranging from anti-aging to the treatment of skin diseases such as atopic dermatitis and hypertrophic scars and keloids. The mechanisms underlying the beneficial effects of ginseng components and byproducts on skin health are discussed. In addition, this review shows how ginseng components, such as gintonin, a newly identified ginseng component, might contribute to skin health and skin disease when used as a supplementary ingredient in cosmetics and further proposes a novel combination in cosmetic products containing both ginsenosides and gintonin.
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Affiliation(s)
- Ji-Hun Kim
- Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine, Konkuk University, Seoul, Republic of Korea
| | - Rami Lee
- Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine, Konkuk University, Seoul, Republic of Korea
| | - Sung-Hee Hwang
- Department of Pharmaceutical Engineering, College of Health Sciences, Sangji University, Wonju, Republic of Korea
| | - Sun-Hye Choi
- Department of Animal Health, College of Health and Medical Services, Osan University, Osan-si, Republic of Korea
| | - Jong-Hoon Kim
- College of Veterinary Medicine, Biosafety Research Institute, Jeonbuk National University, Iksan City, Jeollabuk-Do, Republic of Korea
| | - Ik-Hyun Cho
- Department of Convergence Medical Science, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Jeong Ik Lee
- Department of Veterinary Obstetrics and Theriogenology, College of Veterinary Medicine, Konkuk University, Seoul, Republic of Korea
| | - Seung-Yeol Nah
- Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine, Konkuk University, Seoul, Republic of Korea
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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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Yun CC, Han Y, McConnell B. Lysophosphatidic Acid Signaling in the Gastrointestinal System. Cell Mol Gastroenterol Hepatol 2024; 18:101398. [PMID: 39233124 PMCID: PMC11532463 DOI: 10.1016/j.jcmgh.2024.101398] [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: 03/12/2024] [Revised: 08/09/2024] [Accepted: 08/13/2024] [Indexed: 09/06/2024]
Abstract
The intestinal epithelium undergoes continuous homeostatic renewal to conduct the digestion and absorption of nutrients. At the same time, the intestinal epithelial barrier separates the host from the intestinal lumen, preventing systemic infection from enteric pathogens. To maintain homeostasis and epithelial functionality, stem cells, which reside in the base of intestinal crypts, generate progenitor cells that ultimately differentiate to produce an array of secretory and absorptive cells. Intestinal regeneration is regulated by niche signaling pathways, specifically, Wnt, bone morphogenetic protein, Notch, and epidermal growth factor. In addition, growth factors and other peptides have emerged as potential modulators of intestinal repair and inflammation through their roles in cellular proliferation, differentiation, migration, and survival. Lysophosphatidic acid (LPA) is such a factor that modulates the proliferation, survival, and migration of epithelial cells while also regulating trafficking of immune cells, both of which are important for tissue homeostasis. Perturbation of LPA signaling, however, has been shown to promote cancer and inflammation. This review focuses on the recent advances in LPA-mediated signaling that contribute to physiological and pathophysiological regulation of the gastrointestinal system.
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Affiliation(s)
- C Chris Yun
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; Gastroenterology Research, Atlanta Veterans Administration Medical Center, Decatur, Georgia.
| | - Yiran Han
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Beth McConnell
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
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11
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Li X, Koyama Y, Taura K, Nishio T, Yoh T, Nishino H, Uemoto Y, Kimura Y, Nakamura D, Nam NH, Sato M, Seo S, Iwaisako K, Hatano E. High expression of autotaxin is associated with poor recurrence-free survival in cholangiocarcinoma. Hepatol Res 2024; 54:817-826. [PMID: 38430513 DOI: 10.1111/hepr.14031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Revised: 02/08/2024] [Accepted: 02/12/2024] [Indexed: 03/04/2024]
Abstract
BACKGROUND AND AIM Autotaxin (ATX) is an extracellular lysophospholipase D that catalyzes the hydrolysis of lysophosphatidylcholine into lysophosphatidic acid (LPA). Recent accumulating evidence indicates the biological roles of ATX in malignant tumors. However, the expression and clinical implications of ATX in human cholangiocarcinoma (CCA) remain elusive. METHODS In this study, the expression of ATX in 97 human CCA tissues was evaluated by immunohistochemistry. Serum ATX levels were determined in CCA patients (n = 26) and healthy subjects (n = 8). Autotaxin expression in cell types within the tumor microenvironment was characterized by immunofluorescence staining. RESULTS High ATX expression in CCA tissue was significantly associated with a higher frequency of lymph node metastasis (p = 0.050). High ATX expression was correlated with shorter overall survival (p = 0.032) and recurrence-free survival (RFS) (p = 0.001) than low ATX expression. In multivariate Cox analysis, high ATX expression (p = 0.019) was an independent factor for shorter RFS. Compared with low ATX expression, high ATX expression was significantly associated with higher Ki-67-positive cell counts (p < 0.001). Serum ATX levels were significantly higher in male CCA patients than in healthy male subjects (p = 0.030). In the tumor microenvironment of CCA, ATX protein was predominantly expressed in tumor cells, cancer-associated fibroblasts, plasma cells, and biliary epithelial cells. CONCLUSIONS Our study highlights the clinical evidence and independent prognostic value of ATX in human CCA.
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Affiliation(s)
- Xuefeng Li
- Division of Hepatobiliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yukinori Koyama
- Division of Hepatobiliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kojiro Taura
- Division of Hepatobiliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Department of Gastroenterological Surgery and Oncology, Tazuke Kofukai Medical Research Institute, Kitano Hospital, Osaka, Japan
| | - Takahiro Nishio
- Division of Hepatobiliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Tomoaki Yoh
- Division of Hepatobiliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroto Nishino
- Division of Hepatobiliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yusuke Uemoto
- Division of Hepatobiliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yusuke Kimura
- Division of Hepatobiliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Daichi Nakamura
- Division of Hepatobiliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Nguyen Hai Nam
- Department of Liver Tumor, Cancer Center, Cho Ray Hospital, Ho Chi Minh City, Vietnam
| | - Motohiko Sato
- Division of Hepatobiliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Satoru Seo
- Department of Surgery, Kochi Medical School, Kochi, Japan
| | - Keiko Iwaisako
- Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Japan
| | - Etsuro Hatano
- Division of Hepatobiliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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12
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Hague WB, Williamson C, Beuers U. Intrahepatic cholestasis of pregnancy: Introduction and overview 2024. Obstet Med 2024; 17:138-143. [PMID: 39262909 PMCID: PMC11384812 DOI: 10.1177/1753495x241265772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Accepted: 06/04/2024] [Indexed: 09/13/2024] Open
Abstract
Considerable progress has been made to explain the aetiology of intrahepatic cholestasis of pregnancy (ICP) and of the adverse pregnancy outcomes associated with high maternal total serum bile acids (TSBAs). The reported thresholds for non-fasting TSBA associated with the risk of stillbirth and spontaneous preterm birth can be used to identify pregnancies at risk of these adverse outcomes to decide on appropriate interventions and to give reassurance to women with lower concentrations of TSBA. Data also support the use of ursodeoxycholic acid to protect against the risk of spontaneous preterm birth. A previous history of ICP may be associated with higher rates of subsequent hepatobiliary disease: if there is a suspicion of underlying susceptibility, clinicians caring for women with ICP should screen for associated disorders or for genetic susceptibility and, where appropriate, refer for ongoing hepatology review.
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Affiliation(s)
- Wm Bill Hague
- Robinson Research Institute, The University of Adelaide, North Adelaide, Australia
| | | | - Ulrich Beuers
- Department of Gastroenterology and Hepatology and Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Centres, Amsterdam, Netherlands
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13
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Hassan A, Hurtado Diaz De Leon I, Tapper EB. Symptom burden in chronic liver disease. Gastroenterol Rep (Oxf) 2024; 12:goae078. [PMID: 39131950 PMCID: PMC11315653 DOI: 10.1093/gastro/goae078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Accepted: 07/03/2024] [Indexed: 08/13/2024] Open
Abstract
Chronic liver disease (CLD) is a significant contributor to global mortality. For people who are living with CLD, however, there is a substantial and often overlooked burden of physical and psychological symptoms that significantly affect health-related quality of life. CLD frequently presents with a multitude of interrelated and intricate symptoms, including fatigue, pruritus, muscle cramps, sexual dysfunction, and falls. Increasingly, there is interest in studying and developing interventional strategies to provide a more global approach to managing these complex patients. Moreover, in addition to established guidelines for the management of conventional complications, such as ascites and hepatic encephalopathy, there have been efforts in developing evidence-based guidance for the treatment of the more subjective yet still problematic elements. This review will address the management of these less "classical" but nonetheless important symptoms.
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Affiliation(s)
- Ammar Hassan
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan Health West, University of Michigan Medicine, Grand Rapids, MI, USA
| | - Ivonne Hurtado Diaz De Leon
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Elliot B Tapper
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
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14
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Fischer C, Schreiber Y, Nitsch R, Vogt J, Thomas D, Geisslinger G, Tegeder I. Lysophosphatidic Acid Receptors LPAR5 and LPAR2 Inversely Control Hydroxychloroquine-Evoked Itch and Scratching in Mice. Int J Mol Sci 2024; 25:8177. [PMID: 39125747 PMCID: PMC11312285 DOI: 10.3390/ijms25158177] [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: 06/12/2024] [Revised: 07/20/2024] [Accepted: 07/24/2024] [Indexed: 08/12/2024] Open
Abstract
Lysophosphatidic acids (LPAs) evoke nociception and itch in mice and humans. In this study, we assessed the signaling paths. Hydroxychloroquine was injected intradermally to evoke itch in mice, which evoked an increase of LPAs in the skin and in the thalamus, suggesting that peripheral and central LPA receptors (LPARs) were involved in HCQ-evoked pruriception. To unravel the signaling paths, we assessed the localization of candidate genes and itching behavior in knockout models addressing LPAR5, LPAR2, autotaxin/ENPP2 and the lysophospholipid phosphatases, as well as the plasticity-related genes Prg1/LPPR4 and Prg2/LPPR3. LacZ reporter studies and RNAscope revealed LPAR5 in neurons of the dorsal root ganglia (DRGs) and in skin keratinocytes, LPAR2 in cortical and thalamic neurons, and Prg1 in neuronal structures of the dorsal horn, thalamus and SSC. HCQ-evoked scratching behavior was reduced in sensory neuron-specific Advillin-LPAR5-/- mice (peripheral) but increased in LPAR2-/- and Prg1-/- mice (central), and it was not affected by deficiency of glial autotaxin (GFAP-ENPP2-/-) or Prg2 (PRG2-/-). Heat and mechanical nociception were not affected by any of the genotypes. The behavior suggested that HCQ-mediated itch involves the activation of peripheral LPAR5, which was supported by reduced itch upon treatment with an LPAR5 antagonist and autotaxin inhibitor. Further, HCQ-evoked calcium fluxes were reduced in primary sensory neurons of Advillin-LPAR5-/- mice. The results suggest that LPA-mediated itch is primarily mediated via peripheral LPAR5, suggesting that a topical LPAR5 blocker might suppress "non-histaminergic" itch.
