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Räisänen L, Balouch F, McLaren-Kennedy A, Clark JE, Lewindon P. Outcomes of oral vancomycin therapy in children with atypical ulcerative colitis with or without confirmed primary sclerosing cholangitis: a real-world observational study. BMJ Open Gastroenterol 2025; 12:e001605. [PMID: 39938966 PMCID: PMC11822383 DOI: 10.1136/bmjgast-2024-001605] [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: 09/20/2024] [Accepted: 01/08/2025] [Indexed: 02/14/2025] Open
Abstract
OBJECTIVES Atypical ulcerative colitis (UC) presenting reverse gradient colitis, backwash ileitis, or rectal sparing and/or positive atypical antineutrophil cytoplasmic antibody serology is often associated with primary sclerosing cholangitis (PSC) and can be resistant to conventional medical therapies (CMT) for inflammatory bowel diseases. We report short-term and long-term outcomes of oral vancomycin therapy (OVT) in children with atypical UC and confirmed PSC in imaging/biopsy (PSC-UC) or treatment-resistant atypical UC without detectable PSC (aUC-non-PSC). METHODS In this retrospective real-world observational study from a tertiary paediatric centre in Brisbane, Australia, 44 children with aUC (29 PSC-UC, 15 aUC-non-PSC) received 79 OVT courses between 2014 and 2023. Pre-post-OVT characteristics were compared and relapses/repeated courses were recorded. RESULTS Pre-OVT, all had active colitis by Paediatric Ulcerative Colitis Activity Index (PUCAI), Feacal Calprotectin (FC) and/or colonoscopy. Post-OVT, PUCAI reduced from 15 (IQR 5-33) to 0 (IQR 0-5); 85% of children with pre-OVT PUCAI ≥10 achieved clinical remission (100% PSC-UC vs 64% aUC-non-PSC, p=0.019). FC reduced from 995 (IQR 319-1825) to 44 (IQR 16-79) µg/g; 83% of children with pre-OVT FC ≥100 µg/g achieved biochemical remission (92% PSC-UC vs 64% aUC-non-PSC, p=0.063). Colonoscopy confirmed Mayo 0 healing in 62% (67% PSC-UC vs 54% aUC-non-PSC, p=0.443) and 46% achieved pan-colonic histological remission (54% PSC-UC vs 31% aUC-non-PSC, p=0.173). All pre-post-OVT changes in these four markers were significant in both groups. After ceasing first OVT, 25/44 relapsed within 8.2 (IQR 1.9-14.5) months. Recommencing OVT regained biomarker remission in 13/25. During 3.8 (IQR 2.0-5.3) years of follow-up, 79 OVT courses in conjunction with CMT maintained deep remission in 67%. Routine stool testing (n=138) detected no vancomycin-resistant Enterococcus (VRE). CONCLUSIONS OVT induced and reinduced remission in children with atypical UC. Relapse often followed ceasing vancomycin, half responded to reinduction. No VRE was developed.
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Affiliation(s)
- Laura Räisänen
- Tampere University Faculty of Medicine and Health Technology, Tampere, Finland
- Queensland Children's Hospital, South Brisbane, Queensland, Australia
| | - Fariha Balouch
- Queensland Children's Hospital, South Brisbane, Queensland, Australia
| | | | | | - Peter Lewindon
- Queensland Children's Hospital, South Brisbane, Queensland, Australia
- The University of Queensland Medicine Program Children's Health Queensland Clinical Unit, South Brisbane, Queensland, Australia
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Lopez-Nunez OF, Ranganathan S. Unveiling distinctive patterns in pediatric PSC-IBD: Time for a tailored histopathologic index? J Pediatr Gastroenterol Nutr 2025; 80:257-259. [PMID: 39670526 DOI: 10.1002/jpn3.12435] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Accepted: 11/26/2024] [Indexed: 12/14/2024]
Affiliation(s)
- Oscar F Lopez-Nunez
- Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
- Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Sarangarajan Ranganathan
- Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
- Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
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Little R, Putra J, Kamath BM, Griffiths AM, Ricciuto A, Siddiqui I. Intestinal histopathology in pediatric PSC-IBD: Characterization of phenotype and assessment of the Nancy Index. J Pediatr Gastroenterol Nutr 2025; 80:290-299. [PMID: 39690834 PMCID: PMC11788967 DOI: 10.1002/jpn3.12434] [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: 11/22/2023] [Revised: 04/01/2024] [Accepted: 06/22/2024] [Indexed: 12/19/2024]
Abstract
OBJECTIVES We aimed to characterize the histologic gut phenotype of pediatric primary sclerosing cholangitis (PSC)-associated inflammatory bowel disease (IBD) against non-PSC colitis, and to assess Nancy Index (NI) performance in pediatric PSC-IBD. METHODS Single-center retrospective cohort study including children diagnosed with PSC-IBD or non-PSC colitis (ulcerative colitis [UC] or IBD-unclassified) from 2000 to 2018, with diagnostic intestinal biopsies. Biopsies were re-reviewed by two independent pathologists who assessed microscopic disease distribution, NI scores, and specific histological features in the right and left colons, overall and stratified by endoscopic severity (moderate-severe vs. no more than mild). We examined NI inter-rater reliability with Fleiss' weighted (quadratic) kappa and NI construct validity against global endoscopic severity (Spearman correlation) and clinical outcomes (logistic regression). RESULTS Fifty children with PSC-IBD and 81 colitis controls were included. Histologically, pancolitis (84% vs. 55%), right colon-predominant colitis (48% vs. 3%), and backwash ileitis (53% vs. 12%) (all p < 0.01) were significantly more common in PSC-IBD; histologic rectal sparing occurred at similar rates (6% vs. 10%, p = 0.54). Lamina propria-predominant neutrophils, prominent eosinophilic infiltration (left colon), and surface villiform change (right colon) were more common in PSC-IBD than colitis controls (p < 0.01). NI showed excellent inter-rater reliability (kappa > 0.9) and correlated moderately with global endoscopic severity but poorly with clinical activity in PSC-IBD. CONCLUSIONS Pediatric PSC-IBD has a distinct histologic phenotype that largely mirrors the endoscopic phenotype in distribution and includes a greater frequency of features not included in conventional UC histologic activity indices. Future work should investigate whether a PSC-IBD-specific index incorporating these features is warranted.
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Affiliation(s)
- Rebecca Little
- Division of Gastroenterology, Hepatology and NutritionThe Hospital for Sick ChildrenTorontoOntarioCanada
| | - Juan Putra
- Division of PathologyThe Hospital for Sick ChildrenTorontoOntarioCanada
| | - Binita M. Kamath
- Division of Gastroenterology, Hepatology and NutritionThe Hospital for Sick ChildrenTorontoOntarioCanada
- Department of PaediatricsUniversity of TorontoTorontoOntarioCanada
| | - Anne M. Griffiths
- Division of Gastroenterology, Hepatology and NutritionThe Hospital for Sick ChildrenTorontoOntarioCanada
- Department of PaediatricsUniversity of TorontoTorontoOntarioCanada
| | - Amanda Ricciuto
- Division of Gastroenterology, Hepatology and NutritionThe Hospital for Sick ChildrenTorontoOntarioCanada
- Department of PaediatricsUniversity of TorontoTorontoOntarioCanada
| | - Iram Siddiqui
- Division of PathologyThe Hospital for Sick ChildrenTorontoOntarioCanada
- Department of Laboratory Medicine & Pathobiology – Anatomic PathologyUniversity of TorontoTorontoOntarioCanada
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4
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van Rheenen PF, Kolho K, Russell RK, Aloi M, Deganello A, Hussey S, Junge N, De Laffolie J, Deneau MR, Fitzpatrick E, Griffiths AM, Hojsak I, Nicastro E, Nita A, Pakarinen M, Ricciuto A, de Ridder L, Sonzogni A, Tenca A, Samyn M, Indolfi G. Primary sclerosing cholangitis in children with inflammatory bowel disease: An ESPGHAN position paper from the Hepatology Committee and the IBD Porto group. J Pediatr Gastroenterol Nutr 2025; 80:374-393. [PMID: 39741383 PMCID: PMC11788976 DOI: 10.1002/jpn3.12378] [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: 04/20/2024] [Revised: 07/31/2024] [Accepted: 08/21/2024] [Indexed: 01/03/2025]
Abstract
OBJECTIVE We aimed to provide an evidence-supported approach to diagnose, monitor, and treat children with inflammatory bowel disease (IBD) and primary sclerosing cholangitis (PSC). METHODS The core group formulated seven PICO-structured clinical questions. A systematic literature search from inception to December 2022 was conducted by a medical librarian using MEDLINE and EMBASE. Core messages from the literature were phrased as position statements and then circulated to a sounding board composed of international experts in pediatric gastroenterology and hepatology, histopathology, adult gastroenterology and hepatology, radiology, and surgery. Statements reaching at least 80% agreement were considered as final. The other statements were refined and then subjected to a second online vote or rejection. RESULTS Regular screening for gamma-glutamyltransferase (GGT) is essential for detecting possible biliary disease in children with IBD. MR cholangiopancreatography is the radiological modality of choice for establishing the diagnosis of PSC. Liver biopsy is relevant in the evaluation of small duct PSC or autoimmune hepatitis. Children who do not have known IBD at the time of PSC diagnosis should undergo initial screening with fecal calprotectin for asymptomatic colitis, and then at least once yearly thereafter. Children with a cholestatic liver enzyme profile can be considered for treatment with ursodeoxycholic acid and can continue if there is a meaningful reduction or normalization in GGT. Oral vancomycin may have a beneficial effect on GGT and intestinal inflammation, but judicious use is recommended due to the lack of long-term studies. Children with PSC-IBD combined with convincing features of autoimmune hepatitis may benefit from corticosteroids and antimetabolites. CONCLUSIONS We present state-of-the-art guidance on the diagnostic criteria, follow-up strategies, and therapeutic strategies and point out research gaps in children and adolescents with PSC-IBD.
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Affiliation(s)
- Patrick F. van Rheenen
- Department of Paediatric Gastroenterology, Hepatology, and NutritionUniversity Medical Center Groningen, University of GroningenGroningenThe Netherlands
| | | | - Richard K. Russell
- Department of Paediatric Gastroenterology, and NutritionRoyal Hospital for Children and Young PeopleEdinburghUK
| | - Marina Aloi
- Sapienza University of Rome ‐ Umberto I HospitalRomeItaly
| | - Annamaria Deganello
- Department of RadiologyKing's College Hospital, School of Biomedical Engineering and Imaging Sciences, King's College LondonLondonUK
| | - Séamus Hussey
- Children's Health Ireland and University College DublinDublinIreland
| | - Norman Junge
- Division for Pediatric Gastroenterology and Hepatology, Department of Pediatric Kidney, Liver, and Metabolic DiseasesHannover Medical SchoolHannoverGermany
| | - Jan De Laffolie
- General Paediatrics and Neonatology, GastroenterologyJustus Liebig University GiessenGiessenGermany
| | - Mark R. Deneau
- University of Utah and Intermountain Healthcare Primary Children's HospitalSalt Lake CityUtahUSA
| | - Emer Fitzpatrick
- Children's Health Ireland and University College DublinDublinIreland
| | - Anne M. Griffiths
- Faculty of Medicine, IBD Centre, SickKids HospitalUniversity of TorontoTorontoOntarioCanada
| | - Iva Hojsak
- Children's Hospital ZagrebUniversity of Zagreb Medical SchoolZagrebCroatia
| | - Emanuele Nicastro
- Pediatric HepatologyGastroenterology and Transplantation, Hospital Papa Giovanni XXIIIBergamoItaly
| | - Andreia Nita
- Department of Paediatric GastroenterologyGreat Ormond Street HospitalLondonUK
| | - Mikko Pakarinen
- Department of Pediatric SurgeryThe New Children's HospitalUniversity of Helsinki and Helsinki University HospitalHelsinkiFinland
| | - Amanda Ricciuto
- Faculty of Medicine, IBD Centre, SickKids HospitalUniversity of TorontoTorontoOntarioCanada
| | - Lissy de Ridder
- Department of Paediatric GastroenterologyErasmus University Medical Center Sophia Children's HospitalRotterdamThe Netherlands
| | | | - Andrea Tenca
- Helsinki University and Helsinki University Hospital HUS, Abdominal CenterHelsinkiFinland
| | - Marianne Samyn
- Paediatric Liver, GI and Nutrition ServiceKing's College HospitalLondonUK
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Sannaa W, Almasry M, Peedikayil M, Grimshaw AA, Attamimi M, AlMutairdi A, Al-Bawardy B. Effectiveness and safety of oral vancomycin for the treatment of inflammatory bowel disease associated with primary sclerosing cholangitis: a systematic review and pooled analysis. Therap Adv Gastroenterol 2025; 18:17562848241312766. [PMID: 39802627 PMCID: PMC11719443 DOI: 10.1177/17562848241312766] [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: 09/21/2024] [Accepted: 12/23/2024] [Indexed: 01/16/2025] Open
Abstract
Background Inflammatory bowel disease (IBD) occurs in up to 70%-80% of patients with primary sclerosing cholangitis (PSC). Oral vancomycin therapy (OVT) has been reported to be effective in the treatment of IBD associated with PSC (IBD-PSC). Objectives To examine the effectiveness and safety of OVT in the treatment of IBD-PSC by performing a systematic review and pooled analysis of the literature. Design We performed a systematic review and pooled analysis of studies reporting IBD clinical response to OVT in IBD-PSC. Data sources and methods A systematic search was conducted in Cochrane Library, Embase, Google Scholar, Medline, PubMed, Scopus, and Web of Science from database inception to June 3, 2024. We included adult and pediatric studies that reported on clinical response (defined as any improvement in IBD-related clinical symptoms) of IBD-PSC patients treated with OVT (including pre- and post-liver transplantation cohorts). Pooled analyses of OVT response and safety were performed. Results A total of 21 (open-label, non-controlled) studies including 290 patients with IBD-PSC treated with OVT were included. The median duration of OVT to treat IBD-PSC was 32.5 weeks (interquartile range (IQR): 19-83 weeks). The total daily dose of OVT ranged from 250 to 1500 mg. Concomitant treatment included the following: mesalamine in 14.5% (n = 42), advanced therapies in 10.7% (n = 31), and immunosuppressive agents in 14.1% (n = 41). Clinical response was noted in 47.6% (138/290) and clinical remission in 43.5% (100/230). The biochemical remission rate post-OVT was 68.8% (55/80) and endoscopic remission was 39.4% (80/203). Three studies (n = 11) reported no episodes of acute cholangitis while on OVT. Five studies (n = 69) reported an incidence rate of 8.7% of vancomycin-resistant enterococci post-OVT to treat IBD-PSC. Conclusion OVT was associated with clinical response/remission in almost half of patients with IBD-PSC with a favorable side effect profile. Further prospective randomized trials are needed to confirm the dosing, efficacy, treatment duration, and long-term safety of OVT for the treatment of IBD-PSC. Trial registration The study protocol was registered with PROSPERO a priori (no. CRD42023438341).
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Affiliation(s)
- Wassel Sannaa
- Department of Medicine, University at Buffalo-Catholic Health System, Buffalo, NY, USA
| | - Mazen Almasry
- Department of Medicine, University of Wisconsin School of Medicine & Public Health, Madison, WI, USA
| | - Mustafa Peedikayil
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, King Faisal Specialist Hospital, Riyadh, Saudi Arabia
| | - Alyssa A. Grimshaw
- Harvey Cushing/John Hay Whitney Medical Library, Yale University, New Haven, CT, USA
| | - Mashary Attamimi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, King Faisal Specialist Hospital, Riyadh, Saudi Arabia
| | - Abdulelah AlMutairdi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, King Faisal Specialist Hospital, Riyadh, Saudi Arabia
| | - Badr Al-Bawardy
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, King Faisal Specialist Hospital and Research Center, P. O. Box 3354, Riyadh 11121, Saudi Arabia
- Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
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Alarfaj SJ, Bahaa MM, Elmasry TA, Elberri EI, El-Khateeb E, Hamouda AO, Salahuddin MM, Kamal M, Gadallah ANAA, Eltantawy N, Yasser M, Negm WA, Hamouda MA, Alsegiani AS, Alrubia S, Eldesoqui M, Abdallah MS. Fenofibrate as an Adjunct Therapy for Ulcerative Colitis: Targeting Inflammation via SIRT1, NLRP3, and AMPK Pathways: A Randomized Controlled Pilot Study. Drug Des Devel Ther 2024; 18:5239-5253. [PMID: 39575188 PMCID: PMC11578921 DOI: 10.2147/dddt.s490772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Accepted: 11/08/2024] [Indexed: 11/24/2024] Open
Abstract
Background Ulcerative colitis (UC) is an idiopathic chronic inflammation of colonic and rectal mucosa. The peroxisome proliferator-activated receptor α (PPARα) has been identified as having protective effects in UC. Aim The study aimed to investigate the efficacy of fenofibrate, a PPARα agonist, in UC. Methods A total of 70 patients with mild to moderate UC were allocated randomly and assigned to two groups (n = 35 each) from Gastroenterology Department, Faculty of Medicine, Menoufia University. The mesalamine group received a placebo along with 1 g of mesalamine three times daily, while the fenofibrate group received 1 g of mesalamine three times and fenofibrate 160 mg once daily. The study duration was for six months. A gastroenterologist assessed patients by non-invasive Partial Mayo Score (PMS) and the Inflammatory Bowel Disease Questionnaire (IBDQ) to evaluate clinical response and remission. The serum levels of silent information regulator 1 (SIRT1), NOD-like receptor protein 3 (NLRP3), and adenosine monophosphate activated protein kinase (AMPK), as well as fecal calprotectin levels were examined to determine the biological effect of fenofibrate. Results After treatment, the fenofibrate group showed statistically significant reductions in PMS (p = 0.044) and improved digestive domain of IBDQ (p = 0.023). Additionally, there were significant decreases in serum NLRP3 (p = 0.041) and fecal calprotectin (p = 0.035), along with significant increases in SIRT1 (p = 0.002) and AMPK (p = 0.0003). The fenofibrate group also had higher response and remission rates compared to the mesalamine group. Conclusion Fenofibrate may be a promising adjunct for improving clinical outcomes, quality of life, and modulating inflammation in mild to moderate patients with UC. Trial Registration Identifier NCT05781698.
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Affiliation(s)
- Sumaiah J Alarfaj
- Department of Pharmacy Practice, College of Pharmacy, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia
| | - Mostafa M Bahaa
- Pharmacy Practice Department, Faculty of Pharmacy, Horus University, New Damietta, Egypt
| | - Thanaa A Elmasry
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Eman I Elberri
- Clinical Pharmacy Department, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Eman El-Khateeb
- Clinical Pharmacy Department, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Amir O Hamouda
- Department of Biochemistry and Pharmacology, Faculty of Pharmacy, Horus University, New Damietta, Egypt
| | - Muhammed M Salahuddin
- Department of Biochemistry and Pharmacology, Faculty of Pharmacy, Horus University, New Damietta, Egypt
| | - Marwa Kamal
- Department of Clinical Pharmacy, Faculty of Pharmacy, Fayoum University, Fayoum, Egypt
| | | | - Nashwa Eltantawy
- Department of Pharmacy Practice, Faculty of Pharmacy and Drug Technology, Egyptian Chinese University, Cairo, Egypt
| | - Mohamed Yasser
- Department of Pharmaceutics, Faculty of Pharmacy, Port Said University, Port Said, Egypt
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Horus University, New Damietta, Egypt
- Department of Pharmaceutics, Faculty of Pharmacy, East Port Said National University, Port Said, Egypt
| | - Walaa A Negm
- Pharmacognosy Department, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Manal A Hamouda
- Department of Clinical Pharmacy, Faculty of Pharmacy, Menofia University, Menofia, Egypt
| | - Amsha S Alsegiani
- Pharmaceutical Chemistry Department, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Sarah Alrubia
- Pharmaceutical Chemistry Department, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Mamdouh Eldesoqui
- Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, Riyadh, Saudi Arabia
| | - Mahmoud S Abdallah
- Department of Clinical Pharmacy, Faculty of Pharmacy, University of Sadat City (USC), Sadat City, Menoufia, Egypt
- Department of PharmD, Faculty of Pharmacy, Jadara University, Irbid, Jordan
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Arbabzada N, Dennett L, Meng G, Peerani F. The Effectiveness of Oral Vancomycin on Inflammatory Bowel Disease in Patients With Primary Sclerosing Cholangitis: A Systematic Review. Inflamm Bowel Dis 2024:izae257. [PMID: 39495039 DOI: 10.1093/ibd/izae257] [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: 06/26/2024] [Indexed: 11/05/2024]
Abstract
BACKGROUND Approximately 70% of primary sclerosing cholangitis (PSC) patients have inflammatory bowel disease (IBD). The IBD therapies currently used to treat PSC-IBD patients have side effects and can be costly. Oral vancomycin (OV)-a safe, economical, and convenient therapy-has been reported to be a salvage therapy in refractory PSC-IBD patients. This systematic review aims to summarize the current literature regarding the effectiveness and safety of OV to treat IBD in PSC patients. METHODS A systematic literature review of Scopus, Embase, Web of Science, MEDLINE, and CINAHL was performed until March 2024. The Murad scale, Newcastle-Ottawa scale, and Cochrane Collaboration Risk of Bias Tool were used to determine the quality of the case reports and case series, cohort studies, and randomized controlled trial (RCT), respectively. The outcomes sought were response or remission across clinical, biochemical, endoscopic, and histological parameters. RESULTS Of the 1725 published studies, we identified 9 case reports, 7 case series, 3 cohort studies, and 1 RCT. Most studies reported an improvement in clinical IBD symptoms such as diarrhea and hematochezia. Fewer publications provided supporting objective data in the form of fecal calprotectin, endoscopic Mayo scores, and histology. There were no reports of vancomycin-resistant enterococci infections. CONCLUSIONS Oral vancomycin appears safe and effective to treat IBD in a subset of PSC patients. Future studies would benefit from prospective data collection incorporating standardized symptomatic, endoscopic, and histologic indices. Ultimately, a well-powered RCT is needed to better assess the effectiveness, safety, and durability of OV therapy.
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Affiliation(s)
- Naik Arbabzada
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, AB, Canada
| | - Liz Dennett
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, AB, Canada
- Geoffrey and Robyn Sperber Health Sciences Library, University of Alberta, Edmonton, AB, Canada
| | - Guanmin Meng
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, AB, Canada
| | - Farhad Peerani
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, AB, Canada
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Catassi G, D'Arcangelo G, Norsa L, Bramuzzo M, Hojsak I, Kolho KL, Romano C, Gasparetto M, Di Giorgio A, Hussey S, Yerushalmy-Feler A, Turner D, Matar M, Weiss B, Karoliny A, Alvisi P, Tzivinikos C, Aloi M. Outcome of Very Early Onset Inflammatory Bowel Disease Associated With Primary Sclerosing Cholangitis: A Multicenter Study From the Pediatric IBD Porto Group of ESPGHAN. Inflamm Bowel Dis 2024; 30:1662-1669. [PMID: 37768032 DOI: 10.1093/ibd/izad218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Indexed: 09/29/2023]
Abstract
BACKGROUND Whether primary sclerosing cholangitis related to inflammatory bowel disease (PSC-IBD) diagnosed before 6 years (ie, VEO-IBD) has a distinct phenotype and disease course is uninvestigated. We aimed to analyze the characteristics and natural history of VEO-PSC-IBD, compared with early and adolescent-onset PSC-IBD. METHODS This is a multicenter, retrospective, case-control study from 15 centers affiliated with the Porto and Interest IBD group of ESPGHAN. Demographic, clinical, laboratory, endoscopic, and imaging data were collected at baseline and every 6 months. Inflammatory bowel disease-related (clinical remission, need for systemic steroids and biologics, and surgery) and PSC-related (biliary and portal hypertensive complications, need for treatment escalation and liver transplantation, cholangiocarcinoma, or death) outcomes were compared between the 2 groups. RESULTS Sixty-nine children were included, with a median follow-up of 3.63 years (interquartile range, 1-11): 28 with VEO-PSC-IBD (23 UC [82%], 2 IBD-U [7%] and 3 [11%] CD), and 41 with PSC-IBD (37 UC [90%], 3 IBDU [7.5%] and 1 [2.5%] CD). Most patients with UC presented with pancolitis (92% in VEO-PSC-UC vs 85% in PSC-UC, P = .2). A higher number of patients with VEO-PSC-IBD were diagnosed with PSC/autoimmune hepatitis overlap syndrome than older children (24 [92%] vs 27 [67.5%] PSC-IBD, P = .03), whereas no other differences were found for PSC-related variables. Time to biliary strictures and infective cholangitis was lower in the VEO-PSC-IBD group (P = .01 and P = .04, respectively), while no difference was found for other outcomes. No cases of cholangiocarcinoma were reported. CONCLUSIONS Primary sclerosing cholangitis related to inflammatory bowel disease has similar baseline characteristics whether diagnosed as VEO-IBD or thereafter. A milder disease course in terms of biliary complications characterizes VEO-PSC-IBD.
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Affiliation(s)
- Giulia Catassi
- Pediatric Gastroenterology and Liver Unit, Sapienza University of Rome, Umberto I Hospital, Rome, Italy
| | - Giulia D'Arcangelo
- Pediatric Gastroenterology and Liver Unit, Sapienza University of Rome, Umberto I Hospital, Rome, Italy
| | - Lorenzo Norsa
- Pediatric Hepatology Gastroenterology and Transplantation, Papa Giovanni XXIII Hospital, Bergamo, Italy
| | - Matteo Bramuzzo
- Institute for Maternal and Child Health, IRCCS "Burlo Garofolo," Trieste, Italy
| | - Iva Hojsak
- University Children's Hospital Zagreb, University of Zagreb Medical School, Zagreb, Croatia
| | - Kaija-Leena Kolho
- Children's Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Claudio Romano
- Pediatric Gastroenterology and Cystic Fibrosis Unit, University of Messina, Messina, Italy
| | - Marco Gasparetto
- Department of Paediatric Gastroenterology, Barts Health Trust, The Royal London Children's Hospital, London, UK
| | - Angelo Di Giorgio
- Pediatric Hepatology Gastroenterology and Transplantation, Papa Giovanni XXIII Hospital, Bergamo, Italy
| | - Seamus Hussey
- National Children's Research Centre, Royal College of Surgeons of Ireland and University College Dublin, Dublin, Ireland
| | - Anat Yerushalmy-Feler
- Pediatric Gastroenterology Institute "Dana-Dwek" Children's Hospital, Tel Aviv University, Tel Aviv, Israel
| | - Dan Turner
- Shaare Zedek Medical Center, the Hebrew University of Jerusalem, Israel
| | - Manar Matar
- Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center, Petach Tikva, Israel
| | - Batia Weiss
- Pediatric Gastroenterology and Cystic Fibrosis Unit, University of Messina, Messina, Italy
| | - Anna Karoliny
- Heim Pal National Pediatric Institute, Budapest, Hungary
| | - Patrizia Alvisi
- Pediatric Unit, Maggiore Hospital, Largo Bartolo Nigrisoli, 2, 40133 Bologna, Italy
| | - Christos Tzivinikos
- Department of Pediatric Gastroenterology, Al Jalila Children's Specialty Hospital, Dubai, United Arab Emirates
| | - Marina Aloi
- Pediatric Gastroenterology and Liver Unit, Sapienza University of Rome, Umberto I Hospital, Rome, Italy
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Räisänen L, Nikkonen A, Kolho KL. Liver enzyme profiles after initiating biological treatment in children with inflammatory bowel diseases. J Pediatr Gastroenterol Nutr 2024; 79:583-591. [PMID: 38946705 DOI: 10.1002/jpn3.12300] [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: 03/27/2024] [Revised: 06/06/2024] [Accepted: 06/17/2024] [Indexed: 07/02/2024]
Abstract
OBJECTIVES Biological treatments (BTs) are essential in managing pediatric inflammatory bowel diseases (PIBDs). Elevated liver enzymes sometimes succeed BT, yet elucidating studies are scarce. We addressed liver biochemistry after introducing BT and searched for their determinants. METHODS We identified PIBD patients receiving infliximab, adalimumab, vedolizumab, or ustekinumab at the Children's Hospital, University of Helsinki, Finland, in 2000-2023, and followed their alanine transaminase (ALT) and γ-glutamyl transpeptidase (GT) levels for 24 months. ALT was categorized based on the age- and sex-specific upper limit of normal. We disregarded 46 patients with underlying primary sclerosing cholangitis with/without autoimmune hepatitis (AIH), pretreatment AIH diagnosis, and elevated liver enzymes at the beginning of BT from the analyses. RESULTS Of 618 BT episodes in 403 patients, 22.2% exhibited increased ALT or GT (ALT in 117, GT in 4, and both ALT/GT in 16 episodes). Of all ALT elevations (n = 133), 41.4% occurred within the first 3 months. ALT elevation was more common after infliximab (representing 59.5% of BTs) than other BTs (25.9% vs. 14.2%, adjusted odds ratio [OR]: 2.41, 95% confidence interval [CI]: 1.23-4.72). AIH followed 1.5% (n = 9) of BT episodes. Ninety-five percent of ALT elevations resolved within 6 months. Antibiotic exposure (particularly to metronidazole) was associated with ALT elevation in general (adjusted OR: 5.76, 95% CI: 2.40-13.9) and short disease duration before starting BT with notable ALT elevation (adjusted OR: 1.10, 95% CI: 1.01-1.22). CONCLUSIONS Benign ALT elevation is common within 3 months after starting BT (especially infliximab) and scarcely led to cessation of the treatment. AIH is a rare finding during the first year of BT.