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Affiliation(s)
- Caroline Fischer
- Institute for Clinical Pharmacology, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt am Main, Germany; (C.F.); (D.T.); (G.G.)
| | - Yannick Schreiber
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, 60596 Frankfurt am Main, Germany;
| | - Robert Nitsch
- Institute for Translational Neuroscience, Medical Faculty, WWU Münster, 48149 Münster, Germany;
| | - Johannes Vogt
- Department of Molecular and Translational Neurosciences, Institute for Anatomy and Center of Molecular Medicine Cologne (CMMC), and Cologne Excellence Cluster for Aging associated Diseases (CECAD), University of Cologne, 50923 Köln, Germany;
| | - Dominique Thomas
- Institute for Clinical Pharmacology, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt am Main, Germany; (C.F.); (D.T.); (G.G.)
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, 60596 Frankfurt am Main, Germany;
| | - Gerd Geisslinger
- Institute for Clinical Pharmacology, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt am Main, Germany; (C.F.); (D.T.); (G.G.)
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, 60596 Frankfurt am Main, Germany;
- Fraunhofer Cluster of Excellence of Immune Mediated Diseases (CIMD), 60596 Frankfurt am Main, Germany
| | - Irmgard Tegeder
- Institute for Clinical Pharmacology, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt am Main, Germany; (C.F.); (D.T.); (G.G.)
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15
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Drazilova S, Koky T, Macej M, Janicko M, Simkova D, Tsedendamba A, Komarova S, Jarcuska P. Pruritus, Fatigue, Osteoporosis and Dyslipoproteinemia in Pbc Patients: A Clinician’s Perspective. GASTROENTEROLOGY INSIGHTS 2024; 15:419-432. [DOI: 10.3390/gastroent15020030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2025] Open
Abstract
In this review article, we summarize the most common clinical manifestations of Primary biliary cholangitis (PBC): pruritus, fatigue, osteoporosis, and dyslipoproteinemia and discuss their impact of the patients’ quality of life. More than half of PBC patients suffer from pruritus or fatigue at the time of diagnosis. We discuss the pathophysiological aspects of the PBC clinical manifestations and treatment options. The pathophysiology of pruritus and fatigue is not adequately elucidated, but IL-31 is associated with the severity of pruritus and could be used to objectify the subjective reporting by questionnaires. Although PBC patients suffer from atherogenic dyslipidemia, they do not seem to have a higher cardiovascular risk; however, this observation needs to be clarified by further clinical studies. The second-line of PBC treatment affects pruritus severity: Obeticholic acid (OCA) worsens pruritus while fibrates improve it. Itching can be alleviated by both non-pharmacological and pharmacological approach, however the are multiple barriers to pharmacological treatment. There is no adequate treatment for fatigue today. Treatment of osteoporosis and dyslipidemia is similar for non-PBC patients; stage of liver disease should be considered in treatment. Further research to clarify the pathophysiology and to eventually discover an effective treatment to improve survival and quality of life (especially pruritus and fatigue) in PBC patients is needed.
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Affiliation(s)
- Sylvia Drazilova
- 2nd Department of Internal Medicine, Faculty of Medicine, Louis Pasteur University Hospital, Pavol Jozef Safarik University, Trieda SNP 1, 040 11 Kosice, Slovakia
| | - Tomas Koky
- 2nd Department of Internal Medicine, Faculty of Medicine, Louis Pasteur University Hospital, Pavol Jozef Safarik University, Trieda SNP 1, 040 11 Kosice, Slovakia
| | - Marian Macej
- 2nd Department of Internal Medicine, Faculty of Medicine, Louis Pasteur University Hospital, Pavol Jozef Safarik University, Trieda SNP 1, 040 11 Kosice, Slovakia
| | - Martin Janicko
- 2nd Department of Internal Medicine, Faculty of Medicine, Louis Pasteur University Hospital, Pavol Jozef Safarik University, Trieda SNP 1, 040 11 Kosice, Slovakia
| | - Dagmar Simkova
- Department of Hepatogastroenterology, Institute for Clinical and Experimental Medicine IKEM, Videnska 1921, 140 21 Prague, Czech Republic
| | - Ariunzaya Tsedendamba
- 2nd Department of Internal Medicine, Faculty of Medicine, Louis Pasteur University Hospital, Pavol Jozef Safarik University, Trieda SNP 1, 040 11 Kosice, Slovakia
| | - Slavomira Komarova
- 2nd Department of Internal Medicine, Faculty of Medicine, Louis Pasteur University Hospital, Pavol Jozef Safarik University, Trieda SNP 1, 040 11 Kosice, Slovakia
| | - Peter Jarcuska
- 2nd Department of Internal Medicine, Faculty of Medicine, Louis Pasteur University Hospital, Pavol Jozef Safarik University, Trieda SNP 1, 040 11 Kosice, Slovakia
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16
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Gairola A, Wetten A, Dyson J. Sodium/bile acid co-transporter inhibitors currently in preclinical or early clinical development for the treatment of primary biliary cholangitis. Expert Opin Investig Drugs 2024; 33:485-495. [PMID: 38613839 DOI: 10.1080/13543784.2024.2343789] [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: 01/25/2024] [Accepted: 04/12/2024] [Indexed: 04/15/2024]
Abstract
INTRODUCTION Pruritus is common and often undertreated in patients with primary biliary cholangitis (PBC). Existing treatments largely have an aging and low-quality evidence base, and studies included only small numbers of patients. More recent data that has added to our understanding of pruritus treatments has often come from clinical trials where itching was a secondary outcome measure in a trial designed primarily to assess disease-modifying agents. This area represents an unmet clinical need in the management of PBC. AREAS COVERED In this manuscript, we first summarize the proposed mechanisms for PBC-related pruritus and the current treatment paradigm. We then present an appraisal of the existing pre-clinical and clinical evidence for the use of ileal bile acid transporter inhibitors (IBATis) for this indication in PBC patients. EXPERT OPINION Evidence for the efficacy of IBATis is promising but limited by the currently available volume of data. Furthermore, larger clinical trials with long-term data on efficacy, safety and tolerability are needed to confirm the role of using IBATis in clinical practice and their place on the itch treatment ladder. Additional focus should also be given to exploring the disease-modifying potential of IBATis in PBC.
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Affiliation(s)
- Abhishek Gairola
- Liver Unit, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK
| | - Aaron Wetten
- Liver Unit, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK
- Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle, UK
| | - Jessica Dyson
- Liver Unit, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle, UK
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17
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Kode V, Yimam KK. Cholestatic Pruritus: Pathophysiology, Current Management Approach, and Emerging Therapies. CURRENT HEPATOLOGY REPORTS 2024; 23:123-136. [DOI: 10.1007/s11901-024-00638-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 01/08/2024] [Indexed: 01/06/2025]
Abstract
Abstract
Purpose of Review
Cholestatic pruritus refers to the sensation of itch experienced by patients with disease processes impairing bile flow. This article aims to illustrate the burden of cholestatic pruritus, review the proposed mechanisms, and summarize its available and emerging therapies.
Recent Findings
Pruritus is experienced by many patients with cholestatic liver diseases. It is underdiagnosed and negatively impacts patients’ quality of life. Its direct cause remains unclear though multiple pathways have been explored. Current therapies are insufficient but newly approved ileal bile acid transporter (IBAT) inhibitors and emerging peroxisome proliferator-activated receptor (PPAR) agonists are promising.
Summary
Cholestatic pruritus affects many patients with cholestatic liver diseases and can be debilitating. In moderate to severe cases, current guidelines provide treatment options that are ineffective. Emerging agents such as IBAT inhibitors and PPAR agonists should be considered, including referral to clinical trials. Further exploration into the pathophysiology and effective therapeutic agents is needed.
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18
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Faisal MS, Gonzalez HC, Gordon SC. Primary Biliary Cholangitis: Epidemiology, Diagnosis, and Presentation. Clin Liver Dis 2024; 28:63-77. [PMID: 37945163 DOI: 10.1016/j.cld.2023.06.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2023]
Abstract
Using ursodeoxycholic acid as a standard treatment and for its ability to test for antimitochondrial antibody to accelerate diagnosis, survival of primary biliary cholangitis patients has approached that of the general population, leading to a change in nomenclature from primary biliary cirrhosis to primary biliary cholangitis to more accurately describe the disease.
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Affiliation(s)
- Muhammad Salman Faisal
- Department of Gastroenterology and Hepatology, Henry Ford Health, 2799 West Grand Boulevard, Detroit, MI 48202, USA
| | - Humberto C Gonzalez
- Department of Gastroenterology and Hepatology, Henry Ford Health, 2799 West Grand Boulevard, Detroit, MI 48202, USA; Wayne State University School of Medicine, 540 East Canfield Street, Detroit, MI 48201, USA
| | - Stuart C Gordon
- Department of Gastroenterology and Hepatology, Henry Ford Health, 2799 West Grand Boulevard, Detroit, MI 48202, USA; Wayne State University School of Medicine, 540 East Canfield Street, Detroit, MI 48201, USA.
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19
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Faisal A. Understanding fatigue and pruritus in primary biliary cholangitis. Clin Liver Dis (Hoboken) 2024; 23:e0216. [PMID: 38831766 PMCID: PMC11146472 DOI: 10.1097/cld.0000000000000216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 04/08/2024] [Indexed: 06/05/2024] Open
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20
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Marenco-Flores A, Sierra L, Goyes D, Kahan T, Patwardhan VR, Bonder A. Managing pruritus in chronic liver disease: An in-depth narrative review. Clin Liver Dis (Hoboken) 2024; 23:e0187. [PMID: 38872783 PMCID: PMC11168844 DOI: 10.1097/cld.0000000000000187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Accepted: 03/20/2024] [Indexed: 06/15/2024] Open
Affiliation(s)
- Ana Marenco-Flores
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - Leandro Sierra
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - Daniela Goyes
- Department of Internal Medicine, Division of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut, USA
| | - Tamara Kahan
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - Vilas R. Patwardhan
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - Alan Bonder
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
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21
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Tan N, Lubel J, Kemp W, Roberts S, Majeed A. Current Therapeutics in Primary Sclerosing Cholangitis. J Clin Transl Hepatol 2023; 11:1267-1281. [PMID: 37577219 PMCID: PMC10412694 DOI: 10.14218/jcth.2022.00068s] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Revised: 01/01/2023] [Accepted: 01/20/2023] [Indexed: 07/03/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) is an orphan, cholestatic liver disease that is characterized by inflammatory biliary strictures with variable progression to end-stage liver disease. Its pathophysiology is poorly understood. Chronic biliary inflammation is likely driven by immune dysregulation, gut dysbiosis, and environmental exposures resulting in gut-liver crosstalk and bile acid metabolism disturbances. There is no proven medical therapy that alters disease progression in PSC, with the commonly prescribed ursodeoxycholic acid being shown to improve liver biochemistry at low-moderate doses (15-23 mg/kg/day) but not alter transplant-free survival or liver-related outcomes. Liver transplantation is the only option for patients who develop end-stage liver disease or refractory complications of PSC. Immunosuppressive and antifibrotic agents have not proven to be effective, but there is promise for manipulation of the gut microbiome with fecal microbiota transplantation and antibiotics. Bile acid manipulation via alternate synthetic bile acids such as norursodeoxycholic acid, or interaction at a transcriptional level via nuclear receptor agonists and fibrates have shown potential in phase II trials in PSC with several leading to larger phase III trials. In view of the enhanced malignancy risk, statins, and aspirin show potential for reducing the risk of colorectal cancer and cholangiocarcinoma in PSC patients. For patients who develop clinically relevant strictures with cholestatic symptoms and worsening liver function, balloon dilatation is safer compared with biliary stent insertion with equivalent clinical efficacy.