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Affiliation(s)
- Laura Räisänen
- Department of Pediatrics, Tampere University Hospital, Tampere, Finland
- Department of Pediatrics, Faculty of Medicine and Health Technology (MET), Tampere University, Tampere, Finland
| | - Anne Nikkonen
- Department of Pediatrics, Faculty of Medicine and Children's Hospital, Helsinki University Hospital HUS, University of Helsinki, Helsinki, Finland
| | - Kaija-Leena Kolho
- Department of Pediatrics, Faculty of Medicine and Health Technology (MET), Tampere University, Tampere, Finland
- Department of Pediatrics, Faculty of Medicine and Children's Hospital, Helsinki University Hospital HUS, University of Helsinki, Helsinki, Finland
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10
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Swaminathan G, Sethi A, Patrizi S, Elhawary A, Al-Howthi N, Saha U, Defillo-Lopez C. It's Not Always Infections When It Comes to Resource-Poor Countries: A Fascinating Case Report. Cureus 2024; 16:e66469. [PMID: 39252731 PMCID: PMC11382437 DOI: 10.7759/cureus.66469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/07/2024] [Indexed: 09/11/2024] Open
Abstract
A patient's demographics often guide healthcare providers toward clues to a diagnosis. A recent travel history becomes an essential piece of the puzzle when there is a high suspicion of an infectious cause. When a patient walks into the hospital after having traveled to or from a resource-poor country with systemic afflictions, a physician's mind quickly jumps to infectious causes, and in most circumstances, it proves to be correct. We report an interesting case of a 28-year-old male from Guatemala who experienced acute gastrointestinal (GI) symptoms. Previous research in this field has shown that patients with inflammatory bowel disease (IBD) are prone to a slew of GI infections. Interestingly, our patient's presenting symptoms were initially attributed to "infections," but a thorough investigation revealed an unexpected twist of events. Our patient presented with multiple GI infections after the usual triggers, which masqueraded the coexistence of underlying primary sclerosing cholangitis and ulcerative colitis for a short course but were diagnosed promptly after a thorough workup.
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Affiliation(s)
- Gowri Swaminathan
- Internal Medicine, Icahn School of Medicine at Mount Sinai, Queens Hospital Center, New York, USA
| | - Arshia Sethi
- Internal Medicine, Icahn School of Medicine at Mount Sinai, Queens Hospital Center, New York, USA
| | - Santino Patrizi
- Internal Medicine, Icahn School of Medicine at Mount Sinai, Queens Hospital Center, New York, USA
| | - Ahmed Elhawary
- Internal Medicine, Icahn School of Medicine at Mount Sinai, Queens Hospital Center, New York, USA
| | - Nuha Al-Howthi
- Internal Medicine, Icahn School of Medicine at Mount Sinai, Queens Hospital Center, New York, USA
| | - Utsow Saha
- Internal Medicine, Icahn School of Medicine at Mount Sinai, Queens Hospital Center, New York, USA
| | - Celeste Defillo-Lopez
- Internal Medicine, Icahn School of Medicine at Mount Sinai, Queens Hospital Center, New York, USA
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11
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Jerregård Skarby A, Casswall T, Bergquist A, Lindström L. Good long-term outcomes of primary sclerosing cholangitis in childhood. JHEP Rep 2024; 6:101123. [PMID: 39139456 PMCID: PMC11321284 DOI: 10.1016/j.jhepr.2024.101123] [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: 11/17/2023] [Revised: 05/14/2024] [Accepted: 05/21/2024] [Indexed: 08/15/2024] Open
Abstract
Background & Aims Primary sclerosing cholangitis (PSC) is a rare progressive liver disease associated with inflammatory bowel disease (IBD). It is usually diagnosed in adults but can also present in children. Data on long-term outcomes of pediatric PSC are limited. Our aim was to study the natural history of pediatric PSC in Sweden. Methods This is a cohort study, including all children (<18 years), diagnosed with PSC between January 2000 and December 2015 at the Pediatric Liver Unit at Karolinska University Hospital, Stockholm. Patients were followed until liver transplantation, death or last date of follow-up (August 2021). Results We identified 124 children with a median age of 14 (1.9-17.8) years at PSC diagnosis. Sixty percent were boys, 93% had IBD. Median follow-up time was 13 years (5.7-21.6). Overall event-free survival in the cohort was 91% (95% CI 0.84-0.95) at 5 years and 77% (95% CI 0.68-0.84) at 10 years after diagnosis. Autoimmune hepatitis (AIH) was present in 31% (n = 39). Portal hypertension developed in 13% (n = 16), biliary complications in 24% (n = 30), cholangiocarcinoma (CCA) in 0.8% (n = 1), while 13% (n = 16) underwent liver transplantation and three patients died. Transplant-free survival was 91% after 10 years. Individuals with a high SCOPE index at diagnosis had a 2.3-fold increased risk of requiring liver transplantation (hazard ratio 2.35, 95% CI 1.18-4.66, c-statistics = 0.70). Patients with an additional diagnosis of autoimmune hepatitis had slightly higher risk of reaching transplantation during follow-up (hazard ratio 2.85, 95% CI 1.06-7.67, p = 0.038). Conclusions Children diagnosed with PSC have a good prognosis during the first decade after diagnosis. A high SCOPE index at diagnosis was associated with a less favorable outcome. Impact and implications Data on long-term outcome in pediatric primary sclerosing cholangitis bridging over to adulthood is limited. There is a great need among children with primary sclerosing cholangitis and their parents for more knowledge about the natural history of this disease and what they can expect from the future. We hope that the data presented in this study may help counsel health professionals, young individuals and families affected by this disease.
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Affiliation(s)
- Anna Jerregård Skarby
- Department of Medicine Huddinge, Karolinska Institutet, Department of Acute Geriatrics, Stroke and Palliative care, Nyköping Hospital Nyköping, Sweden
| | - Thomas Casswall
- Department of Clinical Science, Intervention and Technology (CLINTEC), Unit of Pediatrics, Karolinska Institutet, Pediatric Gastroenterology, Hepatology and Nutrition, Karolinska University Hospital, Stockholm, Sweden
| | - Annika Bergquist
- Department of Medicine Huddinge, Karolinska Institutet, Department of Upper GI Disease, Division of Hepatology, Karolinska University Hospital, Stockholm, Sweden
| | - Lina Lindström
- Department of Medicine Huddinge, Karolinska Institutet, Department of Gastroenterology, Dermatovenereology and Rheumatology, Centre for Digestive Health, Karolinska University Hospital, Stockholm, Sweden
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12
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Wittek A, Steglich B, Casar C, Seiz O, Huber P, Ehlken H, Reher D, Wende S, Bedke T, Kempski J, Böttcher M, Bang C, Thingholm L, Krech T, Lohse AW, Sauter G, Rösch T, Franke A, Schramm C, Gagliani N, Pelczar P, Huber S. A Gradient of Intestinal Inflammation in Primary Sclerosing Cholangitis. Inflamm Bowel Dis 2024; 30:900-910. [PMID: 37540889 DOI: 10.1093/ibd/izad137] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Indexed: 08/06/2023]
Abstract
BACKGROUND Primary sclerosing cholangitis (PSC) is a progressive liver disease associated with inflammatory bowel disease (IBD). The percentage of PSC patients diagnosed with concomitant IBD varies considerably between studies. This raises the question whether all PSC patients would show intestinal inflammation if screened thoroughly, even in the absence of symptoms. METHODS To address this question, we collected intestinal biopsies of healthy controls (n = 34), PSC (n = 25), PSC-IBD (n = 41), and IBD (n = 51) patients in a cross-sectional study and carried out cytokine expression profiling, 16S sequencing, in-depth histology, and endoscopy scoring. RESULTS We found that the vast majority of PSC patients even without clinically manifest IBD showed infiltration of immune cells and increased expression of IL17A and IFNG in intestinal biopsies. However, expression of IL10 and FOXP3 were likewise increased, which may explain why these PSC patients have intestinal inflammation only on a molecular level. This subclinical inflammation in PSC patients was focused in the distal colon, whereas PSC-IBD patients showed inflammation either at the distal colon or on the right side of the colon and the terminal ileum. Furthermore, we observed that PSC patients without IBD showed signs of dysbiosis and exhibited a distinct microbial profile compared with healthy controls. CONCLUSIONS We found a gradient of intestinal inflammation in the vast majority of PSC patients even in the absence of IBD. Thus, further studies evaluating the effect of anti-inflammatory therapies in PSC patients and their impact on the emergence of clinically manifest IBD and colorectal cancer development are needed.
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Affiliation(s)
- Agnes Wittek
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Babett Steglich
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christian Casar
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Oliver Seiz
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Philipp Huber
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Hanno Ehlken
- Department for Interdisciplinary Endoscopy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Dominik Reher
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sandra Wende
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Tanja Bedke
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jan Kempski
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Marius Böttcher
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Corinna Bang
- Institute for Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany
| | - Louise Thingholm
- Institute for Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany
| | - Till Krech
- Institute for Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ansgar W Lohse
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Guido Sauter
- Institute for Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Thomas Rösch
- Department for Interdisciplinary Endoscopy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andre Franke
- Institute for Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany
| | - Christoph Schramm
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Nicola Gagliani
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Penelope Pelczar
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Samuel Huber
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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13
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Hudson AS, Huynh HQ. Pediatric inflammatory bowel disease: What's new and what has changed? Paediatr Child Health 2024; 29:144-149. [PMID: 38827368 PMCID: PMC11141611 DOI: 10.1093/pch/pxae013] [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: 11/16/2023] [Accepted: 02/19/2024] [Indexed: 06/04/2024] Open
Abstract
The incidence and prevalence of inflammatory bowel disease (IBD) is on the rise in North America and worldwide, with young children being the fastest growing patient population. It is therefore essential for pediatricians and pediatric sub-specialists to be able to recognize signs and symptoms suspicious for a new diagnosis of IBD, as well as potential complications associated with IBD or its treatment. This article reviews the most recent literature regarding clinical presentation, helpful diagnostic clues, newer monitoring tools being used by pediatric gastroenterologists, and emerging new biologic and small molecule treatments.
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Affiliation(s)
- Alexandra S Hudson
- Division of Pediatric Gastroenterology and Nutrition, Department of Pediatrics, Edmonton Pediatric IBD Clinic (EPIC), University of Alberta, Edmonton, Alberta, Canada
| | - Hien Q Huynh
- Division of Pediatric Gastroenterology and Nutrition, Department of Pediatrics, Edmonton Pediatric IBD Clinic (EPIC), University of Alberta, Edmonton, Alberta, Canada
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14
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Ricciuto A, Liu K, El-Matary W, Amin M, Amir AZ, Aumar M, Auth M, Di Guglielmo MD, Druve Tavares Fagundes E, Rodrigues Ferreira A, Furuya KN, Gupta N, Guthery S, Horslen SP, Jensen K, Kamath BM, Kerkar N, Koot BGP, Laborda TJ, Lee CK, Loomes KM, Mack C, Martinez M, Montano-Loza A, Ovchinsky N, Papadopoulou A, Perito ER, Sathya P, Schwarz KB, Shah U, Shteyer E, Soufi N, Stevens JP, Taylor A, Tessier ME, Valentino P, Woynarowski M, Deneau M. Oral vancomycin is associated with improved inflammatory bowel disease clinical outcomes in primary sclerosing cholangitis-associated inflammatory bowel disease (PSC-IBD): A matched analysis from the Paediatric PSC Consortium. Aliment Pharmacol Ther 2024; 59:1236-1247. [PMID: 38462727 DOI: 10.1111/apt.17936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 09/18/2023] [Accepted: 02/22/2024] [Indexed: 03/12/2024]
Abstract
BACKGROUND Data on oral vancomycin for primary sclerosing cholangitis (PSC)-associated inflammatory bowel disease (IBD) are limited. AIMS Using data from the Paediatric PSC Consortium, to examine the effect of vancomycin on IBD activity. METHODS In this retrospective multi-centre cohort study, we matched vancomycin-treated and untreated patients (1:3) based on IBD duration at the time of primary outcome assessment. The primary outcome was Physician Global Assessment (PGA) of IBD clinical activity after 1 year (±6 months) of vancomycin. We used generalised estimating equations (GEE) to examine the association between vancomycin and PGA remission, adjusting for IBD type, severity and medication exposures. Secondary outcomes included serum labs and endoscopic remission (global rating of no activity) among those with available data and also analysed with GEE. RESULTS 113 PSC-IBD patients received vancomycin (median age 12.7 years, 63% male). The matched cohort included 70 vancomycin-treated and 210 untreated patients. Vancomycin was associated with greater odds of IBD clinical remission (odds ratio [OR] 3.52, 95% CI 1.97-6.31; adjusted OR [aOR] 5.24, 95% CI 2.68-10.22). Benefit was maintained in sensitivity analyses restricted to non-transplanted patients and those with baseline moderate-severe PGA. Vancomycin was associated with increased odds of endoscopic remission (aOR 2.76, 95% CI 1.002-7.62; N = 101 with data), and with lower CRP (p = 0.03) and higher haemoglobin and albumin (both p < 0.01). CONCLUSION Vancomycin was associated with greater odds of IBD clinical and endoscopic remission. Additional, preferably randomised, controlled studies are needed to characterise efficacy using objective markers of mucosal inflammation, and to examine safety and define optimal dosing.