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Affiliation(s)
- Natassia Tan
- Department of Gastroenterology and Hepatology, Alfred Health; Central Clinical School, Monash University, Melbourne, Australia
| | - John Lubel
- Department of Gastroenterology and Hepatology, Alfred Health; Central Clinical School, Monash University, Melbourne, Australia
| | - William Kemp
- Department of Gastroenterology and Hepatology, Alfred Health; Central Clinical School, Monash University, Melbourne, Australia
| | - Stuart Roberts
- Department of Gastroenterology and Hepatology, Alfred Health; Central Clinical School, Monash University, Melbourne, Australia
| | - Ammar Majeed
- Department of Gastroenterology and Hepatology, Alfred Health; Central Clinical School, Monash University, Melbourne, Australia
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22
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Bowlus CL, Eksteen B, Cheung AC, Thorburn D, Moylan CA, Pockros PJ, Forman LM, Dorenbaum A, Hirschfield GM, Kennedy C, Jaecklin T, McKibben A, Chien E, Baek M, Vig P, Levy C. Safety, tolerability, and efficacy of maralixibat in adults with primary sclerosing cholangitis: Open-label pilot study. Hepatol Commun 2023; 7:02009842-202306010-00003. [PMID: 37184523 DOI: 10.1097/hc9.0000000000000153] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Accepted: 03/16/2023] [Indexed: 05/16/2023] Open
Abstract
BACKGROUND Primary sclerosing cholangitis (PSC) is frequently associated with pruritus, which significantly impairs quality of life. Maralixibat is a selective ileal bile acid transporter (IBAT) inhibitor that lowers circulating bile acid (BA) levels and reduces pruritus in cholestatic liver diseases. This is the first proof-of-concept study of IBAT inhibition in PSC. METHODS This open-label study evaluated the safety and tolerability of maralixibat ≤10 mg/d for 14 weeks in adults with PSC. Measures of pruritus, biomarkers of BA synthesis, cholestasis, and liver function were also assessed. RESULTS Of 27 enrolled participants, 85.2% completed treatment. Gastrointestinal treatment-emergent adverse events (TEAEs) occurred in 81.5%, with diarrhea in 51.9%. TEAEs were mostly mild or moderate (63.0%); 1 serious TEAE (cholangitis) was considered treatment related. Mean serum BA (sBA) levels decreased by 16.7% (-14.84 µmol/L; 95% CI, -27.25 to -2.43; p = 0.0043) by week 14/early termination (ET). In participants with baseline sBA levels above normal (n = 18), mean sBA decreased by 40.0% (-22.3 µmol/L, 95% CI, -40.38 to -4.3; p = 0.004) by week 14/ET. Liver enzyme elevations were not significant; however, increases of unknown clinical significance in conjugated bilirubin levels were observed. ItchRO weekly sum scores decreased from baseline to week 14/ET by 8.4% (p = 0.0495), by 12.6% (p = 0.0275) in 18 participants with pruritus at baseline, and by 70% (p = 0.0078) in 8 participants with ItchRO daily average score ≥3 at baseline. CONCLUSIONS Maralixibat was associated with reduced sBA levels in adults with PSC. In participants with more severe baseline pruritus, pruritus improved significantly from baseline. TEAEs were mostly gastrointestinal related. These results support further investigation of IBAT inhibitors for adults with PSC-associated pruritus. ClinicalTrials.gov: NCT02061540.
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Affiliation(s)
- Christopher L Bowlus
- Division of Gastroenterology and Hepatology, University of California Davis School of Medicine, Sacramento, California, USA
| | | | - Angela C Cheung
- Division of Gastroenterology, University of Ottawa, The Ottawa Hospital, Ottawa, Ontario, Canada
| | - Douglas Thorburn
- Sheila Sherlock Liver Centre, Royal Free Hospital and Institute of Liver and Digestive Health, University College London, Royal Free Campus, Hampstead, London, UK
| | - Cynthia A Moylan
- Division of Gastroenterology and Hepatology, Duke University, Durham, North Carolina, USA
| | - Paul J Pockros
- Scripps Clinic and Scripps Translational Science Institute, La Jolla, California, USA
| | - Lisa M Forman
- Division of Gastroenterology-Hepatology, University of Colorado, Aurora, Colorado, USA
| | | | - Gideon M Hirschfield
- Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | | | | | | | - Elaine Chien
- Mirum Pharmaceuticals, Foster City, California, USA
| | | | - Pamela Vig
- Mirum Pharmaceuticals, Foster City, California, USA
| | - Cynthia Levy
- Division of Digestive Health and Liver Diseases, University of Miami Miller School of Medicine, Miami, Florida, USA
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23
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Rodrigo M, Dong X, Chien D, Karnsakul W. Cholestatic Pruritus in Children: Conventional Therapies and Beyond. BIOLOGY 2023; 12:biology12050756. [PMID: 37237568 DOI: 10.3390/biology12050756] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 05/12/2023] [Accepted: 05/18/2023] [Indexed: 05/28/2023]
Abstract
Pruritus in the setting of cholestatic liver disease is difficult to treat and occurs in patients ranging in age from infancy to adulthood. Likely multifactorial in etiology, this symptom often involves multimodal therapy targeting several pathways and mechanisms proposed in the underlying etiology of cholestatic pruritus. Many patients in both the pediatric and adult populations continue to experience unrelenting pruritus despite maximal conventional therapy. Options are further limited in treating pediatric patients due to sparse data regarding medication safety and efficacy in younger patients. Conventional therapies for the treatment of cholestatic pruritus in children include ursodeoxycholic acid, cholestyramine, hydroxyzine, and rifampin. Certain therapies are more routinely used in the adult populations but with limited data available for use in child and adolescent patients, including opioid antagonists and selective serotonin reuptake inhibitors. Recently, ileal bile acid transport inhibitors have been shown to alleviate pruritus in many children with Alagille syndrome and progressive familial intrahepatic cholestasis and is an additional therapy available for consideration for these patients. Ultimately, surgical options such as biliary diversion or liver transplantation are considered in specific circumstances when medical therapies have been exhausted and pruritus remains debilitating. While further investigation regarding underlying etiologies and effective therapies are needed to better understand itch pathogenesis and treatment in pediatric cholestasis, current considerations beyond conventional management include the use of opioid antagonists, selective serotonin reuptake inhibitors, ileal bile acid transport inhibitors, and surgical intervention.
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Affiliation(s)
- Minna Rodrigo
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Xinzhong Dong
- Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Daphne Chien
- Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Wikrom Karnsakul
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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24
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Tsuchida R, Nishizawa D, Fukuda KI, Ichinohe T, Kano K, Kurano M, Ikeda K, Sumitani M. Genetic Polymorphisms of ENPP2 Are Possibly Associated with Pain Severity and Opioid Dose Requirements in Patients with Inflammatory Pain Conditions: Clinical Observation Study. Int J Mol Sci 2023; 24:ijms24086986. [PMID: 37108150 PMCID: PMC10139129 DOI: 10.3390/ijms24086986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 04/03/2023] [Accepted: 04/06/2023] [Indexed: 04/29/2023] Open
Abstract
Autotaxin, encoded by the ENPP2 gene, is a known key element of neuropathic pain; however, its involvement in nociceptive pain processing remains unclear. We explored the associations between postoperative pain intensity, 24-h postoperative opioid dose requirements, and 93 ENNP2-gene single-nucleotide polymorphisms (SNPs) in 362 healthy patients who underwent cosmetic surgery using the dominant, recessive, and genotypic models. Next, we validated the associations between relevant SNPs on the one hand and pain intensity and daily opioid dosages on the other in 89 patients with cancer-related pain. In this validation study, a Bonferroni correction for multiplicity was applied on all relevant SNPs of the ENPP2 gene and their respective models. In the exploratory study, three models of two SNPs (rs7832704 and rs2249015) were significantly associated with postoperative opioid doses, although the postoperative pain intensity was comparable. In the validation study, the three models of the two SNPs were also significantly associated with cancer pain intensity (p < 0.017). Patients with a minor allele homozygosity complained of more severe pain compared with patients with other genotypes when using comparable daily opioid doses. Our findings might suggest that autotaxin is associated with nociceptive pain processing and the regulation of opioid requirements.
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Affiliation(s)
- Rikuhei Tsuchida
- Department of Anesthesiology and Pain Relief Center, The University of Tokyo Hospital, Hongo 7-3-1, Bunkyoku, Tokyo 113-8655, Japan
| | - Daisuke Nishizawa
- Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Kami Kitazawa 2-1-6, Setagayaku, Tokyo 156-0057, Japan
| | - Ken-Ichi Fukuda
- Department of Oral Health and Clinical Science, Tokyo Dental College, Kanda Misakichou 2-9-18, Chiyodaku, Tokyo 101-0061, Japan
| | - Tatsuya Ichinohe
- Department of Dental Anesthesiology, Tokyo Dental College, Kanda Misakichou 2-9-18, Chiyodaku, Tokyo 101-0061, Japan
| | - Kuniyuki Kano
- Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo 7-3-1, Bunkyoku, Tokyo 113-8655, Japan
| | - Makoto Kurano
- Department of Clinical Laboratory Medicine, The University of Tokyo Hospital, Hongo 7-3-1, Bunkyoku, Tokyo 113-8655, Japan
| | - Kazutaka Ikeda
- Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Kami Kitazawa 2-1-6, Setagayaku, Tokyo 156-0057, Japan
| | - Masahiko Sumitani
- Department of Pain and Palliative Medicine, The University of Tokyo Hospital, Hongo 7-3-1, Bunkyoku, Tokyo 113-8655, Japan
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25
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Colapietro F, Gershwin ME, Lleo A. PPAR agonists for the treatment of primary biliary cholangitis: Old and new tales. J Transl Autoimmun 2023; 6:100188. [PMID: 36684809 PMCID: PMC9850184 DOI: 10.1016/j.jtauto.2023.100188] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 12/30/2022] [Accepted: 01/02/2023] [Indexed: 01/06/2023] Open
Abstract
INTRODUCTION Primary biliary cholangitis (PBC) is an autoimmune liver disease involving the small intrahepatic bile ducts; when untreated or undertreated, it may evolve to liver fibrosis and cirrhosis. Ursodeoxycholic Acid (UDCA) is the standard of care treatment, Obeticholic Acid (OCA) has been approved as second-line therapy for those non responder or intolerant to UDCA. However, due to moderate rate of UDCA-non responders and to warnings recently issued against OCA use in patients with cirrhosis, further therapies are needed.Areas covered. Deep investigations into the pathogenesis of PBC is leading to proposal of new therapeutic agents, among which peroxisome proliferator-activated receptor (PPAR) ligands seem to be highly promising given the preliminary, positive results in Phase 2 and 3 trials. Bezafibrate, the most evaluated, is currently used in clinical practice in combination with UDCA in referral centers. We herein describe completed and ongoing trials involving PPAR agonists use in PBC, analyzing pits and falls. EXPERT OPINION Testing new therapeutic opportunities in PBC is challenging due to its low prevalence and slow progression. However, new drugs including PPAR agonists, are currently under investigation and should be considered for at-risk PBC patients.
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Key Words
- AEs, adverse events
- AIH, Autoimmune Hepatitis
- ALP, Alkaline Phosphatase
- AMA, Antimitochondrial antibodies
- BZF, Bezafibrate
- CKD, chronic kidney disease
- Elafibranor
- FDA, Food and Drug
- FF, Fenofibrate
- FXR, Farnesoid X Receptor
- Fibrates
- GGT, γ-glutamil transferase
- HCC, Hepatocellular Carcinoma
- HDL, high-density lipoprotein
- HR, Hazard Ratio
- HSC, Hepatic Stellate Cells
- IL-1β, Interleukin-1
- IgM, Immunoglobulin M
- LDL, low-density- lipoprotein
- LT, Liver Transplant
- MDR3, multidrug resistance protein 3
- NASH, Non Alcoholic Steato-Hepatits
- NRS, Numerical Raing Scale
- OCA, Obeticholic Acid
- OR, Odds Ratio
- PAR, protease-activated receptors
- PBC, Primary Biliary Cholangitis
- PC, phosphatidylcholine
- PH, Portal Hypertension
- PPAR agonists
- PPAR, peroxisome proliferator-activated receptor
- Primary biliary cholangitis
- QoL, Quality of Life
- RCT, randomized controlled trial
- SAE, Severe Adverse Event
- Saroglitazar
- Seladelpar
- TGR, transmembrane G protein-coupled receptor
- TLR, Toll Like Receptor
- TNF-α, Tumor Necrosis Factor- α
- UDCA
- UDCA, ursodeoxycholic acid
- UK, United Kingdom
- ULN, upper limit of normal
- VAS, Visual Analogue Scale
- VRS, Verbal Rating Scale
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Affiliation(s)
- Francesca Colapietro
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, Humanitas Research Hospital IRCCS, Rozzano, Milan, Italy
| | - M. Eric Gershwin
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California at Davis, Davis, CA, USA
| | - Ana Lleo
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, Humanitas Research Hospital IRCCS, Rozzano, Milan, Italy
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26
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Mechanisms of pruritus in cholestasis: understanding and treating the itch. Nat Rev Gastroenterol Hepatol 2023; 20:26-36. [PMID: 36307649 DOI: 10.1038/s41575-022-00687-7] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/07/2022] [Indexed: 02/01/2023]
Abstract
Pruritus in cholestatic liver diseases can be a major burden and dramatically impair the quality of life of those affected. Here, we provide an update on the latest insights into the molecular pathogenesis of and novel therapeutic approaches for cholestasis-associated itch. Endogenous and exogenous small-molecule pruritogen candidates bind to their receptors on unmyelinated itch C-fibres in the skin. Candidate pruritogens in cholestasis include certain lysophospholipids and sulfated progesterone metabolites, among others, whereas total bile acid or bilirubin conjugates seem unlikely to have a dominant role in the pathogenesis of cholestasis-associated pruritus. Transmission of itch signals via primary, secondary and tertiary itch neurons to the postcentral gyrus and activation of scratch responses offer various targets for therapeutic intervention. At present, evidence-based treatment options for pruritus in fibrosing cholangiopathies, such as primary biliary cholangitis and primary sclerosing cholangitis, are the peroxisome proliferator-associated receptor (PPAR) agonist bezafibrate and the pregnane X receptor (PXR) agonist rifampicin. In pruritus of intrahepatic cholestasis of pregnancy, ursodeoxycholic acid is recommended and might be supported in the third trimester by rifampicin if needed. Alternatively, non-absorbable anion exchange resins, such as cholestyramine, can be administered, albeit with poor trial evidence. Liver transplantation for intolerable refractory pruritus has become an extremely rare therapeutic strategy.
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Xu J, Wang Y, Khoshdeli M, Peach M, Chuang J, Lin J, Tsai W, Mahadevan S, Minto W, Diehl L, Gupta R, Trauner M, Patel K, Noureddin M, Kowdley KV, Gulamhusein A, Bowlus CL, Huss RS, Myers RP, Chung C, Billin AN. IL-31 levels correlate with pruritus in patients with cholestatic and metabolic liver diseases and is farnesoid X receptor responsive in NASH. Hepatology 2023; 77:20-32. [PMID: 35686937 PMCID: PMC9970017 DOI: 10.1002/hep.32599] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 05/03/2022] [Accepted: 05/12/2022] [Indexed: 02/03/2023]
Abstract
BACKGROUND AND AIMS Pruritus is associated with multiple liver diseases, particularly those with cholestasis, but the mechanism remains incompletely understood. Our aim was to evaluate serum IL-31 as a putative biomarker of pruritus in clinical trials of an farnesoid X receptor (FXR) agonist, cilofexor, in patients with NASH, primary sclerosing cholangitis (PSC), and primary biliary cholangitis (PBC). APPROACH AND RESULTS Serum IL-31 was measured in clinical studies of cilofexor in NASH, PSC, and PBC. In patients with PSC or PBC, baseline IL-31 was elevated compared to patients with NASH and healthy volunteers (HVs). IL-31 correlated with serum bile acids among patients with NASH, PBC, and PSC. Baseline IL-31 levels in PSC and PBC were positively correlated with Visual Analog Scale for pruritus and 5-D itch scores. In patients with NASH, cilofexor dose-dependently increased IL-31 from Week (W)1 to W24. In patients with NASH receiving cilofexor 100 mg, IL-31 was higher in those with Grade 2-3 pruritus adverse events (AEs) than those with Grade 0-1 pruritus AEs. IL-31 weakly correlated with C4 at baseline in patients with NASH, and among those receiving cilofexor 100 mg, changes in IL-31 and C4 from baseline to W24 were negatively correlated. IL-31 messenger RNA (mRNA) was elevated in hepatocytes from patients with PSC and NASH compared to HVs. In a humanized liver murine model, obeticholic acid increased IL-31 mRNA expression in human hepatocytes and serum levels of human IL-31. CONCLUSIONS IL-31 levels correlate with pruritus in patients with cholestatic disease and NASH, with FXR agonist therapy resulting in higher serum levels in the latter group. IL-31 appears to derive in part from increased hepatocyte expression. These findings have therapeutic implications for patients with liver disease and pruritus.
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Affiliation(s)
- Jun Xu
- Gilead Sciences, Inc., Foster City, California, USA
| | - Ya Wang
- Gilead Sciences, Inc., Foster City, California, USA
| | | | - Matt Peach
- Gilead Sciences, Inc., Foster City, California, USA
| | | | - Julie Lin
- Gilead Sciences, Inc., Foster City, California, USA
| | - Wen‐Wei Tsai
- Gilead Sciences, Inc., Foster City, California, USA
| | | | - Wesley Minto
- Gilead Sciences, Inc., Foster City, California, USA
| | - Lauri Diehl
- Gilead Sciences, Inc., Foster City, California, USA
| | - Ruchi Gupta
- Gilead Sciences, Inc., Foster City, California, USA
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Keyur Patel
- University of Toronto, Toronto, Ontario, Canada
| | - Mazen Noureddin
- Fatty Liver Program, Cedars‐Sinai Medical Center, Los Angeles, California, USA
| | | | | | | | - Ryan S. Huss
- Gilead Sciences, Inc., Foster City, California, USA
| | | | - Chuhan Chung
- Gilead Sciences, Inc., Foster City, California, USA
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28
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Schramm C, Wedemeyer H, Mason A, Hirschfield GM, Levy C, Kowdley KV, Milkiewicz P, Janczewska E, Malova ES, Sanni J, Koo P, Chen J, Choudhury S, Klickstein LB, Badman MK, Jones D. Farnesoid X receptor agonist tropifexor attenuates cholestasis in a randomised trial in patients with primary biliary cholangitis. JHEP Rep 2022; 4:100544. [PMID: 36267872 PMCID: PMC9576902 DOI: 10.1016/j.jhepr.2022.100544] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 07/12/2022] [Indexed: 11/17/2022] Open
Abstract
Background & Aims The safety, tolerability, and efficacy of the non-bile acid farnesoid X receptor agonist tropifexor were evaluated in a phase II, double-blind, placebo-controlled study as potential second-line therapy for patients with primary biliary cholangitis (PBC) with an inadequate ursodeoxycholic acid response. Methods Patients were randomised (2:1) to receive tropifexor (30, 60, 90, or 150 μg) or matched placebo orally once daily for 28 days, with follow-up on Days 56 and 84. Primary endpoints were safety and tolerability of tropifexor and reduction in levels of γ-glutamyl transferase (GGT) and other liver biomarkers. Other objectives included patient-reported outcome measures using the PBC-40 quality-of-life (QoL) and visual analogue scale scores and tropifexor pharmacokinetics. Results Of 61 enrolled patients, 11, 9, 12, and 8 received 30-, 60-, 90-, and 150-μg tropifexor, respectively, and 21 received placebo; 3 patients discontinued treatment because of adverse events (AEs) in the 150-μg tropifexor group. Pruritus was the most frequent AE in the study (52.5% [tropifexor] vs. 28.6% [placebo]), with most events of mild to moderate severity. Decreases seen in LDL-, HDL-, and total-cholesterol levels at 60-, 90-, and 150 μg doses stabilised after treatment discontinuation. By Day 28, tropifexor caused 26-72% reduction in GGT from baseline at 30- to 150-μg doses (p <0.001 at 60-, 90-, and 150-μg tropifexor vs. placebo). Day 28 QoL scores were comparable between the placebo and tropifexor groups. A dose-dependent increase in plasma tropifexor concentration was observed, with 5- to 5.55-fold increases in AUC0-8h and Cmax between 30- and 150-μg doses. Conclusions Tropifexor showed improvement in cholestatic markers relative to placebo, predictable pharmacokinetics, and an acceptable safety-tolerability profile, thereby supporting its potential further clinical development for PBC. Lay summary The bile acid ursodeoxycholic acid (UDCA) is the standard-of-care therapy for primary biliary cholangitis (PBC), but approximately 40% of patients have an inadequate response to this therapy. Tropifexor is a highly potent non-bile acid agonist of the farnesoid X receptor that is under clinical development for various chronic liver diseases. In the current study, in patients with an inadequate response to UDCA, tropifexor was found to be safe and well tolerated, with improved levels of markers of bile duct injury at very low (microgram) doses. Itch of mild to moderate severity was observed in all groups including placebo but was more frequent at the highest tropifexor dose. Clinical Trials Registration This study is registered at ClinicalTrials.gov (NCT02516605).