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Affiliation(s)
- Amanda Ricciuto
- The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Kuan Liu
- Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
| | - Wael El-Matary
- Max Rady College of Medicine, Children's Hospital Research Institute of Manitoba, Winnipeg, Manitoba, Canada
| | - Mansi Amin
- Duke University Medical Center, Durham, North Carolina, USA
| | - Achiya Z Amir
- Dana-Dwek Children's Hospital, Tel-Aviv Medical Center, Tel-Aviv University, Tel Aviv, Israel
| | | | - Marcus Auth
- Alder Hey Children's NHS Foundation Trust, University of Liverpool, Liverpool, UK
| | | | | | | | - Katryn N Furuya
- University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, USA
| | - Nitika Gupta
- Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Stephen Guthery
- Intermountain Primary Children's Hospital, University of Utah, Salt Lake City, Utah, USA
| | - Simon P Horslen
- UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Kyle Jensen
- Intermountain Primary Children's Hospital, University of Utah, Salt Lake City, Utah, USA
| | - Binita M Kamath
- The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Nanda Kerkar
- Golisano Children's Hospital, University of Rochester Medical Center, Rochester, New York, USA
| | - B G P Koot
- Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Trevor J Laborda
- Intermountain Primary Children's Hospital, University of Utah, Salt Lake City, Utah, USA
| | | | - Kathleen M Loomes
- The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Cara Mack
- Children's Hospital Colorado, University of Colorado Anschutz Medical Campus, Children's Wisconsin, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Mercedes Martinez
- Columbia University Irving Medical Center, New York-Presbyterian, New York, New York, USA
| | - Aldo Montano-Loza
- Zeidler Ledcor Centre, University of Alberta, Edmonton, Alberta, Canada
| | - Nadia Ovchinsky
- NYU Grossman School of Medicine, New York City, New York, USA
| | - Alexandra Papadopoulou
- First Department of Pediatrics, Athens Children's Hospital "AGIA SOFIA", University of Athens, Athens, Greece
| | - Emily R Perito
- University of California San Francisco, San Francisco, California, USA
| | - Pushpa Sathya
- Memorial University of Newfoundland, St. John's, Newfoundland, Canada
| | | | - Uzma Shah
- Henry Ford Health, Detroit, Michigan, USA
| | | | - Nisreen Soufi
- Children's Hospital Los Angeles, Los Angeles, California, USA
| | | | - Amy Taylor
- Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | | | - Pamela Valentino
- University of Washington School of Medicine, Seattle Children's, Seattle, Washington, USA
| | | | - Mark Deneau
- Children's Hospital Colorado, University of Colorado Anschutz Medical Campus, Children's Wisconsin, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
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15
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Cornillet M, Villard C, Rorsman F, Molinaro A, Nilsson E, Kechagias S, von Seth E, Bergquist A. The Swedish initiative for the st udy of Primary sclerosing cholangitis (SUPRIM). EClinicalMedicine 2024; 70:102526. [PMID: 38500838 PMCID: PMC10945116 DOI: 10.1016/j.eclinm.2024.102526] [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: 11/04/2023] [Revised: 02/19/2024] [Accepted: 02/20/2024] [Indexed: 03/20/2024] Open
Abstract
Background Despite more than 50 years of research and parallel improvements in hepatology and oncology, there is still today neither a treatment to prevent disease progression in primary sclerosing cholangitis (PSC), nor reliable early diagnostic tools for the associated hepatobiliary cancers. Importantly, the limited understanding of the underlying biological mechanisms in PSC and its natural history not only affects the identification of new drug targets but implies a lack of surrogate markers that hampers the design of clinical trials and the evaluation of drug efficacy. The lack of easy access to large representative well-characterised prospective resources is an important contributing factor to the current situation. Methods We here present the SUPRIM cohort, a national multicentre prospective longitudinal study of unselected PSC patients capturing the representative diversity of PSC phenotypes. We describe the 10-year effort of inclusion and follow-up, an intermediate analysis report including original results, and the associated research resource. All included patients gave written informed consent (recruitment: November 2011-April 2016). Findings Out of 512 included patients, 452 patients completed the five-year follow-up without endpoint outcomes. Liver transplantation was performed in 54 patients (10%) and hepatobiliary malignancy was diagnosed in 15 patients (3%). We draw a comprehensive landscape of the multidimensional clinical and biological heterogeneity of PSC illustrating the diversity of PSC phenotypes. Performances of available predictive scores are compared and perspectives on the continuation of the SUPRIM cohort are provided. Interpretation We envision the SUPRIM cohort as an open-access collaborative resource to accelerate the generation of new knowledge and independent validations of promising ones with the aim to uncover reliable diagnostics, prognostic tools, surrogate markers, and new treatment targets by 2040. Funding This work was supported by the Swedish Cancer Society, Stockholm County Council, and the Cancer Research Funds of Radiumhemmet.
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Affiliation(s)
- Martin Cornillet
- Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Christina Villard
- Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
- Department of Transplantation Surgery, Karolinska University Hospital, Stockholm, Sweden
| | - Fredrik Rorsman
- Department of Gastroenterology and Hepatology, Akademiska University Hospital, Uppsala, Sweden
| | - Antonio Molinaro
- Department of Hepatology, Sahlgrenska University Hospital, Göteborg, Sweden
| | - Emma Nilsson
- Gastroenterology Clinic, Skåne University Hospital, Sweden
| | - Stergios Kechagias
- Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden
| | - Erik von Seth
- Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
- Department of Upper Abdominal Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - Annika Bergquist
- Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
- Department of Upper Abdominal Diseases, Karolinska University Hospital, Stockholm, Sweden
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16
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Stumme F, Steffens N, Steglich B, Mathies F, Nawrocki M, Sabihi M, Soukou-Wargalla S, Göke E, Kempski J, Fründt T, Weidemann S, Schramm C, Gagliani N, Huber S, Bedke T. A protective effect of inflammatory bowel disease on the severity of sclerosing cholangitis. Front Immunol 2024; 15:1307297. [PMID: 38510236 PMCID: PMC10950911 DOI: 10.3389/fimmu.2024.1307297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Accepted: 02/12/2024] [Indexed: 03/22/2024] Open
Abstract
Background Primary sclerosing cholangitis (PSC) is a chronic liver disease marked by inflammation of the bile ducts and results in the development of strictures and fibrosis. A robust clinical correlation exists between PSC and inflammatory bowel disease (IBD). At present, published data are controversial, and it is yet unclear whether IBD drives or attenuates PSC. Methods Mdr2-deficient mice or DDC-fed mice were used as experimental models for sclerosing cholangitis. Additionally, colitis was induced in mice with experimental sclerosing cholangitis, either through infection with Citrobacter rodentium or by feeding with DSS. Lastly, fibrosis levels were determined through FibroScan analysis in people with PSC and PSC-IBD. Results Using two distinct experimental models of colitis and two models of sclerosing cholangitis, we found that colitis does not aggravate liver pathology, but rather reduces liver inflammation and liver fibrosis. Likewise, people with PSC-IBD have decreased liver fibrosis compared to those with PSC alone. Conclusions We found evidence that intestinal inflammation attenuates liver pathology. This study serves as a basis for further research on the pathogenesis of PSC and PSC-IBD, as well as the molecular mechanism responsible for the protective effect of IBD on PSC development. This study could lead to the discovery of novel therapeutic targets for PSC.
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Affiliation(s)
- Friederike Stumme
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Niklas Steffens
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Babett Steglich
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of General Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Franziska Mathies
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Mikolaj Nawrocki
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Morsal Sabihi
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Shiwa Soukou-Wargalla
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Emilia Göke
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jan Kempski
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Thorben Fründt
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sören Weidemann
- Center of Diagnostics, Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christoph Schramm
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Nicola Gagliani
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of General Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Samuel Huber
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Tanja Bedke
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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17
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Sutton H, Karpen SJ, Kamath BM. Pediatric Cholestatic Diseases: Common and Unique Pathogenic Mechanisms. ANNUAL REVIEW OF PATHOLOGY 2024; 19:319-344. [PMID: 38265882 DOI: 10.1146/annurev-pathmechdis-031521-025623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2024]
Abstract
Cholestasis is the predominate feature of many pediatric hepatobiliary diseases. The physiologic flow of bile requires multiple complex processes working in concert. Bile acid (BA) synthesis and excretion, the formation and flow of bile, and the enterohepatic reuptake of BAs all function to maintain the circulation of BAs, a key molecule in lipid digestion, metabolic and cellular signaling, and, as discussed in the review, a crucial mediator in the pathogenesis of cholestasis. Disruption of one or several of these steps can result in the accumulation of toxic BAs in bile ducts and hepatocytes leading to inflammation, fibrosis, and, over time, biliary and hepatic cirrhosis. Biliary atresia, progressive familial intrahepatic cholestasis, primary sclerosing cholangitis, and Alagille syndrome are four of the most common pediatric cholestatic conditions. Through understanding the commonalities and differences in these diseases, the important cellular mechanistic underpinnings of cholestasis can be greater appreciated.
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Affiliation(s)
- Harry Sutton
- The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada;
| | - Saul J Karpen
- Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Binita M Kamath
- The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada;
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18
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van Munster KN, Bergquist A, Ponsioen CY. Inflammatory bowel disease and primary sclerosing cholangitis: One disease or two? J Hepatol 2024; 80:155-168. [PMID: 37940453 DOI: 10.1016/j.jhep.2023.09.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 09/01/2023] [Accepted: 09/29/2023] [Indexed: 11/10/2023]
Abstract
Primary sclerosing cholangitis (PSC) was declared one of the biggest unmet needs in hepatology during International Liver Congress 2016 in Berlin. Since then, not much has changed unfortunately, largely due to the still elusive pathophysiology of the disease. One of the most striking features of PSC is its association with inflammatory bowel disease (IBD), with the majority of patients with PSC being diagnosed with extensive colitis. This review describes the epidemiology of IBD in PSC, its specific phenotype, complications and potential pathophysiological mechanisms connecting the two diseases. Whether PSC is merely an extra-intestinal manifestation of IBD or if PSC and IBD are two distinct diseases that happen to share a common susceptibility that leads to a dual phenotype is debated. Implications for the management of the two diseases together are also discussed. Overall, this review summarises the available data in PSC-IBD and discusses whether PSC and IBD are one or two disease(s).
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Affiliation(s)
- Kim N van Munster
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, the Netherlands
| | - Annika Bergquist
- Department of Medicine Huddinge, Division of Hepatology, Karolinska Institutet, Department of Upper GI Disease, Karolinska University Hospital, Stockholm, Sweden
| | - Cyriel Y Ponsioen
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, the Netherlands.
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19
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Kazmi I, Altamimi ASA, Afzal M, Majami AA, Abbasi FA, Almalki WH, Alzera SI, Kukreti N, Fuloria NK, Fuloria S, Sekar M, Abida. Non-coding RNAs: Emerging biomarkers and therapeutic targets in ulcerative colitis. Pathol Res Pract 2024; 253:155037. [PMID: 38160482 DOI: 10.1016/j.prp.2023.155037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2023] [Revised: 12/10/2023] [Accepted: 12/11/2023] [Indexed: 01/03/2024]
Abstract
Ulcerative colitis (UC) is a persistent inflammatory condition affecting the colon's mucosal lining, leading to chronic bowel inflammation. Despite extensive research, the precise molecular mechanisms underlying UC pathogenesis remain elusive. NcRNAs form a category of functional RNA molecules devoid of protein-coding capacity. They have recently surfaced as pivotal modulators of gene expression and integral participants in various pathological processes, particularly those related to inflammatory disorders. The diverse classes of ncRNAs, encompassing miRNAs, circRNAs, and lncRNAs, have been implicated in UC. It highlights their involvement in key UC-related processes, such as immune cell activation, epithelial barrier integrity, and the production of pro-inflammatory mediators. ncRNAs have been identified as potential biomarkers for UC diagnosis and monitoring disease progression, offering promising avenues for personalized medicine. This approach may pave the way for novel, more specific treatments with reduced side effects, addressing the current limitations of conventional therapies. A comprehensive understanding of the interplay between ncRNAs and UC will advance our knowledge of the disease, potentially leading to more effective and personalized treatments for patients suffering from this debilitating condition. This review explores the pivotal role of ncRNAs in the context of UC, shedding light on their possible targets for diagnosis, prognosis, and therapeutic interventions.
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Affiliation(s)
- Imran Kazmi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | | | - Muhammad Afzal
- Department of Pharmaceutical Sciences, Pharmacy Program, Batterjee Medical College, P.O. Box 6231, Jeddah 21442, Saudi Arabia
| | - Abdullah A Majami
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Fahad Al Abbasi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Waleed Hassan Almalki
- Department of Pharmacology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Sami I Alzera
- Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka 72341, Al-Jouf, Saudi Arabia
| | - Neelima Kukreti
- School of Pharmacy, Graphic Era Hill University, Dehradun 248007, India
| | | | - Shivkanya Fuloria
- Faculty of Pharmacy, AIMST University, Bedong 08100, Kedah, Malaysia
| | - Mahendran Sekar
- School of Pharmacy, Monash University Malaysia, Bandar Sunway, Subang Jaya 47500, Selangor, Malaysia
| | - Abida
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Northern Border University, Rafha 91911, Saudi Arabia
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20
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Radmard AR, Amouei M, Torabi A, Sima AR, Saffar H, Geahchan A, Davarpanah AH, Taouli B. MR Enterography in Ulcerative Colitis: Beyond Endoscopy. Radiographics 2024; 44:e230131. [PMID: 38127661 DOI: 10.1148/rg.230131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2023]
Abstract
Ulcerative colitis (UC) is a chronic idiopathic inflammatory bowel disease (IBD) that progressively affects mucosa and submuccosa of the colon and rectum in a continual pattern. In comparison, Crohn disease (CD), the other type of IBD, is a chronic transmural inflammatory disorder that can involve any part of the gastrointestinal tract. MR enterography (MRE) has emerged as an important imaging modality for the diagnosis and detection of disease activity and complications in CD, with comparable results to those of endoscopy. But MRE has been underused for assessment of UC in recent years, and clinicians heavily rely on endoscopic findings for management of UC. Despite UC being considered an endoscopically assessable disease, MRE can provide useful information beyond that obtained with endoscopy about mural or extramural abnormalities, inaccessible parts of the colonic lumen, associated extraintestinal diseases, and superimposed pathologic conditions. Moreover, endoscopy might be contraindicated in some clinical settings due to the risk of colonic perforation. In addition to depicting the features of UC activity in different phases, MRE demonstrates findings of disease chronicity that cannot be achieved with endoscopy, particularly in a patient with colitis of unknown cause. The valuable diagnostic role of MRE to exclude undiagnosed CD in patients with UC who have refractory disease or those with postproctocolectomy complications is also emphasized. Radiologists can play a crucial role in the management of UC with MRE by addressing what is beyond endoscopy. ©RSNA, 2023 Test Your Knowledge questions are available in the supplemental material.