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Key Words
- AE, adverse event
- ALP, alkaline phosphatase
- ALT, alanine aminotransferase
- AUC, area under the concentration–time curve
- C4, 7-alpha-hydroxy-4-cholesten-3-one
- CL/F,ss, the apparent systemic clearance following oral administration at steady state
- Cmax, maximum plasma concentration
- FGF19, fibroblast growth factor 19
- FXR, farnesoid X receptor
- Farnesoid X receptor
- GGT, γ-glutamyl transferase
- HDL, high-density lipoprotein
- LDL, low-density lipoprotein
- NASH, non-alcoholic steatohepatitis
- OCA, obeticholic acid
- PBC, primary biliary cholangitis
- PD, pharmacodynamic
- PRO, patient-reported outcome
- Primary biliary cholangitis
- Proof of concept
- Pruritus
- QoL, quality of life
- Racc, accumulation ratio
- SAE, serious adverse event
- Tmax, time to reach Cmax
- Tropifexor
- ULN, upper limit of normal
- VAS, visual analogue scale
- pBAD, primary bile acid diarrhoea
- qd, once daily
- γ-Glutamyl transferase
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Affiliation(s)
- Christoph Schramm
- Medizinische Klinik und Poliklinik Universitätsklinikum Hamburg Eppendorf, Hamburg, Germany.,Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,Hamburg Center of Translational Immunology, Hamburg, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology and Hepatology, Essen University Hospital, Essen, Germany
| | - Andrew Mason
- Division of Gastroenterology, University of Alberta, Edmonton, AB, Canada
| | - Gideon M Hirschfield
- Toronto Centre for Liver Disease, Department of Medicine, University of Toronto, Toronto, ON, Canada
| | - Cynthia Levy
- University of Miami, Schiff Center for Liver Diseases, Miami, FL, USA
| | - Kris V Kowdley
- Liver Institute Northwest, Washington State University, Seattle, WA, USA
| | - Piotr Milkiewicz
- Liver and Internal Medicine Unit, Medical University of Warsaw, Warsaw, Poland.,Translational Medicine Group, Pomeranian Medical University, Szczecin, Poland
| | - Ewa Janczewska
- ID Clinic, Myslowice Poland.,Department of Basic Medical Sciences, School of Health Sciences in Bytom, Medical University of Silesia, Bytom, Poland
| | | | - Johanne Sanni
- Novartis Institutes for Biomedical Research, Basel, Switzerland.,Sannity Consulting Ltd, Worthing, UK
| | - Phillip Koo
- Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA
| | - Jin Chen
- Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA
| | | | | | | | - David Jones
- The Newcastle Upon Tyne Hospitals, NHS Foundation Trust, Royal Victoria Infirmary, Newcastle, UK
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29
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Abstract
Chronic pruritus is a classic symptom in patients with primary biliary cholangitis. It affects up to two-thirds of patients in the course of the disease. Efficient therapy consists of topical treatment combined with systemic options such as anion exchangers, rifampicin, bezafibrate, μ-opioid receptor antagonists, selective-serotonin receptor uptake inhibitors, and gabapentinoids. Future therapeutic approaches may contain the selective blockade of the enterohepatic cycle by inhibiting the ileal bile acid transporter, the agonism at κ-opioid receptors, and antagonism of the mas-related G protein-coupled receptor X4. As nondrug treatment, ultraviolet B therapy, albumin dialysis, and biliary drainage are available at specialized centers.
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Affiliation(s)
- Miriam M Düll
- Department of Medicine 1, Gastroenterology, Hepatology, Pneumology, Endocrinology, University Hospital Erlangen and Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Ulmenweg 18, 91054 Erlangen, Germany
| | - Andreas E Kremer
- Department of Gastroenterology and Hepatology, Universitäts Spital Zürich, Rämistrasse 100, 8091 Zürich, Switzerland.
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30
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Süzen Çaypınar S, Oğlak SC, Behram M, Gedik Özköse Z, Sezer S, Karakaş S. Serum autotaxin levels correlate with the severity of pruritus in intrahepatic cholestasis of pregnancy. J Obstet Gynaecol Res 2022; 48:3093-3102. [PMID: 36164271 DOI: 10.1111/jog.15444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 08/25/2022] [Accepted: 09/14/2022] [Indexed: 11/28/2022]
Abstract
PURPOSE This study aimed to examine autotaxin (ATX) concentrations in the serum of pregnant women complicated with intrahepatic cholestasis of pregnancy (ICP) and compare them with individuals with uncomplicated healthy pregnancies. METHODS This prospective case-control study took place with 83 pregnant women. The study group included 43 pregnant women presenting with a singleton pregnancy diagnosed with ICP in their third trimester of pregnancy. The diagnostic power of the ATX variable was examined by receiver operating characteristic analysis, and the cut-off value calculated according to the Youden index was summarized with the related sensitivity and specificity points. RESULTS The mean serum concentration of maternal ATX was significantly higher in the ICP cases (8.91 ± 2.69 pg/mL) compared to the pregnant women in the control group (3.59 ± 1.39 ng/mL, p < 0.001). According to the Youden index, a 5.80 ng/mL cut-off value of serum ATX concentrations can be used to diagnose ICP with 97.7% sensitivity and 97.5% specificity. A significant highly positive correlation was found between maternal serum ATX levels and maternal serum total bile acid levels (r = 0.633 and p < 0.001) and itch intensity, which was objectified by the visual analog scale score (r = 0.951 and p < 0.001). CONCLUSION Maternal serum ATX levels were significantly increased in ICP patients as compared with healthy pregnant women. Also, serum ATX activity was highly correlated with the itch intensity. We consider that ATX might represent a robust, accurate, and reliable circulating biomarker to diagnose ICP.
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Affiliation(s)
- Sema Süzen Çaypınar
- Department of Perinatology, Başakşehir Çam ve Sakura City Hospital, Istanbul, Turkey
| | - Süleyman Cemil Oğlak
- Department of Obstetrics and Gynecology, Health Sciences University, Gazi Yaşargil Training and Research Hospital, Diyarbakır, Turkey
| | - Mustafa Behram
- Department of Perinatology, Health Sciences University, Antalya Training and Research Hospital, Istanbul, Turkey
| | - Zeynep Gedik Özköse
- Department of Perinatology, Health Sciences University, Kanuni Sultan Süleyman Training and Research Hospital, Istanbul, Turkey
| | - Salim Sezer
- Department of Perinatology, Esenyurt University Hospital, Istanbul, Turkey
| | - Sema Karakaş
- Department of Gynecologic Oncology, Health Sciences University, Bakırköy Dr Sadi Konuk Training and Research Hospital, Istanbul, Turkey
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31
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Critical Players and Therapeutic Targets in Chronic Itch. Int J Mol Sci 2022; 23:ijms23179935. [PMID: 36077340 PMCID: PMC9456029 DOI: 10.3390/ijms23179935] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 08/28/2022] [Accepted: 08/29/2022] [Indexed: 12/04/2022] Open
Abstract
Chronic itch is one of the most prominent clinical characteristics of diverse systematic diseases. It is a devastating sensation in pathological diseases. Despite its importance, there are no FDA-labelled drugs specifically geared toward chronic itch. The associated complex pathogenesis and diverse causes escalate chronic itch to being one of the top challenges in healthcare. Humanized antibodies against IL-13, IL-4, and IL-31 proved effective in treatment of itch-associated atopic dermatitis but remain to be validated in chronic itch. There are still no satisfactory anti-itch therapeutics available toward itch-related neuropeptides including GRP, BNP, SST, CGRP, and SP. The newly identified potential itch targets including OSM, NMB, glutamate, periostin, and Serpin E1 have opened new avenues for therapeutic development. Proof-of-principle studies have been successfully performed on antagonists against these proteins and their receptors in itch treatment in animal models. Their translational interventions in humans need to be evaluated. It is of great importance to summarize and compare the newly emerging knowledge on chronic itch and its pathways to promote the development of novel anti-itch therapeutics. The goal of this review is to analyze the different physiologies and pathophysiologies of itch mediators, whilst assessing their suitability as new targets and discussing future therapeutic development.
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32
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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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van Munster KN, Dijkgraaf MGW, Oude Elferink RPJ, Beuers U, Ponsioen CY. Symptom patterns in the daily life of PSC patients. Liver Int 2022; 42:1562-1570. [PMID: 35396817 PMCID: PMC9325051 DOI: 10.1111/liv.15271] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Revised: 03/28/2022] [Accepted: 04/01/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Patients with primary sclerosing cholangitis (PSC) may suffer from complaints such as pruritus, right upper abdominal quadrant pain (RUQ-A) and fatigue. However, the severity of these complaints, daily and/or seasonal patterns and other factors of influence in PSC are largely unknown. The aim of this study is to assess daily symptoms and patterns thereof in PSC patients in their natural setting. METHODS A mobile application was designed according to the experience sampling method. Push notifications with a response time of max 4 h were sent during tiers of 3 months. Questions comprised VAS scales on degree of pruritus, fatigue, RUQ-A, time of the day these symptoms were worst, as well as time of intake of medication. Linear mixed modelling was used to identify patient- and external factors associated with pruritus, fatigue and RUQ-A pain. RESULTS A total of 6713 questionnaires were completed by 137 patients. Fatigue was the most prevalent symptom among PSC patients being reported in a striking 71% of measurements, followed by pruritus (38%). Both increased during the day and were associated with longer disease duration. A highly significant correlation between pruritus and day temperature was observed (ρ = -0.14, p = .000), and itch was generally worse during winter (p = .000). Patient preference for the tool was high. CONCLUSION Pruritus and fatigue are prevalent symptoms in the daily life of PSC patients and show a distinct diurnal pattern. This may have implications for efficient dosing of anti-pruritic agents. The level of pruritus is highly correlated with day temperature, which may have several implications.