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Affiliation(s)
- Amir Reza Radmard
- From the Departments of Radiology (A.R.R., M.A., A.T.) and Pathology (H.S.), Shariati Hospital, Tehran University of Medical Sciences, North Kargar St, Tehran 14117, Iran; Advanced Diagnostic and Interventional Radiology Research Center (ADIR), Tehran University of Medical Sciences, Tehran, Iran (A.R.R., M.A., A.T.); Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran (A.R.S.); Sasan Alborz Biomedical Research Center, Masoud Gastroenterology and Hepatology Center, Tehran, Iran (A.R.S.); Department of Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY (A.G., B.T.); Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY (A.G., B.T.); and Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Ga (A.H.D.)
| | - Mehrnam Amouei
- From the Departments of Radiology (A.R.R., M.A., A.T.) and Pathology (H.S.), Shariati Hospital, Tehran University of Medical Sciences, North Kargar St, Tehran 14117, Iran; Advanced Diagnostic and Interventional Radiology Research Center (ADIR), Tehran University of Medical Sciences, Tehran, Iran (A.R.R., M.A., A.T.); Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran (A.R.S.); Sasan Alborz Biomedical Research Center, Masoud Gastroenterology and Hepatology Center, Tehran, Iran (A.R.S.); Department of Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY (A.G., B.T.); Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY (A.G., B.T.); and Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Ga (A.H.D.)
| | - Ala Torabi
- From the Departments of Radiology (A.R.R., M.A., A.T.) and Pathology (H.S.), Shariati Hospital, Tehran University of Medical Sciences, North Kargar St, Tehran 14117, Iran; Advanced Diagnostic and Interventional Radiology Research Center (ADIR), Tehran University of Medical Sciences, Tehran, Iran (A.R.R., M.A., A.T.); Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran (A.R.S.); Sasan Alborz Biomedical Research Center, Masoud Gastroenterology and Hepatology Center, Tehran, Iran (A.R.S.); Department of Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY (A.G., B.T.); Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY (A.G., B.T.); and Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Ga (A.H.D.)
| | - Ali Reza Sima
- From the Departments of Radiology (A.R.R., M.A., A.T.) and Pathology (H.S.), Shariati Hospital, Tehran University of Medical Sciences, North Kargar St, Tehran 14117, Iran; Advanced Diagnostic and Interventional Radiology Research Center (ADIR), Tehran University of Medical Sciences, Tehran, Iran (A.R.R., M.A., A.T.); Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran (A.R.S.); Sasan Alborz Biomedical Research Center, Masoud Gastroenterology and Hepatology Center, Tehran, Iran (A.R.S.); Department of Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY (A.G., B.T.); Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY (A.G., B.T.); and Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Ga (A.H.D.)
| | - Hiva Saffar
- From the Departments of Radiology (A.R.R., M.A., A.T.) and Pathology (H.S.), Shariati Hospital, Tehran University of Medical Sciences, North Kargar St, Tehran 14117, Iran; Advanced Diagnostic and Interventional Radiology Research Center (ADIR), Tehran University of Medical Sciences, Tehran, Iran (A.R.R., M.A., A.T.); Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran (A.R.S.); Sasan Alborz Biomedical Research Center, Masoud Gastroenterology and Hepatology Center, Tehran, Iran (A.R.S.); Department of Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY (A.G., B.T.); Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY (A.G., B.T.); and Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Ga (A.H.D.)
| | - Amine Geahchan
- From the Departments of Radiology (A.R.R., M.A., A.T.) and Pathology (H.S.), Shariati Hospital, Tehran University of Medical Sciences, North Kargar St, Tehran 14117, Iran; Advanced Diagnostic and Interventional Radiology Research Center (ADIR), Tehran University of Medical Sciences, Tehran, Iran (A.R.R., M.A., A.T.); Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran (A.R.S.); Sasan Alborz Biomedical Research Center, Masoud Gastroenterology and Hepatology Center, Tehran, Iran (A.R.S.); Department of Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY (A.G., B.T.); Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY (A.G., B.T.); and Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Ga (A.H.D.)
| | - Amir H Davarpanah
- From the Departments of Radiology (A.R.R., M.A., A.T.) and Pathology (H.S.), Shariati Hospital, Tehran University of Medical Sciences, North Kargar St, Tehran 14117, Iran; Advanced Diagnostic and Interventional Radiology Research Center (ADIR), Tehran University of Medical Sciences, Tehran, Iran (A.R.R., M.A., A.T.); Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran (A.R.S.); Sasan Alborz Biomedical Research Center, Masoud Gastroenterology and Hepatology Center, Tehran, Iran (A.R.S.); Department of Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY (A.G., B.T.); Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY (A.G., B.T.); and Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Ga (A.H.D.)
| | - Bachir Taouli
- From the Departments of Radiology (A.R.R., M.A., A.T.) and Pathology (H.S.), Shariati Hospital, Tehran University of Medical Sciences, North Kargar St, Tehran 14117, Iran; Advanced Diagnostic and Interventional Radiology Research Center (ADIR), Tehran University of Medical Sciences, Tehran, Iran (A.R.R., M.A., A.T.); Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran (A.R.S.); Sasan Alborz Biomedical Research Center, Masoud Gastroenterology and Hepatology Center, Tehran, Iran (A.R.S.); Department of Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY (A.G., B.T.); Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY (A.G., B.T.); and Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Ga (A.H.D.)
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21
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Han S, Wang K, Shen J, Xia H, Lu Y, Zhuge A, Li S, Qiu B, Zhang S, Dong X, Yao M, Li L. Probiotic Pediococcus pentosaceus Li05 Improves Cholestasis through the FXR-SHP and FXR-FGF15 Pathways. Nutrients 2023; 15:4864. [PMID: 38068723 PMCID: PMC10708340 DOI: 10.3390/nu15234864] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 11/16/2023] [Accepted: 11/16/2023] [Indexed: 12/18/2023] Open
Abstract
Primary sclerosing cholangitis (PSC), a rare chronic cholestatic liver disease, is characterized by intrahepatic or extrahepatic strictures accompanied by biliary fibrosis. So far, there are no effective therapies to slow down the progression of this disease. Farnesoid X receptors (FXRs) are ligand-activated transcription factors involved in the control of bile acid (BA) synthesis and enterohepatic circulation. Therefore, targeting FXRs holds promise as a potential approach for treating PSC. Pediococcus pentosaceus Li05 is a probiotic that was isolated from healthy volunteers and has previously been shown to have an anti-inflammatory effect in DSS-induced colitis. In this study, we established a 3,5-diethoxycarbonyl-1,4-Dihydrocollidine (DDC)-induced cholestasis mouse model and investigated the effects of Pediococcus pentosaceus Li05 on PSC. Our findings revealed that administration of Li05 significantly attenuated liver damage, hepatic inflammation, and fibrosis, as well as bile duct hyperplasia. Li05 activated the hepatic FXR-SHP and ileal FXR-FGF15 signaling pathways to decrease the expression of Cyp7a1. In addition, the Li05-modulated gut microbiota structure especially improved the abundance of 7α-dehydroxylation bacteria like Eubacterium. The intervention of Li05 also improved the intestinal barrier and reduced bacterial endotoxin translocation. Based on these findings, Li05 shows promise for future application as a therapeutic strategy for cholestasis.
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Affiliation(s)
- Shengyi Han
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China
| | - Kaicen Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China
| | - Jian Shen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China
| | - He Xia
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China
| | - Yanmeng Lu
- Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China
| | - Aoxiang Zhuge
- Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China
| | - Shengjie Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China
| | - Bo Qiu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China
| | - Shuobo Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China
| | - Xiangmin Dong
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China
| | - Mingfei Yao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan 250000, China
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22
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Fiel MI, Schiano TD. Systemic Disease and the Liver Part 2: Pregnancy-Related Liver Injury, Sepsis/Critical Illness, Hypoxia, Psoriasis, Scleroderma/Sjogren's Syndrome, Sarcoidosis, Common Variable Immune Deficiency, Cystic Fibrosis, Inflammatory Bowel Disease, and Hematologic Disorders. Surg Pathol Clin 2023; 16:485-498. [PMID: 37536884 DOI: 10.1016/j.path.2023.04.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/05/2023]
Abstract
The liver is involved in many multisystem diseases and commonly may manifest with abnormal liver chemistry tests. The liver test perturbations may be multifactorial in nature, however, as patients are receiving many different medications and can also have intrinsic liver disease that may be exacerbated by the systemic disorder. Some disorders have typical histologic findings that can be diagnosed on liver biopsy, whereas others will show a more nonspecific histology. Clinicians should be aware of these conditions so as to consider the performance of a liver biopsy at the most opportune time and setting to help establish the diagnosis of acute or chronic liver disease.
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Affiliation(s)
- Maria Isabel Fiel
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY 10029, USA.
| | - Thomas D Schiano
- Division of Liver Diseases, Recanati-Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place-Box 1104, New York, NY 10029, USA
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23
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Lee DU, Menegas S, Lee KJ, Pu A, Bhowmick K, Ponder R, Fan GH, Chou H, Lee K, Urrunaga NH. Impact of Inflammatory Bowel Disease Subtypes on the Post-liver Transplant Outcomes of Patients with Primary Sclerosing Cholangitis. Dig Dis Sci 2023; 68:3781-3800. [PMID: 37450231 PMCID: PMC10789194 DOI: 10.1007/s10620-023-08023-y] [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: 12/21/2022] [Accepted: 06/24/2023] [Indexed: 07/18/2023]
Abstract
BACKGROUND AND AIMS Liver transplant patients with primary sclerosing cholangitis often present with concurrent inflammatory bowel disease. The effect of comorbid conditions on post-transplant prognosis was evaluated. METHODS The 2005-2019 United Network of Organ Sharing Standard Transplant Analysis and Research database was used to identify patients with primary sclerosing cholangitis. Patients were categorized as having Crohn's Disease, ulcerative colitis, unclassified inflammatory bowel disease, or no inflammatory bowel disease. Baseline characteristics were assessed between cohorts, and outcomes were examined using Cox regression. Outcomes included all-cause mortality, graft failure, infection-induced mortality, and organ system-delineated mortality. Supplementary analyses with unique exclusion and stratification criteria were also performed. RESULTS Among 2829 patients undergoing transplant, 1360 were considered to have ulcerative colitis, 372 were considered to have Crohn's Disease, and 69 were considered to have an unclassified form of inflammatory bowel disease. Primary sclerosing cholangitis patients with some form of inflammatory bowel disease had no increased risk for any outcomes. However, patients with ulcerative colitis had lower risks of general infectious (aHR 0.65 95%CI 0.44-0.95) and sepsis-induced (aHR 0.56 95%CI 0.35-0.91) mortality, whereas patients with Crohn's Disease had higher risks of sepsis-induced mortality (aHR 2.13 95%CI 1.22-3.70). Supplementary analyses showed effect modification by abdominal surgery history and era. CONCLUSION The type of inflammatory bowel disease in liver transplant patients with primary sclerosing cholangitis was found to portend risk difference for infection-induced mortality, with ulcerative colitis found to be protective and Crohn's Disease predictive of increased mortality secondary to infectious etiologies. These associations warrant further investigation.
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Affiliation(s)
- David Uihwan Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Maryland School of Medicine, 22 S. Greene Street, N3W50, Baltimore, 21201, USA.
| | - Samantha Menegas
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Maryland School of Medicine, 22 S. Greene Street, N3W50, Baltimore, 21201, USA
| | - Ki Jung Lee
- Department of Medicine, Tufts University School of Medicine, Boston, MA, USA
| | - Alex Pu
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Maryland School of Medicine, 22 S. Greene Street, N3W50, Baltimore, 21201, USA
| | - Kuntal Bhowmick
- Department of Medicine, Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Reid Ponder
- Department of Medicine, Tufts University School of Medicine, Boston, MA, USA
| | - Gregory Hongyuan Fan
- Division of Gastroenterology, Liver Center, Tufts Medical Center, Boston, MA, USA
| | - Harrison Chou
- Department of Medicine, Tufts University School of Medicine, Boston, MA, USA
| | - KeeSeok Lee
- Department of Medicine, Tufts University School of Medicine, Boston, MA, USA
| | - Nathalie H Urrunaga
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Maryland School of Medicine, 22 S. Greene Street, N3W50, Baltimore, 21201, USA
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24
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Le Berre C, Honap S, Peyrin-Biroulet L. Ulcerative colitis. Lancet 2023; 402:571-584. [PMID: 37573077 DOI: 10.1016/s0140-6736(23)00966-2] [Citation(s) in RCA: 452] [Impact Index Per Article: 226.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 05/03/2023] [Accepted: 05/08/2023] [Indexed: 08/14/2023]
Abstract
Ulcerative colitis is a lifelong inflammatory disease affecting the rectum and colon to a variable extent. In 2023, the prevalence of ulcerative colitis was estimated to be 5 million cases around the world, and the incidence is increasing worldwide. Ulcerative colitis is thought to occur in people with a genetic predisposition following environmental exposures; gut epithelial barrier defects, the microbiota, and a dysregulated immune response are strongly implicated. Patients usually present with bloody diarrhoea, and the diagnosis is based on a combination of clinical, biological, endoscopic, and histological findings. The aim of medical management is, first, to induce a rapid clinical response and normalise biomarkers and, second, to maintain clinical remission and reach endoscopic normalisation to prevent long-term disability. Treatments for inducing remission include 5-aminosalicylic acid drugs and corticosteroids. Maintenance treatments include 5-aminosalicylic acid drugs, thiopurines, biologics (eg, anti-cytokines and anti-integrins), and small molecules (Janus kinase inhibitors and sphingosine-1-phosphate receptor modulators). Although the therapeutic options are expanding, 10-20% of patients still require proctocolectomy for medically refractory disease. The keys to breaking through this therapeutic ceiling might be the combination of therapeutics with precision and personalised medicine.
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Affiliation(s)
- Catherine Le Berre
- Institut des Maladies de l'Appareil Digestif, Hépato-Gastro-Entérologie et Assistance Nutritionnelle, Inserm CIC 1413, Inserm UMR 1235, Nantes Université, CHU Nantes, Nantes, France
| | - Sailish Honap
- Department of Gastroenterology, St George's University Hospitals NHS Foundation Trust, London, UK; School of Immunology and Microbial Sciences, King's College London, London UK
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, INFINY Institute, FHU-CURE, INSERM NGERE, Nancy University Hospital, Vandœuvre-lès-Nancy, France; Division of Gastroenterology and Hepatology, McGill University Health Centre, Montreal, QC, Canada.
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Single Center Experience of Oral Vancomycin Therapy in Young Patients with Primary Sclerosing Cholangitis: A Case Series. LIVERS 2023. [DOI: 10.3390/livers3010009] [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: 03/08/2023] Open
Abstract
There is no single proven therapy that prolongs hepatic transplant-free survival in patients with primary sclerosing cholangitis (PSC). Oral vancomycin (OV) has shown some benefit in small pediatric and adult series. We describe the effect of OV on pediatric onset PSC at our tertiary hospital. This is a single-center, retrospective, descriptive case series involving patients (<21 years at diagnosis) with PSC on OV from 2001 till 2021. The therapy effect was assessed based on symptoms, biochemical labs, imaging and liver biopsy at six and twelve months, and then annually until therapy was discontinued. The inclusion criteria identified 17 patients. Baseline GGT (n = 17) was elevated among 88.2% which then normalized among 53.8% (n = 13) at six months and 55.6% (n = 9) at one year post-OV. Baseline ALT normalized in 58.8% (n = 17) at six months and 42.8% (n = 14) at one year. Imaging findings within one year of OV revealed improved/stable biliary findings among 66.7% (n = 8/12). No adverse events were reported. OV was associated with an improvement in bile duct injury marker (GGT) after at least six months of therapy, with no disease progression on imaging within one year of therapy.
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Jarmakiewicz-Czaja S, Gruszecka J, Filip R. What Do NAFLD, Liver Fibrosis, and Inflammatory Bowel Disease Have in Common? Review of the Current Literature. Metabolites 2023; 13:metabo13030378. [PMID: 36984818 PMCID: PMC10051776 DOI: 10.3390/metabo13030378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 02/22/2023] [Accepted: 02/27/2023] [Indexed: 03/08/2023] Open
Abstract
Liver disease is one of the most common extraintestinal manifestations of inflammatory bowel disease (IBD). Often the course of liver disease is associated with an exacerbation of the underlying disease (Crohn’s Disease/Ulcerative Colitis). Nonalcoholic steatohepatitis encompasses a wide spectrum of liver damage. The most common form is nonalcoholic fatty liver disease (NAFLD) (75–80%), and the less common but more dangerous form is nonalcoholic steatohepatitis (NASH). NAFLD is now the most common cause of chronic liver disease in developed countries and the leading indication for liver transplantation in the United States. Genetic, demographic, clinical, and environmental factors can play a role in the pathogenesis of NAFLD. The increasing prevalence of NAFLD is associated with a widespread obesity epidemic, metabolic complications, including hypertension, type 2 diabetes, and dyslipidaemia. Some of the most common manifestations of IBD are liver, biliary tract, and gallbladder diseases. The liver fibrosis process has a complex pathophysiology and is often dependent on exogenous factors such as the treatment used and endogenous factors such as the gut microbiome. However, the factors that link IBD and liver fibrosis are not yet clear. The main purpose of the review is to try to find links between IBD and selected liver diseases and to identify knowledge gaps that will inform further research.
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Affiliation(s)
| | - Jolanta Gruszecka
- Institute of Health Sciences, Medical College of Rzeszow University, 35-959 Rzeszow, Poland
- Department of Clinical Microbiology, Clinical Hospital No. 2, 35-959 Rzeszow, Poland
| | - Rafał Filip
- Institute of Medicine, Medical College of Rzeszow University, 35-959 Rzeszow, Poland
- Department of Gastroenterology with IBD Unit, Clinical Hospital No. 2, 35-959 Rzeszow, Poland
- Correspondence:
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Outcomes of immunomodulator and advanced therapies for primary sclerosing cholangitis-associated inflammatory bowel disease. Eur J Gastroenterol Hepatol 2023; 35:270-274. [PMID: 36708297 DOI: 10.1097/meg.0000000000002510] [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: 01/29/2023]
Abstract
BACKGROUND Inflammatory bowel disease (IBD) coexists in up to 80% of patients with primary sclerosing cholangitis (PSC). The aim of this study is to investigate the outcomes of immunomodulator (IMM)/advanced therapies for the treatment of PSC-IBD. METHODS This was a single-center, retrospective study of patients with PSC from 1 January 2012 to 1 April 2021. Adult patients (age ≥ 18 years) with PSC-IBD were included. Primary outcomes were rates and predictors of IMM/advanced therapies to treat PSC-IBD. Secondary outcomes included rates of cholangitis, PSC-IBD clinical remission, and endoscopic healing. RESULTS A total of 106 patients with PSC were reviewed and 72 (68%) with confirmed PSC-IBD were included in the study. The median age was 48 years (IQR, 33-59.5) and 69.4% were male. Overall, 28 patients (38.9%) required IMM/advanced therapies to treat PSC-IBD (22 biologic/small molecule therapy and six thiopurine monotherapy). Patients in the IMM/advanced therapies group were more likely to have small bowel involvement (32.1% vs. 4.6%; P = 0.002). In the IMM/advanced therapies group, clinical remission was achieved in 78.6% but endoscopic healing in only 50%. The rate of acute ascending cholangitis was 42.9% in the IMM/advanced therapies group compared with 31.8% in the non-IMM/advanced therapies group (P = 0.34). CONCLUSION In our cohort, up to a third of patients with PSC-IBD required IMM/advanced therapies with only 50% of these patients achieving endoscopic healing. The use of IMM/advanced therapies was not associated with a higher risk of cholangitis, but larger studies are needed to investigate the risk with different classes of advanced therapies.
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28
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Berhane B, van Rheenen PF, Verkade HJ. Gamma-glutamyl transferase and disease course in pediatric-onset primary sclerosing cholangitis: A single-center cohort study. Health Sci Rep 2023; 6:e1086. [PMID: 36751275 PMCID: PMC9892024 DOI: 10.1002/hsr2.1086] [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: 09/29/2022] [Revised: 12/29/2022] [Accepted: 01/16/2023] [Indexed: 02/05/2023] Open
Abstract
Background and Aims Patients with pediatric-onset primary sclerosing cholangitis (PSC) are at risk of developing hepatic complications with liver transplantation as only curative treatment. Complications usually occur over many years, underlining the need for reliable surrogate markers to predict the clinical course. Recently, gamma-glutamyl transferase (GGT) has been suggested to allow prediction of the clinical course. In a single-center cohort study, we tested the potency of GGT in this respect. Methods We used longitudinal data of patients from our academic center, diagnosed with pediatric-onset PSC between 2000 and 2020. Patients with a GGT decrease from baseline >25% (n = 36) were compared with those who did not have this decrease (n = 7). We performed Kaplan-Meier analysis and log-rank testing to assess the occurrence of portal hypertensive or biliary complications, hepatobiliary malignancies, liver transplantation, or death. Results The median age diagnosis was 15.2 years and 12.1 years in the group with ≤25% decrease of GGT and the group with >25% decrease, respectively (p = 0.078). The probability of developing ≥1 complications in the first 5 years after diagnosis was 50% in the group with ≤25% decrease of GGT and 20% in the group with >25% decrease of GGT (p = 0.031). The use of medication was not associated with the development of complications. Conclusion In a retrospective cohort study, we report that a GGT decrease of >25% within 1 year of diagnosis of pediatric-onset PSC is associated with a lower occurrence of complications within 5 years. Our results provide further support for the recently hypothesized predictive value of first-year GGT change in predicting the disease course in pediatric-onset PSC.
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Affiliation(s)
- Besrat Berhane
- Pediatric Gastroenterology & Hepatology, Department of Pediatrics, Beatrix Children's Hospital, University Medical Center GroningenUniversity of GroningenGroningenThe Netherlands
| | - Patrick F. van Rheenen
- Pediatric Gastroenterology & Hepatology, Department of Pediatrics, Beatrix Children's Hospital, University Medical Center GroningenUniversity of GroningenGroningenThe Netherlands
| | - Henkjan J. Verkade
- Pediatric Gastroenterology & Hepatology, Department of Pediatrics, Beatrix Children's Hospital, University Medical Center GroningenUniversity of GroningenGroningenThe Netherlands
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Loh K, Badalyan V. Acute Hepatitis. PRINCIPLES AND PRACTICE OF PEDIATRIC INFECTIOUS DISEASES 2023:419-423.e2. [DOI: 10.1016/b978-0-323-75608-2.00059-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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30
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Little R, Kamath BM, Ricciuto A. Liver Disease in Pediatric Inflammatory Bowel Disease. PEDIATRIC INFLAMMATORY BOWEL DISEASE 2023:129-149. [DOI: 10.1007/978-3-031-14744-9_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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31
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Chazouilleres O, Beuers U, Bergquist A, Karlsen TH, Levy C, Samyn M, Schramm C, Trauner M. EASL Clinical Practice Guidelines on sclerosing cholangitis. J Hepatol 2022; 77:761-806. [PMID: 35738507 DOI: 10.1016/j.jhep.2022.05.011] [Citation(s) in RCA: 152] [Impact Index Per Article: 50.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 05/16/2022] [Indexed: 02/07/2023]
Abstract
Management of primary or secondary sclerosing cholangitis is challenging. These Clinical Practice Guidelines have been developed to provide practical guidance on debated topics including diagnostic methods, prognostic assessment, early detection of complications, optimal care pathways and therapeutic (pharmacological, endoscopic or surgical) options both in adults and children.
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Stevens JP, Gupta NA. Recent Insights into Pediatric Primary Sclerosing Cholangitis. Clin Liver Dis 2022; 26:489-519. [PMID: 35868687 DOI: 10.1016/j.cld.2022.03.009] [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] [Indexed: 01/31/2023]
Abstract
This article reviews recent literature on the pathogenesis, presentation, diagnosis, comorbidities, natural history, and management of pediatric primary sclerosing cholangitis (PSC). The authors shed light on the role of genetic and environmental factors in PSC, although recognize the limitations in the understanding of PSC pathogenesis. They reflect on presenting disease phenotypes, including the association with inflammatory bowel disease and frequent histologic presence of autoimmune hepatitis features. The current lack of effective medications is discussed, and disease complications and prognosis are described. Finally, the authors highlight available evidence while acknowledging the paucity of prospective pediatric data.
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Affiliation(s)
- James P Stevens
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, 1760 Haygood Drive, Atlanta GA 30322, USA
| | - Nitika A Gupta
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, 1760 Haygood Drive, Atlanta GA 30322, USA.
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Akiyama S, Fukuda S, Steinberg JM, Suzuki H, Tsuchiya K. Characteristics of inflammatory bowel diseases in patients with concurrent immune-mediated inflammatory diseases. World J Gastroenterol 2022; 28:2843-2853. [PMID: 35978883 PMCID: PMC9280738 DOI: 10.3748/wjg.v28.i25.2843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 03/10/2022] [Accepted: 05/28/2022] [Indexed: 02/06/2023] Open
Abstract
Patients with inflammatory bowel disease (IBD) are more likely to have concurrent immune-mediated inflammatory diseases (IMIDs) than those without IBD. IMIDs have been observed to alter the phenotype and outcomes of IBD in recent studies. Several studies have found that IBD patients with concurrent IMIDs may have more extensive or severe disease phenotypes, and are considered to be at increased risk of requiring biologics and IBD-related surgeries, suggesting that having multiple IMIDs is a poor prognostic factor for IBD. Furthermore, IBD patients with primary sclerosing cholangitis and Takayasu arteritis are reported to have unique endoscopic phenotypes, suggesting concurrent IMIDs can influence IBD phenotype with specific intestinal inflammatory distributions. In this review, we discuss the pathogenesis, disease phenotypes, and clinical outcomes in IBD patients with concomitant IMIDs.
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Affiliation(s)
- Shintaro Akiyama
- Department of Gastroenterology, University of Tsukuba, Tsukuba 305-8575, Ibaraki, Japan
| | - Soma Fukuda
- Department of Gastroenterology, University of Tsukuba, Tsukuba 305-8575, Ibaraki, Japan
| | - Joshua M Steinberg
- Inflammatory Bowel Disease, Gastroenterology of the Rockies, Denver, CO 80218, United States
| | - Hideo Suzuki
- Department of Gastroenterology, University of Tsukuba, Tsukuba 305-8575, Ibaraki, Japan
| | - Kiichiro Tsuchiya
- Department of Gastroenterology, University of Tsukuba, Tsukuba 305-8575, Ibaraki, Japan
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Park YE. Is primary sclerosing cholangitis with inflammatory bowel disease different between patients in the East and West? Intest Res 2022; 20:157-158. [PMID: 35508951 PMCID: PMC9081988 DOI: 10.5217/ir.2022.00041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 04/05/2022] [Indexed: 11/26/2022] Open
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Majumder S, Shivaji UN, Kasturi R, Sigamani A, Ghosh S, Iacucci M. Inflammatory bowel disease-related colorectal cancer: Past, present and future perspectives. World J Gastrointest Oncol 2022; 14:547-567. [PMID: 35321275 PMCID: PMC8919014 DOI: 10.4251/wjgo.v14.i3.547] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 04/21/2021] [Accepted: 02/27/2022] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease-related colorectal cancer (IBD-CRC) is one of the most serious complications of IBD contributing to significant mortality in this cohort of patients. IBD is often associated with diet and lifestyle-related gut microbial dysbiosis, the interaction of genetic and environmental factors, leading to chronic gut inflammation. According to the “common ground hypothesis”, microbial dysbiosis and intestinal barrier impairment are at the core of the chronic inflammatory process associated with IBD-CRC. Among the many underlying factors known to increase the risk of IBD-CRC, perhaps the most important factor is chronic persistent inflammation. The persistent inflammation in the colon results in increased proliferation of cells necessary for repair but this also increases the risk of dysplastic changes due to chromosomal and microsatellite instability. Multiple pathways have been identified, regulated by many positive and negative factors involved in the development of cancer, which in this case follows the ‘inflammation-dysplasia-carcinoma’ sequence. Strategies to lower this risk are extremely important to reduce morbidity and mortality due to IBD-CRC, among which colonoscopic surveillance is the most widely accepted and implemented modality, forming part of many national and international guidelines. However, the effectiveness of surveillance in IBD has been a topic of much debate in recent years for multiple reasons — cost-benefit to health systems, resource requirements, and also because of studies showing conflicting long-term data. Our review provides a comprehensive overview of past, present, and future perspectives of IBD-CRC. We explore and analyse evidence from studies over decades and current best practices followed globally. In the future directions section, we cover emerging novel endoscopic techniques and artificial intelligence that could play an important role in managing the risk of IBD-CRC.
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Affiliation(s)
- Snehali Majumder
- Department of Clinical Research, Narayana Health, Bangalore 560099, Karnataka, India
| | - Uday Nagesh Shivaji
- National Institute for Health Research Birmingham Biomedical Research Centre, University Hospitals Birmingham, Birmingham B15 2TH, United Kingdom
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TH, United Kingdom
| | - Rangarajan Kasturi
- Department of Gastroenterology, Narayana Health, Bangalore 560099, India
| | - Alben Sigamani
- Department of Clinical Research, Narayana Health, Bangalore 560099, Karnataka, India
| | - Subrata Ghosh
- National Institute for Health Research Birmingham Biomedical Research Centre, University Hospitals Birmingham, Birmingham B15 2TH, United Kingdom
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TH, United Kingdom
| | - Marietta Iacucci
- National Institute for Health Research Birmingham Biomedical Research Centre, University Hospitals Birmingham, Birmingham B15 2TH, United Kingdom
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TH, United Kingdom
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Yu J, Refsum E, Helsingen LM, Folseraas T, Ploner A, Wieszczy P, Barua I, Jodal HC, Melum E, Løberg M, Blom J, Bretthauer M, Adami H, Kalager M, Ye W. Risk of hepato-pancreato-biliary cancer is increased by primary sclerosing cholangitis in patients with inflammatory bowel disease: A population-based cohort study. United European Gastroenterol J 2022; 10:212-224. [PMID: 35107865 PMCID: PMC8911542 DOI: 10.1002/ueg2.12204] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 01/17/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND There is continued uncertainty regarding the risks of hepato-pancreato-biliary cancers in patients with inflammatory bowel disease (IBD) with or without concomitant primary sclerosing cholangitis (PSC). OBJECTIVE To give updated estimates on risk of hepato-pancreato-biliary cancers in patients with IBD, including pancreatic cancer, hepatocellular carcinoma, gall bladder cancer, and intra - and extrahepatic cholangiocarcinoma. METHODS In a population-based cohort study, we included all patients diagnosed with IBD in Norway and Sweden from 1987 to 2016. The cohort comprised of 141,960 patients, identified through hospital databases and the National Patient Register. Participants were followed through linkage to national cancer, cause of death, and population registries. We calculated absolute risk and standardized incidence ratios (SIRs) of hepato-pancreato-biliary cancers by PSC and other clinical characteristics. RESULTS Of the 141,960 IBD patients, 3.2% were diagnosed with PSC. During a median follow-up of 10.0 years, we identified 443 biliary tract cancers (SIR 5.2, 95% confidence interval [CI] 4.8-5.7), 161 hepatocellular carcinomas (SIR 2.4, 95% CI 2.0-2.7) and 282 pancreatic cancers (SIR 1.3, 95% CI 1.2-1.5). The relative risks were considerably higher in PSC-IBD patients, with SIR of 140 (95% CI 123-159) for biliary tract, 38.6 (95% CI 29.2-50.0) for hepatocellular, and 9.0 (95% CI 6.3-12.6) for pancreatic cancer. The SIRs were still slightly increased in non-PSC-IBD patients, compared to the general population. For biliary tract cancer, the cumulative probability at 25 years was 15.6% in PSC-IBD patients, and 0.4% in non-PSC-IBD patients. CONCLUSIONS The dramatically increased risks of hepato-pancreato-biliary cancers in PSC-IBD patients support periodic surveillance for these malignancies. While much lower, the excess relative risks in non-PSC-IBD patients were not trivial compared to non-IBD related risk factors.