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Affiliation(s)
- Kim N. van Munster
- Department of Gastroenterology and Hepatology, Amsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
| | | | - Ronald P. J. Oude Elferink
- Tytgat Laboratory for Liver and Intestinal DiseasesAmsterdam University Medical CentersUniversity of AmsterdamAmsterdamthe Netherlands
| | - Ulrich Beuers
- Department of Gastroenterology and Hepatology, Amsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
| | - Cyriel Y. Ponsioen
- Department of Gastroenterology and Hepatology, Amsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
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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: 6] [Impact Index Per Article: 2.0] [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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Bile acid metabolism and FXR-mediated effects in human cholestatic liver disorders. Biochem Soc Trans 2022; 50:361-373. [PMID: 35191955 DOI: 10.1042/bst20210658] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/28/2022] [Accepted: 02/07/2022] [Indexed: 02/06/2023]
Abstract
Intrahepatic cholestasis is the main feature of a group of liver diseases that are characterized by hepatic and systemic accumulation of bile acids due to impaired excretion of bile, based on inflammation of intrahepatic and extrahepatic bile ducts or dysfunction of hepatobiliary transport proteins. The nuclear bile acid sensor farnesoid X receptor (FXR) is central for the regulation of bile acid turnover, including synthesis, hepatic excretion and intestinal and hepatic uptake. Several drugs targeting FXR have been developed for the treatment of cholestatic liver diseases, and so far one of them has been granted conditional approval. In this review, we will discuss the current knowledge and the clinical and experimental data available on agents affecting FXR and bile acid turnover.
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Gallo C, Howardson BO, Cristoferi L, Carbone M, Gershwin ME, Invernizzi P. An Update on Novel Pharmacological Agents for Primary Sclerosing Cholangitis. Expert Opin Ther Targets 2022; 26:69-77. [PMID: 35040733 DOI: 10.1080/14728222.2022.2030707] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION : Primary sclerosing cholangitis (PSC) is a rare chronic cholestatic liver disease with heterogeneous phenotypes that may lead to liver transplantation and/or end-stage liver disease. Its multifactorial etiopathogenesis remains uncertain, but gut-liver axis and bile composition and excretion are widely demonstrated to influence the immune-mediated fibrogenic reactive cascade. AREAS COVERED : Different experimental therapeutic options are under investigation, mainly aiming at modulating bile acids excretion, limiting inflammatory-cascade reactions, and changing intestinal microbiota composition; none of them yet demonstrated to prolong transplant free survival. This review provides a comprehensive description of the experimental drugs recently tested and/or currently under investigation. A bibliographical search was performed in Pubmed, MEDLINE, EMBASE, OVID and clinicaltrial.gov until July 2021. EXPERT OPINION : The heterogeneity and poor prevalence of PSC, its uncertain pathophysiology, and the lack of surrogate endpoints are the major challenges in drug discovery. Strategies that synergistically target microbiota, bile acids, and liver fibrosis are needed. In parallel, we must enhance biomarker discovery to develop surrogate endpoints, as biochemical markers' fluctuations over the time hamper their effectiveness. Magnetic resonance cholangiopancreatography tools that accurately measure bile duct changes represent a potential, novel marker for disease monitoring. A collaboration between academia, research consortia, patient's associations and industry is required.
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Affiliation(s)
- Camilla Gallo
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Bright Oworae Howardson
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Laura Cristoferi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Marco Carbone
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - M Eric Gershwin
- Division of Rheumatology and Clinical Immunology, University of California at Davis School of Medicine, Davis California 95616 USA
| | - Pietro Invernizzi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
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Meinel K, Szabo D, Dezsofi A, Pohl S, Strini T, Greimel T, Aguiriano-Moser V, Haidl H, Wagner M, Schlagenhauf A, Jahnel J. The Covert Surge: Murine Bile Acid Levels Are Associated With Pruritus in Pediatric Autoimmune Sclerosing Cholangitis. Front Pediatr 2022; 10:903360. [PMID: 35633951 PMCID: PMC9130722 DOI: 10.3389/fped.2022.903360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 04/25/2022] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVES The exact etiology of pruritus in chronic cholestasis is unknown. Pruritus intensity does not correlate with common biochemical indices and there is a lack of biomarkers guiding diagnosis and treatment. We explored profiles of bile acids (BA) and muricholic acids (MCA) as well as autotaxin (ATX) antigen levels as potential circulating biomarkers of pruritus in pediatric patients. METHODS In 27 pediatric cholestatic patients [autoimmune sclerosing cholangitis (ASC) n = 20 (with pruritus n = 6, without pruritus n = 14); progressive familial intrahepatic cholestasis (PFIC) n = 7 (with pruritus n = 5, without pruritus n = 2)] and 23 age-matched controls pruritus was assessed by a visual analog scale of pruritus (PVAS). We obtained profiles of serum human BA including MCA using a mass-spectrometry assay and ATX antigen levels with a commercial ELISA. RESULTS PFIC and ASC patients exhibited significantly higher BA-, and MCA levels, than healthy controls, but only PFIC patients showed elevated ATX antigen levels higher [median: 1,650 ng/ml, interquartile rang (IQR): 776.9-3,742] compared to controls (median: 315.9 ng/ml, IQR: 251.1-417.2; PFIC p = 0.0003). ASC patients with pruritus showed only a minor increase in total BA (tBA) levels (median: 76.5 μmol/L, IQR: 54.7-205), but strikingly higher T-conjugated BA (median: 16.4 μmol/L, IQR: 8.9-41.4) and total MCA (tMCA) (median: 1.15 μmol/L, IQR: 0.77-2.44) levels compared to ASC patients without pruritus (tBA median: 24.3 μmol/L, IQR: 16.2-80.8; p < 0.0408; T-conjugated BA median: 1.3 μmol/L, IQR: 0.8-4.9; p = 0.0023; tMCA median: 0.30 μmol/L, IQR: 0.13-0.64, p = 0.0033). BA/MCA profiles distinctly differed depending on presence/absence of pruritus. Different from PFIC patients, ATX antigen levels were not significantly elevated in ASC patients with (median: 665.8 ng/ml, IQR: 357.8-1,203) and without pruritus (median: 391.0 ng/ml, IQR: 283.2-485.6). In ASC patients, tBA, tMCA, and ATX antigen levels did not correlate with pruritus severity. CONCLUSION Despite the same underlying disease, pediatric ASC patients with pruritus exhibit significantly altered BA profiles and MCA levels compared to ASC patients without pruritus. ATX antigen levels seem to have little diagnostic or prognostic meaning in ASC patients. An increased ATX activity alone seems not to be causal for pruritus genesis in ASC patients. CLINICAL TRIAL REGISTRATION [www.drks.de], identifier [DRKS00026913].
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Affiliation(s)
- Katharina Meinel
- Division of General Pediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
| | - Doloresz Szabo
- First Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Antal Dezsofi
- First Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Sina Pohl
- Division of General Pediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
| | - Tanja Strini
- Division of General Pediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
| | - Theresa Greimel
- Division of General Pediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
| | - Victor Aguiriano-Moser
- Division of General Pediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
| | - Harald Haidl
- Division of General Pediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
| | - Martin Wagner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Axel Schlagenhauf
- Division of General Pediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
| | - Jörg Jahnel
- Division of General Pediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
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New agents for immunosuppression. Best Pract Res Clin Gastroenterol 2021; 54-55:101763. [PMID: 34874846 DOI: 10.1016/j.bpg.2021.101763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 08/16/2021] [Accepted: 08/30/2021] [Indexed: 01/31/2023]
Abstract
The human abdomen harbors organs that the host's immune system can attack easily. This immunological storm front leads to diseases like Crohn's Disease, Ulcerative Colitis or Autoimmune Hepatitis. Serious symptoms like pain, diarrhea, fatigue, or malnutrition accompany these diseases. Moreover, many patients have an increased risk for developing special kind of malignancies and some autoimmune disease can show a high mortality. The key to treat them consists of a deep understanding of their pathophysiology. In vitro and especially in vivo basic research laid the foundation for our increasing knowledge about it during the past years. This enabled the development of new therapeutic approaches that interact directly with cytokines or immune cells instead of building the treatment on a total immunosuppression. Different kind of antibodies, kinase inhibitors, and regulatory T cells build the base for these approaches. This review shows new therapeutical approaches in gastrointestinal autoimmune diseases in context to their pathophysiological basis.
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Floreani A, De Martin S. Treatment of primary sclerosing cholangitis. Dig Liver Dis 2021; 53:1531-1538. [PMID: 34011480 DOI: 10.1016/j.dld.2021.04.028] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 04/16/2021] [Accepted: 04/21/2021] [Indexed: 02/06/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by progressive fibro-stenotic strictures and destruction of the biliary tree. Currently, there is no effective treatment which can delay its progression or ameliorate the transplant-free survival. Moreover, a major chontroversy in PSC is whether to use UDCA. More recently, novel pharmacological agents emerged aiming at: i) modulation of bile composition; ii) immunomodulation; iii) targeting the gut microbiome; iv) targeting fibrosis. Successful PSC therapy, however, will be most likely a personalized combination of different drugs plus endoscopic treatment. This review aims at offering an overview on the experimental pharmacological strategies currently exploited for PSC treatment.
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Affiliation(s)
- Annarosa Floreani
- Scientific Consultant, Scientific Institute for Research, Hospitalization and Healthcare, Negrar, Verona, Italy; Senior Scholar, University of Padova, Padova, Italy.
| | - Sara De Martin
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Italy
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Sutaria N, Adawi W, Goldberg R, Roh YS, Choi J, Kwatra SG. Itch: Pathogenesis and treatment. J Am Acad Dermatol 2021; 86:17-34. [PMID: 34648873 DOI: 10.1016/j.jaad.2021.07.078] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 07/22/2021] [Accepted: 07/23/2021] [Indexed: 12/19/2022]
Abstract
Itch pathogenesis is broadly characterized into histaminergic and nonhistaminergic pathways and transmitted via 2 main receptor families: G protein-coupled receptors and transient receptor potential channels. In the skin, itch is primarily transmitted by unmyelinated type C and thinly myelinated type Aδ nerve fibers. Crosstalk between the immune and neural systems modulates itch transmission at the skin, spinal cord, and brain. Among the many known pruritogens, Th2 cytokines, such as interleukin-4, interleukin-13, interleukin-31, and thymic stromal lymphopoietin, are particularly important mediators that signal through shared Janus kinase pathways, representing novel targets for novel itch therapeutics. Emerging evidence has also revealed that the opioidergic system is a potent modulator of itch transmission, with increased μ-opioid activity and decreased κ-opioid activity contributing to itch pathogenesis. Optimal management of itch requires that treatment approaches be tailored to specific etiologic itch subtypes. When the etiology is unknown and patients are given a diagnosis of chronic pruritus of unknown origin, treatment should be guided by the presence of Th2 polarization, often reflected by increased blood eosinophils. In the second article of this 2-part series, we outline our current understanding of itch pathogenesis and discuss available and emerging treatments for itch.