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Affiliation(s)
- Jingru Yu
- Department of Medical Epidemiology and BiostatisticsKarolinska InstitutetStockholmSweden
| | - Erle Refsum
- Department of Transplantation MedicineClinical Effectiveness Research GroupOslo University HospitalOsloNorway
- Clinical Effectiveness Research GroupInstitute of Health and SocietyUniversity of OsloOsloNorway
| | - Lise M. Helsingen
- Department of Transplantation MedicineClinical Effectiveness Research GroupOslo University HospitalOsloNorway
- Clinical Effectiveness Research GroupInstitute of Health and SocietyUniversity of OsloOsloNorway
| | - Trine Folseraas
- Department of Transplantation MedicineNorwegian PSC Research CenterDivision of Surgery, Inflammatory Diseases and TransplantationOslo University HospitalRikshospitaletOsloNorway
- Section of GastroenterologyDepartment of Transplantation MedicineDivision of Surgery, Inflammatory Medicine and TransplantationOslo University HospitalRikshospitaletOsloNorway
| | - Alexander Ploner
- Department of Medical Epidemiology and BiostatisticsKarolinska InstitutetStockholmSweden
| | - Paulina Wieszczy
- Department of Transplantation MedicineClinical Effectiveness Research GroupOslo University HospitalOsloNorway
- Clinical Effectiveness Research GroupInstitute of Health and SocietyUniversity of OsloOsloNorway
- Department of Gastroenterology, Hepatology and Clinical OncologyCentre of Postgraduate Medical EducationWarsawPoland
| | - Ishita Barua
- Department of Transplantation MedicineClinical Effectiveness Research GroupOslo University HospitalOsloNorway
- Clinical Effectiveness Research GroupInstitute of Health and SocietyUniversity of OsloOsloNorway
| | - Henriette C. Jodal
- Department of Transplantation MedicineClinical Effectiveness Research GroupOslo University HospitalOsloNorway
- Clinical Effectiveness Research GroupInstitute of Health and SocietyUniversity of OsloOsloNorway
| | - Espen Melum
- Department of Transplantation MedicineNorwegian PSC Research CenterDivision of Surgery, Inflammatory Diseases and TransplantationOslo University HospitalRikshospitaletOsloNorway
- Section of GastroenterologyDepartment of Transplantation MedicineDivision of Surgery, Inflammatory Medicine and TransplantationOslo University HospitalRikshospitaletOsloNorway
- Research Institute of Internal MedicineDivision of Surgery, Inflammatory Diseases and TransplantationOslo University HospitalOsloNorway
- Institute of Clinical MedicineFaculty of MedicineUniversity of OsloOsloNorway
- Hybrid Technology Hub‐Centre of ExcellenceInstitute of Basic Medical SciencesFaculty of MedicineUniversity of OsloOsloNorway
| | - Magnus Løberg
- Department of Transplantation MedicineClinical Effectiveness Research GroupOslo University HospitalOsloNorway
- Clinical Effectiveness Research GroupInstitute of Health and SocietyUniversity of OsloOsloNorway
| | - Johannes Blom
- Department of Clinical Science and EducationSödersjukhusetKarolinska InstitutetStockholmSweden
| | - Michael Bretthauer
- Department of Transplantation MedicineClinical Effectiveness Research GroupOslo University HospitalOsloNorway
- Clinical Effectiveness Research GroupInstitute of Health and SocietyUniversity of OsloOsloNorway
| | - Hans‐Olov Adami
- Department of Medical Epidemiology and BiostatisticsKarolinska InstitutetStockholmSweden
- Department of Transplantation MedicineClinical Effectiveness Research GroupOslo University HospitalOsloNorway
- Clinical Effectiveness Research GroupInstitute of Health and SocietyUniversity of OsloOsloNorway
| | - Mette Kalager
- Department of Transplantation MedicineClinical Effectiveness Research GroupOslo University HospitalOsloNorway
- Clinical Effectiveness Research GroupInstitute of Health and SocietyUniversity of OsloOsloNorway
| | - Weimin Ye
- Department of Medical Epidemiology and BiostatisticsKarolinska InstitutetStockholmSweden
- Department of Epidemiology and Health Statistics & Key Laboratory of Ministry of Education for Gastrointestinal CancerFujian Medical UniversityFuzhouChina
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Weng MT, Shih IL, Tung CC, Leong YL, Shieh MJ, Wang CY, Wong JM, Ni YH, Wei SC. Association of young age and male sex with primary sclerosing cholangitis in Taiwanese patients with inflammatory bowel disease. Intest Res 2022; 20:224-230. [PMID: 35124955 PMCID: PMC9082000 DOI: 10.5217/ir.2021.00042] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Accepted: 04/10/2021] [Indexed: 12/04/2022] Open
Abstract
Background/Aims Primary sclerosing cholangitis (PSC) is associated with inflammatory bowel disease (IBD). We aimed to evaluate the prevalence, clinical manifestation, and outcomes of PSC in Taiwanese patients with IBD. Methods This retrospective study enrolled patients with IBD admitted from January 1, 1996, to December 31, 2018, to National Taiwan University Hospital. A case-matched analysis was performed comparing patients with IBD with and without PSC according to age, sex, and time of admission, with ratios of 1:4 and 1:2 in the adult and pediatric groups, respectively. Results In total, 763 patients with IBD were enrolled, 12 of whom were also diagnosed with PSC (1.57%). All these patients had ulcerative colitis (UC). A greater incidence of IBD with PSC was observed in younger patients than in older patients. Male sex was a risk factor for PSC in pediatric patients with IBD (P=0.015); 75% of these patients were diagnosed with PSC along with or after the diagnosis of UC. There was no significant difference in colitis extent and severity between the groups; however, a higher proportion of rectal sparing was observed in patients with PSC (P=0.001). There was no significant difference in cancer development between the groups (P=0.679). Conclusions A 1.57% prevalence of PSC was observed in Taiwanese patients with IBD. The majority of patients with IBD and PSC were men and were diagnosed at a younger age. Hence, routine evaluation of biliary enzymes and liver imaging is recommended in young male patients with IBD.
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Affiliation(s)
- Meng-Tzu Weng
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei City, Taiwan
| | - I-Lun Shih
- Department of Medical Imaging, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei City, Taiwan
| | - Chien-Chih Tung
- Department of Integrated Diagnostics and Therapeutics, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei City, Taiwan
| | - Yew-Loong Leong
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei City, Taiwan.,Good Liver Clinic, Taipei City, Taiwan
| | - Ming-Jium Shieh
- Department of Oncology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei City, Taiwan
| | - Cheng-Yi Wang
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei City, Taiwan
| | - Jau-Min Wong
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei City, Taiwan
| | - Yen-Hsuan Ni
- Department of Pediatrics, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei City, Taiwan
| | - Shu-Chen Wei
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei City, Taiwan
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Beheshti-Maal A, Tamimi A, Iravani S, Memarnejadian A, Sorouri M, Aghdaei HA, Zali MR, Hossein Khannazer N, Vosough M. PSC associated inflammatory bowel disease: a distinct entity. Expert Rev Gastroenterol Hepatol 2022; 16:129-139. [PMID: 35078376 DOI: 10.1080/17474124.2022.2031979] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Primary sclerosing cholangitis (PSC) is a rare, chronic, and progressive cholestatic disease involving intra- and/or extrahepatic bile ducts. PSC in many patients results in end-stage liver diseases. Nearly 60% of the PSC patients suffer from concomitant inflammatory bowel diseases (IBDs). Classically, IBDs are divided into two principle types: Crohn's disease (CD) and ulcerative colitis (UC). However, with growing knowledge, PSC-associated IBD (PSC-IBD) seems to be a rather distinct entity with specific genetics, clinical, and microbiota characteristics. AREAS COVERED In this article, we aim to review the unique characteristics of PSC-IBD from clinical, genetic, and microbiota point of view. EXPERT OPINION PSC-IBD's unique characteristics contribute to the notion that it could be a distinct entity. Acknowledgment of PSC-IBD as a novel entity necessitates designing new clinical guidelines for diagnosis and developing novel therapies.
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Affiliation(s)
- Alireza Beheshti-Maal
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Acecr, Tehran, Iran
| | - Atena Tamimi
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Acecr, Tehran, Iran
| | - Shahrokh Iravani
- Gastroenterology and Hepatobiliary Research Center, Imam Reza Hospital, Tehran, Iran
| | | | - Majid Sorouri
- Digestive Diseases Research Center, Digestive Diseases Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamid Asadzadeh Aghdaei
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nikoo Hossein Khannazer
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Acecr, Tehran, Iran
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Mazza S, Soro S, Verga MC, Elvo B, Ferretti F, Cereatti F, Drago A, Grassia R. Liver-side of inflammatory bowel diseases: Hepatobiliary and drug-induced disorders. World J Hepatol 2021; 13:1828-1849. [PMID: 35069993 PMCID: PMC8727201 DOI: 10.4254/wjh.v13.i12.1828] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 07/16/2021] [Accepted: 11/15/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatobiliary disorders are among the most common extraintestinal manifestations in inflammatory bowel diseases (IBD), both in Crohn’s disease and ulcerative colitis (UC), and therefore represent a diagnostic challenge. Immune-mediated conditions include primary sclerosing cholangitis (PSC) as the main form, variant forms of PSC (namely small-duct PSC, PSC-autoimmune hepatitis overlap syndrome and IgG4-related sclerosing cholangitis) and granulomatous hepatitis. PSC is by far the most common, presenting in up to 8% of IBD patients, more frequently in UC. Several genetic foci have been identified, but environmental factors are preponderant on disease pathogenesis. The course of the two diseases is typically independent. PSC diagnosis is based mostly on typical radiological findings and exclusion of secondary cholangiopathies. Risk of cholangiocarcinoma is significantly increased in PSC, as well as the risk of colorectal cancer in patients with PSC and IBD-related colitis. No disease-modifying drugs are approved to date. Thus, PSC management is directed against symptoms and complications and includes medical therapies for pruritus, endoscopic treatment of biliary stenosis and liver transplant for end-stage liver disease. Other non-immune-mediated hepatobiliary disorders are gallstone disease, whose incidence is higher in IBD and reported in up to one third of IBD patients, non-alcoholic fatty liver disease, pyogenic liver abscess and portal vein thrombosis. Drug-induced liver injury (DILI) is an important issue in IBD, since most IBD therapies may cause liver toxicity; however, the incidence of serious adverse events is low. Thiopurines and methotrexate are the most associated with DILI, while the risk related to anti-tumor necrosis factor-α and anti-integrins is low. Data on hepatotoxicity of newer drugs approved for IBD, like anti-interleukin 12/23 and tofacitinib, are still scarce, but the evidence from other rheumatic diseases is reassuring. Hepatitis B reactivation during immunosuppressive therapy is a major concern in IBD, and adequate screening and vaccination is warranted. On the other hand, hepatitis C reactivation does not seem to be a real risk, and hepatitis C antiviral treatment does not influence IBD natural history. The approach to an IBD patient with abnormal liver function tests is complex due to the wide range of differential diagnosis, but it is of paramount importance to make a quick and accurate diagnosis, as it may influence the therapeutic management.
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Affiliation(s)
- Stefano Mazza
- Gastroenterology and Digestive Endoscopy Unit, ASST Cremona, Cremona 26100, Italy
| | - Sara Soro
- Gastroenterology and Digestive Endoscopy Unit, ASST Cremona, Cremona 26100, Italy
| | - Maria Chiara Verga
- Gastroenterology and Digestive Endoscopy Unit, ASST Cremona, Cremona 26100, Italy
| | - Biagio Elvo
- Gastroenterology and Digestive Endoscopy Unit, ASST Cremona, Cremona 26100, Italy
| | - Francesca Ferretti
- Gastroenterology Unit, ASST Fatebenefratelli-Sacco, Department of Biomedical and Clinical Sciences (DIBIC), Università degli Studi di Milano, Milan 20157, Italy
| | - Fabrizio Cereatti
- Gastroenterology and Digestive Endoscopy Unit, ASST Cremona, Cremona 26100, Italy
| | - Andrea Drago
- Gastroenterology and Digestive Endoscopy Unit, ASST Cremona, Cremona 26100, Italy
| | - Roberto Grassia
- Gastroenterology and Digestive Endoscopy Unit, ASST Cremona, Cremona 26100, Italy
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Kemme S, Mack CL. Pediatric Autoimmune Liver Diseases: Autoimmune Hepatitis and Primary Sclerosing Cholangitis. Pediatr Clin North Am 2021; 68:1293-1307. [PMID: 34736590 DOI: 10.1016/j.pcl.2021.07.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
In chronic hepatitis, a broad differential diagnosis should be considered to accurately identify the cause(s) of liver injury. Autoimmune liver diseases (autoimmune hepatitis, primary sclerosing cholangitis, overlap syndrome) can occur in the setting of limited symptoms; therefore, a high index of suspicion and appropriate diagnostic workup should be performed. Most children with autoimmune hepatitis achieve sustained remission with medical therapy; however, there are no equivalent therapies for primary sclerosing cholangitis that impact the progression of disease. Research should include biomarker studies to predict histologic remission in autoimmune hepatitis and mechanistic studies to define future treatment targets for primary sclerosing cholangitis.
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Affiliation(s)
- Sarah Kemme
- Section of Gastroenterology, Hepatology, and Nutrition, Digestive Health Institute, University of Colorado Denver School of Medicine and Children's Hospital Colorado, 13123 East 16th Avenue, Mailstop B290, Aurora, CO 80045, USA.
| | - Cara L Mack
- Section of Gastroenterology, Hepatology, and Nutrition, Digestive Health Institute, University of Colorado Denver School of Medicine and Children's Hospital Colorado, 13123 East 16th Avenue, Mailstop B290, Aurora, CO 80045, USA
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Jiang CB. Impact of clinical manifestations and outcome of ulcerative colitis with primary sclerosing cholangitis in children. Pediatr Neonatol 2021; 62:461-462. [PMID: 34482882 DOI: 10.1016/j.pedneo.2021.08.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Affiliation(s)
- Chuen-Bin Jiang
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, MacKay Children's Hospital, Taipei, Taiwan.