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Affiliation(s)
- Nishadh Sutaria
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Waleed Adawi
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Rebecca Goldberg
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Youkyung S Roh
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Justin Choi
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Shawn G Kwatra
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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Inhibition of autotaxin by bile salts and bile salt-like molecules increases its expression by feedback regulation. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166239. [PMID: 34389475 DOI: 10.1016/j.bbadis.2021.166239] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 07/22/2021] [Accepted: 07/31/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND Autotaxin is an enzyme that converts lysophospholipid into lysophosphatidic acid (LPA), a highly potent signaling molecule through a range of LPA receptors. It is therefore important to investigate which factors play a role in regulating ATX expression. Since we have reported that ATX levels increase dramatically in patients with various forms of cholestasis, we embarked on a study to reveal factors that influence the enzyme activity ATX as well as its expression level in vitro and in vivo. METHODS Bile from cholestatic patients was fractionated by HPLC and analyzed for modulation of ATX activity. ATX expression was measured in fibroblasts upon stimulation or inhibition of LPA signaling. RESULTS Surprisingly, ATX activity was stimulated by most forms of its product LPA, but it was inhibited by bile salts and bile salt-like molecules, particularly by 3-OH sulfated bile salts and sulfated progesterone metabolites that are known to accumulate during chronic cholestasis and cholestasis of pregnancy, respectively. Activation of fibroblasts by LPA decreased ATX expression by 72%. Conversely, inhibition of LPA signaling increased ATX expression 3-fold, indicating strong feedback regulation by LPA signaling. In fibroblasts, we could verify that inhibition of ATX activity by bile salts induces its expression. Furthermore, induction of cholestasis in mice causes increased plasma ATX activity. CONCLUSIONS Multiple biliary compounds that accumulate in the systemic circulation during cholestasis inhibit ATX activity and thereby increase ATX expression through feedback regulation. This mechanism may contribute to increased serum ATX activity in patients with cholestasis.
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Hagenbeck C, Hamza A, Kehl S, Maul H, Lammert F, Keitel V, Hütten MC, Pecks U. Management of Intrahepatic Cholestasis of Pregnancy: Recommendations of the Working Group on Obstetrics and Prenatal Medicine - Section on Maternal Disorders. Geburtshilfe Frauenheilkd 2021; 81:922-939. [PMID: 34393256 PMCID: PMC8354365 DOI: 10.1055/a-1386-3912] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 02/05/2021] [Indexed: 02/07/2023] Open
Abstract
Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disease specific to pregnancy. The cardinal symptom of pruritus and a concomitant elevated level of bile acids in the serum and/or alanine aminotransferase (ALT) are suggestive for the diagnosis. Overall, the maternal prognosis is good. The fetal outcome depends on the bile acid level. ICP is associated with increased risks for adverse perinatal outcomes, including preterm delivery, meconium-stained amniotic fluid, and stillbirth. Acute fetal asphyxia and not chronic uteroplacental dysfunction leads to stillbirth. Therefore, predictive fetal monitoring is not possible. While medication with ursodeoxycholic acid (UDCA) improves pruritus, it has not been shown to affect fetal outcome. The indication for induction of labour depends on bile acid levels and gestational age. There is a high risk of recurrence in subsequent pregnancies.
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Affiliation(s)
| | - Amr Hamza
- Universitätsklinikum des Saarlandes, Klinik für Frauenheilkunde, Geburtshilfe und Reproduktionsmedizin, Homburg, Germany
- Kantonsspital Baden AG, Baden, Switzerland
| | - Sven Kehl
- Frauenklinik, Friedrich Alexander University Erlangen Nuremberg, Faculty of Medicine, Erlangen, Germany
| | - Holger Maul
- Section of Prenatal Disgnostics and Therapy, Asklepios Klinik Barmbek, Hamburg, Germany
| | - Frank Lammert
- Klinik für Innere Medizin II, Universitätsklinikum des Saarlandes und Medizinische Fakultät der Universität des Saarlandes, Homburg, Germany
| | - Verena Keitel
- Universitätsklinikum Düsseldorf, Klinik für Gastroenterologie, Hepatologie und Infektiologie, Düsseldorf, Germany
| | - Matthias C. Hütten
- Clinique E2 Neonatology, Maastricht Universitair Medisch Centrum+, Maastricht, Netherlands
| | - Ulrich Pecks
- Universitätsklinikum Schleswig-Holstein, Campus Kiel, Klinik für Gynäkologie und Geburtshilfe, Kiel, Germany
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Lysophosphatidic acid activates nociceptors and causes pain or itch depending on the application mode in human skin. Pain 2021; 163:445-460. [PMID: 34166323 DOI: 10.1097/j.pain.0000000000002363] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Accepted: 04/13/2021] [Indexed: 11/26/2022]
Abstract
ABSTRACT Lysophosphatidic acid (LPA) is involved in the pathophysiology of cholestatic pruritus and neuropathic pain. Slowly conducting peripheral afferent C-nerve fibers are crucial in the sensations of itch and pain. In animal studies, specialized neurons ("pruriceptors") have been described, expressing specific receptors e.g. from the Mrgpr family. Human nerve fibers involved in pain signaling ("nociceptors") can elicit itch if activated by focalized stimuli such as cowhage spicules.In this study, we scrutinized the effects of LPA in humans by two different application modes on the level of psychophysics and single nerve fiber recordings (microneurography). In healthy human subjects, intracutaneous LPA microinjections elicited burning pain, whereas LPA application via inactivated cowhage spicules evoked a moderate itch sensation. LPA microinjections induced heat hyperalgesia and hypersensitivity to higher electrical stimulus frequencies. Pharmacological blockade of TRPA1 or TRPV1 reduced heat hyperalgesia but not acute chemical pain. Microneurography revealed an application mode-dependent differential activation of mechano-sensitive (CM) and mechano-insensitive (CMi) C-fibers. LPA microinjections activated a greater proportion of CMi and more strongly than CM fibers; spicule-application of LPA activated CM and CMi fibers to a similar extent but excited CM more and CMi fibers less intensely than microinjections.In conclusion, we show for the first time in humans that LPA can cause pain as well as itch dependent on the mode of application and activates afferent human C-fibers. Itch may arise from focal activation of few nerve fibers with distinct spatial contrast to unexcited surrounding afferents, and a specific combination of activated fiber subclasses might contribute.
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Abstract
Cholestatic liver disease is a disease that causes liver damage and fibrosis owing to bile stasis. It is represented by primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), but the pathophysiological pathways that cause bile stasis in both diseases are different. The pathogenesis of the disease is still unclear, although autoimmune mechanisms have been postulated and partially elucidated. Although the disease may progress slowly with only mild liver dysfunction, it may progress to liver cirrhosis or liver failure, which require liver transplantation. As a medical treatment, ursodeoxycholic acid is widely used for PBC and has proved to be very effective against disease progression in cases of PBC. On the other hand, its efficacy is limited in cases of PSC, and the research and development of various drugs are underway. Furthermore, the clinical course of both diseases is quite variable, making the design of clinical trials fairly difficult. In this review, we present the general natural history of PBC and PSC, and provide information on the latest drug therapies currently available and those that are under investigation.
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Golpanian RS, Yosipovitch G, Levy C. Use of Butorphanol as Treatment for Cholestatic Itch. Dig Dis Sci 2021; 66:1693-1699. [PMID: 32556969 DOI: 10.1007/s10620-020-06392-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Accepted: 06/03/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Pruritus is a debilitating symptom of cholestatic diseases such as primary biliary cholangitis and primary sclerosing cholangitis and often results in major reduction in quality of life for afflicted patients. Classic treatment options for the treatment of cholestatic pruritus include antihistamines, bile acid resins, serotonin reuptake inhibitors, and mu-opioid antagonists. Unfortunately, these drugs are not always successful in treating pruritus of cholestasis and may be associated with adverse effects. Recent advances in our understanding of itch pathophysiology have led to the use of butorphanol, a kappa-opioid agonist and mu-opioid antagonist, for the treatment of various forms of pruritus. Reports of butorphanol to treat cholestatic itch specifically are rare. AIMS To better understand the role of butorphanol in the treatment of cholestatic pruritus, including characterization of its side effect profile. METHODS We present a case series of eight adult patients with cholestatic disease who were treated with butorphanol in hopes of alleviating intractable pruritus. Patients were identified through a clinical data request form serviced by University of Miami Information Technology. RESULTS Five out of eight patients (62.5%) reported successful reductions in itch severity after treatment with butorphanol, two patients reported no (or transient) change in itch severity, and one patient reported a paradoxical increase in itching. Side effects included somnolence, sedation, nausea, vomiting, and dizziness. CONCLUSIONS Butorphanol was safe and leads to clinically significant symptomatic improvement. Clinicians should be aware of butorphanol as an off-label treatment option for pruritus of cholestasis. Further studies are needed to better characterize the effect of butorphanol on cholestatic itch.
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Affiliation(s)
- Rachel Shireen Golpanian
- Department of Dermatology and Cutaneous Surgery, Itch Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Gil Yosipovitch
- Department of Dermatology and Cutaneous Surgery, Itch Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Cynthia Levy
- Division of Hepatology, Schiff Center for Liver Diseases, University of Miami Miller School of Medicine, 1500 NW 12th Ave Ste 1101, Miami, FL, USA.
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Hagenbeck C, Pecks U, Lammert F, Hütten MC, Borgmeier F, Fehm T, Schleußner E, Maul H, Kehl S, Hamza A, Keitel V. [Intrahepatic cholestasis of pregnancy]. DER GYNAKOLOGE 2021; 54:341-356. [PMID: 33896963 PMCID: PMC8056200 DOI: 10.1007/s00129-021-04787-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Accepted: 03/08/2021] [Indexed: 12/19/2022]
Abstract
Intrahepatic cholestasis of pregnancy (ICP) is the most frequent pregnancy-specific liver disease. It is characterized by pruritus and an accompanying elevation of serum bile acid concentrations and/or alanine aminotransferase (ALT), which are the key parameters in the diagnosis. Despite good maternal prognosis, elevated bile acid concentration in maternal blood is an influencing factor to advers fetal outcome. The ICP is associated with increased rates of preterm birth, neonatal unit admission and stillbirth. This is the result of acute fetal asphyxia as opposed to a chronic uteroplacental insufficiency. Reliable monitoring or predictive tools (e.g. cardiotocography (CTG) or ultrasound) that help to prevent advers events are yet to be explored. Medicinal treatment with ursodeoxycholic acid (UDCA) does not demonstrably reduce adverse perinatal outcomes but does improve pruritus and liver function test results. Bile acid concentrations and gestational age should be used as indications to determine delivery. There is a high risk of recurrence in subsequent pregnancies.
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Affiliation(s)
- Carsten Hagenbeck
- Klinik für Frauenheilkunde und Geburtshilfe, Universität Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, Deutschland
| | - Ulrich Pecks
- Klinik für Gynäkologie und Geburtshilfe, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel, Deutschland
| | - Frank Lammert
- Klinik für Innere Medizin II, Universitätsklinikum des Saarlandes, Universität des Saarlandes, Homburg, Deutschland
| | - Matthias C. Hütten
- Neonatologie, Maastricht Universitair Medisch Centrum+, Maastricht, Niederlande
| | - Felix Borgmeier
- Klinik für Frauenheilkunde und Geburtshilfe, Universität Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, Deutschland
| | - Tanja Fehm
- Klinik für Frauenheilkunde und Geburtshilfe, Universität Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, Deutschland
| | | | - Holger Maul
- Frauenklinik, Asklepios Kliniken Barmbek, Wandsbek und Nord-Heidberg, Hamburg, Deutschland
| | - Sven Kehl
- Frauenklinik, Universitätsklinikum Erlangen, Erlangen, Deutschland
| | - Amr Hamza
- Kantonsspital Baden, Baden, Schweiz
- Klinikum für Frauenheilkunde, Geburtshilfe und Reproduktionsmedizin, Universität des Saarlandes, Homburg, Deutschland
| | - Verena Keitel
- Klinik für Gastroenterologie, Hepatologie und Infektiologie, Universität Düsseldorf, Düsseldorf, Deutschland
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Abstract
Introduction: Pruritus is adisabling symptom common to cholestatic liver disorders. Its pathophysiology has not been completely elucidated and although multiple mediators have been identified, only lysophosphatidic acid (LPA) and its synthetizing enzyme autotaxin (ATX) appear to consistently correlate with symptom intensity. This review aims to summarize the most relevant safety and efficacy data regarding both standard and new medications utilized to treat pruritus in cholestatic liver disease.Areas covered: International societies like the AASLD and EASL recommend astepwise approach for the management of cholestatic itch. However, therapeutic response is variable. Cholestyramine is considered first-line, followed by rifampicin, naltrexone and sertraline. When used appropriately, these medications have afavorable adverse events profile with most side effects related to drug class and not to the underlying etiology of liver disease.Expert opinion: Although conventional therapies seem to be effective in aproportion of patients, asizable number of cases remain refractory and require the utilization of experimental treatments. Multiple potential targets, especially in the ATX-LPA axis have yet to be pharmacologically explored, with ongoing translational and clinical research. Novel drugs are currently being developed for the management of cholestatic itching with promising results and afavorable safety profile.
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Affiliation(s)
- Juan Trivella
- Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Cynthia Levy
- Division of Digestive Health and Liver Disease, University of Miami Miller School of Medicine, Miami, Florida, USA
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Abstract
Pruritus is one of the most distressing symptoms in cholestatic patients. Plasma autotaxin (ATX) activity correlates with the severity of pruritus in cholestatic patients, but the pathophysiology is unclear. To study pruritus in mice, we measured scratch activity in cholestatic Atp8b1 mutant mice, a model for Progressive Familial Intrahepatic Cholestasis type 1, and wild type mice (WT) with alpha-naphthylisothiocyanate (ANIT)-induced cholestasis. To induce cholestasis, Atp8b1 mutant mice received a diet containing 0.1% cholic acid (CA) and WT mice were treated with ANIT. In these mice ATX was also overexpressed by transduction with AAV-ATX. Scratch activity was measured using an unbiased, electronic assay. Marked cholestasis was accomplished in both Atp8b1 mutant mice on a CA-supplemented diet and in ANIT-treatment in WT mice, but scratch activity was decreased rather than increased while plasma ATX activity was increased. Plasma ATX activity was further increased up to fivefold with AAV-ATX, but this did not induce scratch activity. In contrast to several reports two cholestatic mouse models did not display increased scratch activity as a measure of itch perception. Increasing plasma ATX activity by overexpression also did not lead to increased scratch activity in mice. This questions whether mice are suitable to study cholestatic itch.
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Langedijk JAGM, Beuers UH, Oude Elferink RPJ. Cholestasis-Associated Pruritus and Its Pruritogens. Front Med (Lausanne) 2021; 8:639674. [PMID: 33791327 PMCID: PMC8006388 DOI: 10.3389/fmed.2021.639674] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 02/12/2021] [Indexed: 12/17/2022] Open
Abstract
Pruritus is a debilitating symptom of various cholestatic disorders, including primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and inherited progressive familial intrahepatic cholestasis (PFIC). The molecular mechanisms leading to cholestasis-associated pruritus are still unresolved and the involved pruritogens are indecisive. As a consequence of pruritus, patients suffer from sleep deprivation, loss of daytime concentration, auto-mutilation and sometimes even suicidal ideations. Current guideline-approved therapy of cholestasis-associated pruritus includes stepwise administration of several medications, which may alleviate complaints in some, but not all affected patients. Therefore, also experimental therapeutic approaches are required to improve patients' quality of life. This article reviews the current state of research on pruritogens and their receptors, and shortly discusses the most recent experimental therapies.
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Affiliation(s)
| | | | - Ronald P. J. Oude Elferink
- Amsterdam University Medical Centers, Tytgat Institute for Liver and Intestinal Research, Research Institute Amsterdam Gastroenterology, Endocrinology and Metabolism (AGEM), University of Amsterdam, Amsterdam, Netherlands
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de Vries E, Bolier R, Goet J, Parés A, Verbeek J, de Vree M, Drenth J, van Erpecum K, van Nieuwkerk K, van der Heide F, Mostafavi N, Helder J, Ponsioen C, Oude Elferink R, van Buuren H, Beuers U. Fibrates for Itch (FITCH) in Fibrosing Cholangiopathies: A Double-Blind, Randomized, Placebo-Controlled Trial. Gastroenterology 2021; 160:734-743.e6. [PMID: 33031833 DOI: 10.1053/j.gastro.2020.10.001] [Citation(s) in RCA: 106] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 09/19/2020] [Accepted: 10/01/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS Pruritus may seriously impair quality of life in patients with cholestatic diseases such as primary or secondary sclerosing cholangitis (PSC, SSC) and primary biliary cholangitis (PBC). Pharmacologic strategies show limited efficacy and can provoke serious side effects. We hypothesized that bezafibrate, a broad peroxisome proliferator-activated receptor (PPAR) agonist, relieves cholestasis-associated itch by alleviating hepatobiliary injury. The aim of this investigator-initiated FITCH trial (Fibrates for cholestatic ITCH) was to assess effects of bezafibrate on pruritus in patients with PSC, PBC, and SSC. METHODS Patients with moderate to severe pruritus (≥5 of 10 on visual analog scale [VAS]) due to PSC, PBC, or SSC were recruited for this double-blind, randomized, placebo-controlled trial between 2016 and 2019. Patients received once-daily bezafibrate (400 mg) or placebo for 21 days. The primary end point was ≥50% reduction of pruritus (VAS; intention-to-treat). RESULTS Of 74 randomized patients, 70 completed the trial (95%; 44 PSC, 24 PBC, 2 SSC). For the primary end point, bezafibrate led in 45% (41% PSC, 55% PBC) and placebo in 11% to ≥50% reduction of severe or moderate pruritus (P = .003). For secondary end points, bezafibrate reduced morning (P = .01 vs placebo) and evening (P = .007) intensity of pruritus (VAS) and improved the validated 5D-Itch questionnaire (P = .002 vs placebo). Bezafibrate also reduced serum alkaline phosphatase (-35%, P = .03 vs placebo) correlating with improved pruritus (VAS, P = .01) suggesting reduced biliary damage. Serum bile acids and autotaxin activity remained unchanged. Serum creatinine levels tended to mildly increase (3% bezafibrate, 5% placebo, P = .14). CONCLUSIONS Bezafibrate is superior to placebo in improving moderate to severe pruritus in patients with PSC and PBC. TRIAL REGISTRATION Netherlands Trial Register, ID: NTR5436 (August 3, 2015), ClinicalTrials.gov ID: NCT02701166 (March 2, 2016).
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Affiliation(s)
- Elsemieke de Vries
- Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology & Metabolism, Amsterdam University Medical Centers, location AMC, Amsterdam, the Netherlands
| | - Ruth Bolier
- Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology & Metabolism, Amsterdam University Medical Centers, location AMC, Amsterdam, the Netherlands
| | - Jorn Goet
- Department of Gastroenterology & Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Albert Parés
- Liver Unit, Hospital Clinic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Institut d'Investigacion Biomediques August Pi-Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Jef Verbeek
- Department of Gastroenterology & Hepatology, Maastricht University Medical Center, Maastricht, the Netherlands
| | - Marleen de Vree
- Department of Gastroenterology & Hepatology, University Medical Center Groningen, Groningen, the Netherlands
| | - Joost Drenth
- Department of Gastroenterology & Hepatology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Karel van Erpecum
- Department of Gastroenterology & Hepatology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Karin van Nieuwkerk
- Department of Gastroenterology & Hepatology, Amsterdam University Medical Centers, location Vrije Universiteit Medisch Centrum (VUmc), Amsterdam, the Netherlands
| | - Frans van der Heide
- Department of Gastroenterology & Hepatology, University Medical Center Groningen, Groningen, the Netherlands
| | - Nahid Mostafavi
- Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology & Metabolism, Amsterdam University Medical Centers, location AMC, Amsterdam, the Netherlands
| | - Jeltje Helder
- Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology & Metabolism, Amsterdam University Medical Centers, location AMC, Amsterdam, the Netherlands
| | - Cyriel Ponsioen
- Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology & Metabolism, Amsterdam University Medical Centers, location AMC, Amsterdam, the Netherlands
| | - Ronald Oude Elferink
- Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology & Metabolism, Amsterdam University Medical Centers, location AMC, Amsterdam, the Netherlands
| | - Henk van Buuren
- Department of Gastroenterology & Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Ulrich Beuers
- Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology & Metabolism, Amsterdam University Medical Centers, location AMC, Amsterdam, the Netherlands.
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