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The characteristics of pediatric ulcerative colitis with primary sclerosing cholangitis: A single-center study in Taiwan. Pediatr Neonatol 2021; 62:483-490. [PMID: 34074613 DOI: 10.1016/j.pedneo.2021.05.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 01/17/2021] [Accepted: 05/05/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Primary sclerosing cholangitis (PSC) is often associated with ulcerative colitis (UC). We investigated the clinical characteristics of pediatric UC patients with and without PSC. METHODS We retrospectively recruited children with UC, with and without PSC, from 2006 to 2017 in a tertiary center in Taiwan. The clinical data of the patients, including clinical and endoscopic UC severity scores, medications, and laboratory parameters, were analyzed. RESULTS We recruited five children with PSC-UC (PSC-UC group), and 26 with UC alone (non-PSC UC group) in this retrospective analysis. Among the patients with PSC-UC, four (80%) were compatible with definite or probable autoimmune sclerosing cholangitis (ASC). The UC Endoscopic Index of Severity (5.00 vs. 9.00, P = 0.003) and Mayo score (4.00 vs. 8.00, P = 0.014) were significantly lower in the PSC-UC group than the non-PSC UC group. The prevalence of immunomodulator use was significantly higher in the PSC-UC than the non-PSC UC group (100% vs. 42.3%, P = 0.043), but there was no difference regarding steroids, mesalamine, or biologics. At the end of the study, significantly fewer patients were steroid-free in the PSC-UC than the non-PSC UC group (20.0% vs. 84.6%, P = 0.010). CONCLUSIONS Pediatric patients with PSC-UC had less severe colitis than those with UC alone in terms of the clinical activity index and endoscopic severity index, but they were more likely to need an immunomodulator and less likely to be steroid-free in the long term, for the control of liver disease.
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The Role of Microbiota in Primary Sclerosing Cholangitis and Related Biliary Malignancies. Int J Mol Sci 2021; 22:ijms22136975. [PMID: 34203536 PMCID: PMC8268159 DOI: 10.3390/ijms22136975] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 06/18/2021] [Accepted: 06/21/2021] [Indexed: 02/08/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) is an immune-related cholangiopathy characterized by biliary inflammation, cholestasis, and multifocal bile duct strictures. It is associated with high rates of progression to end-stage liver disease as well as a significant risk of cholangiocarcinoma (CCA), gallbladder cancer, and colorectal carcinoma. Currently, no effective medical treatment with an impact on the overall survival is available, and liver transplantation is the only curative treatment option. Emerging evidence indicates that gut microbiota is associated with disease pathogenesis. Several studies analyzing fecal and mucosal samples demonstrate a distinct gut microbiome in individuals with PSC compared to healthy controls and individuals with inflammatory bowel disease (IBD) without PSC. Experimental mouse and observational human data suggest that a diverse set of microbial functions may be relevant, including microbial metabolites and bacterial processing of pharmacological agents, bile acids, or dietary compounds, altogether driving the intrahepatic inflammation. Despite critical progress in this field over the past years, further functional characterization of the role of the microbiota in PSC and related malignancies is needed. In this review, we discuss the available data on the role of the gut microbiome and elucidate important insights into underlying pathogenic mechanisms and possible microbe-altering interventions.
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Xie Y, Chen X, Deng M, Sun Y, Wang X, Chen J, Yuan C, Hesketh T. Causal Linkage Between Inflammatory Bowel Disease and Primary Sclerosing Cholangitis: A Two-Sample Mendelian Randomization Analysis. Front Genet 2021; 12:649376. [PMID: 33815483 PMCID: PMC8012893 DOI: 10.3389/fgene.2021.649376] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 02/23/2021] [Indexed: 11/13/2022] Open
Abstract
Background Observational studies suggest an association between inflammatory bowel disease (IBD) [including ulcerative colitis (UC) and Crohn’s disease (CD)] and Primary sclerosing cholangitis (PSC), but the causal association between the two diseases remains unclear. Methods We used two-sample Mendelian randomization (MR) to estimate the causal association between IBD and PSC. We chose single nucleotide polymorphisms (SNPs) data for analysis, obtained from previous genome-wide association studies (GWASs). Pleiotropy, heterogeneity, and sensitivity analyses were performed for quality control. Results We found that the causal associations between IBD (both UC and CD) and PSC were significant (e.g., IBD and PSC, Robust adjusted profile score (RAPS) OR = 1.29, 95% CI 1.16∼1.44, p< 0.01; UC and PSC, RAPS OR = 1.40, 95% CI 1.23∼1.58, p< 0.01; CD and PSC, RAPS OR = 1.13, 95% CI 1.02∼1.26, p = 0.02). MR Egger, IVW, and ML tests found statistical heterogeneity between determined IV estimates. The leave-one-out analysis also indicated the sensitivity of the SNPs (e.g., IBD and PSC, MR-Egger Q = 644.30, p< 0.01; UC and PSC, MR-Egger Q = 378.30, p< 0.01; UC and PSC, MR-Egger Q = 538.50, p < 0.01). Conclusion MR analyses support the positive causal effect of IBD (including UC and CD) on PSC in a European population. We provide suggestions for preventing and treating the two diseases.
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Affiliation(s)
- Ying Xie
- Centre for Global Health, Zhejiang University School of Medicine, Hangzhou, China
| | - Xuejie Chen
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Minzi Deng
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Yuhao Sun
- Centre for Global Health, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaoyan Wang
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Jie Chen
- Centre for Global Health, Zhejiang University School of Medicine, Hangzhou, China
| | - Changzheng Yuan
- Department of Big Data and Health Science, Zhejiang University School of Medicine, Hangzhou, China
| | - Therese Hesketh
- Centre for Global Health, Zhejiang University School of Medicine, Hangzhou, China.,Institute for Global Health, University College London, London, United Kingdom
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Aloi M, Bramuzzo M, Norsa L, Arrigo S, Distante M, Miele E, Romano C, Giobbi C, Panceri R, Cucchiara S, Alvisi P. Disease Activity Patterns in the First 5 Years After Diagnosis in Children With Ulcerative Colitis: A Population-Based Study. J Crohns Colitis 2021; 15:367-374. [PMID: 33022055 DOI: 10.1093/ecco-jcc/jjaa203] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND The aim of this study was to define clusters of activity in a population-based cohort during the first 5 years after diagnosis in children with ulcerative colitis [UC] and to identify early prognostic risk factors. METHODS All UC patients from the SIGENP IBD registry with a complete follow-up of at least 5 years were included. Active disease was defined every 6 months in the presence of at least one of the following: clinical activity [Paediatric Ulcerative Colitis Activity Index ≥ 35]; endoscopic activity [Mayo score ≥ 1]; faecal calprotectin > 250 µg/g; hospitalization; surgery; or treatment escalation. Formula-based clusters were generated based on four published questionnaire-based activity patterns in adults, plus one additional cluster. RESULTS In total, 226 patients were identified. Forty-two [19%] had moderate-severe chronically active disease, 31 [14%] chronic-intermittent, 75 [33%] quiescent, 54 [24%] active disease in the first 2 years after the diagnosis, then sustained remission, and 24 [11%] a remission in the first 2 years then an active disease. Mild disease onset along with a lower clinical severity not requiring the use of corticosteroids at 6 months were related to a quiescent disease course at the next follow-up (logistic model area under the curve 0.86 [95% confidence interval 0.78-0.94]; positive predictive value 67%; negative predictive value 70%). Eight per cent of patients needed surgery, none in the quiescent group [p = 0.04]. CONCLUSIONS More than one-third of children with UC present with a chronically active or intermittent course during the first 5 years of follow-up. A significant group of patients has active disease in the first 2 years and then sustained remission. Interestingly, after initial treatment, one-third of patients have well-controlled disease throughout.
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Affiliation(s)
- M Aloi
- Pediatric Gastroenterology and Liver Unit, Sapienza University of Rome, Rome, Italy
| | - M Bramuzzo
- Institute for Maternal and Child Health IRCCS 'Burlo Garofalo', Trieste, Italy
| | - L Norsa
- Pediatric Hepatology Gastroenterology and Transplantation, ASST Papa Giovanni XXIII, Bergamo, Italy
| | - S Arrigo
- Pediatric Gastroenterology Unit, Institute 'Giannina Gaslini', Genoa, Italy
| | - M Distante
- Pediatric Gastroenterology and Liver Unit, Sapienza University of Rome, Rome, Italy
| | - E Miele
- Department of Translational Medical Science, Section of Pediatrics, University of Naples 'Federico II', Naples, Italy
| | - C Romano
- Pediatric Gastroenterology and Endoscopy, University of Messina, Messina, Italy
| | - C Giobbi
- Pediatric Gastroenterology and Liver Unit, Sapienza University of Rome, Rome, Italy
| | - R Panceri
- Department of Pediatrics, University of Milano-Bicocca Fond., MBBM/Hosp., San Gerardo Monza, Italy
| | - S Cucchiara
- Pediatric Gastroenterology and Liver Unit, Sapienza University of Rome, Rome, Italy
| | - P Alvisi
- Pediatric Department, Maggiore Hospital, Bologna, Italy
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Colman RJ, Dhaliwal J, Rosen MJ. Predicting Therapeutic Response in Pediatric Ulcerative Colitis-A Journey Towards Precision Medicine. Front Pediatr 2021; 9:634739. [PMID: 33681110 PMCID: PMC7925616 DOI: 10.3389/fped.2021.634739] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Accepted: 01/08/2021] [Indexed: 12/12/2022] Open
Abstract
Ulcerative colitis (UC) is a disabling disease, characterized by chronic inflammation of the colon, with a rising prevalence worldwide in the pediatric age group. Although UC presents in children with varying severity, disease extent, and comorbidities, initial treatment is essentially uniform, consisting of 5-aminosalicylate drugs with corticosteroid induction for those with moderately to severely active disease. With the advent of anti-tumor necrosis factor (TNF) biologic therapy and several new biologics and small-molecule drugs for UC, precision medicine approaches to treatment are needed to more rapidly achieve sustained remission, restore quality of life, normalize development, and limit exposure to toxic corticosteroids in children with UC. Here, we review available data on clinical, biochemical, histopathologic, and molecular predictors of treatment response in UC. We also address known predictors and special treatment considerations in specific relevant scenarios such as very-early-onset UC, acute severe UC, ileal pouch anal anastomosis, and UC with concomitant primary sclerosing cholangitis. The review concludes with a prediction of how machine learning will integrate multimodal patient data to bring precision medicine to the bedside of children with UC in the future.
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Affiliation(s)
- Ruben J Colman
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
| | - Jasbir Dhaliwal
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Michael J Rosen
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
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Crescente JG, Dellavance A, Diniz MA, Carrilho FJ, de Andrade LEC, Cançado ELR. Antineutrophil cytoplasmic antibody profiles differ according to type of primary sclerosing cholangitis and autoimmune hepatitis. Clinics (Sao Paulo) 2021; 76:e2228. [PMID: 33567045 PMCID: PMC7847259 DOI: 10.6061/clinics/2021/e2228] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 12/09/2020] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVES To determine the frequency of the antineutrophil cytoplasmic antibodies (ANCA), antiproteinase-3 and antimyeloperoxidase, in primary sclerosing cholangitis (PSC) with or without inflammatory bowel disease (IBD+ or IBD-) and in different types of autoimmune hepatitis (AIH). Additionally, to verify the agreement between ANCA patterns by indirect immunofluorescence and their antigenic specificities by ELISA. METHODS For this study, 249 patients were enrolled (42 PSC/IBD+; 33 PSC/IBD-; 31 AIH type-1; 30 AIH type-2; 31 AIH type-3; 52 primary biliary cirrhosis; 30 healthy controls) whose serum samples were tested for ANCA autoantibodies. RESULTS There were fewer female subjects in the PSC/IBD- group (p=0.034). Atypical perinuclear-ANCA was detected more frequently in PSC/IBD+ patients than in PSC/IBD- patients (p=0.005), and was significantly more frequent in type-1 (p<0.001) and type-3 AIH (p=0.012) than in type-2 AIH. Proteinase-3-ANCA was detected in 25 samples (only one with cytoplasmic-ANCA pattern), and more frequently in PSC/IBD+ than in PSC/IBD- patients (p=0.025). Myeloperoxidase-ANCA was identified in eight samples (none with the perinuclear-ANCA pattern). Among the 62 reactive samples for atypical perinuclear-ANCA, 13 had antigenic specific reactions for proteinase-3 and myeloperoxidase. CONCLUSIONS PSC/IBD+ differed from PSC/IBD- in terms of sex and proteinase 3-ANCA and atypical perinuclear-ANCA reactivity, the latter of which was more frequently detected in type-1 and type-3 AIH than in type-2 AIH. There was no agreement between ANCA patterns and antigenic specificities in IBD and autoimmune liver diseases, which reinforces the need for proteinase-3 and myeloperoxidase antibody testing.
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Affiliation(s)
- Juliana Goldbaum Crescente
- Departamento de Gastroenterologia, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, SP, BR
- Laboratorio de Investigacao Medica (LIM 06), Instituto de Medicina Tropical, Universidade de Sao Paulo, Sao Paulo, SP, BR
| | - Alessandra Dellavance
- Disciplina de Reumatologia, Escola Paulista de Medicina, Universidade Federal de Sao Paulo, Sao Paulo, SP, BR
- Divisao de Pesquisa e Desenvolvimento, Laboratorios Fleury Medicina e Saude, Sao Paulo, SP, BR
| | - Marcio Augusto Diniz
- Biostatistics and Bioinformatics Research Center, Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, CA, USA
| | - Flair Jose Carrilho
- Departamento de Gastroenterologia, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, SP, BR
| | - Luis Eduardo Coelho de Andrade
- Disciplina de Reumatologia, Escola Paulista de Medicina, Universidade Federal de Sao Paulo, Sao Paulo, SP, BR
- Divisao de Pesquisa e Desenvolvimento, Laboratorios Fleury Medicina e Saude, Sao Paulo, SP, BR
| | - Eduardo Luiz Rachid Cançado
- Departamento de Gastroenterologia, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, SP, BR
- Laboratorio de Investigacao Medica (LIM 06), Instituto de Medicina Tropical, Universidade de Sao Paulo, Sao Paulo, SP, BR
- *Corresponding author. E-mail:
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Chahal D, Shamatutu C, Salh B, Davies J. The impact of primary sclerosing cholangitis or inflammatory bowel disease on cholangiocarcinoma phenotype, therapy, and survival. JGH Open 2020; 4:1128-1134. [PMID: 33319047 PMCID: PMC7731823 DOI: 10.1002/jgh3.12405] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Revised: 07/20/2020] [Accepted: 07/23/2020] [Indexed: 12/12/2022]
Abstract
Background and Aim Primary sclerosing cholangitis (PSC), with or without inflammatory bowel disease (IBD), confers the risk of cholangiocarcinoma. Isolated IBD may be an independent risk factor for cholangiocarcinoma. We sought to compare cholangiocarcinoma phenotype and outcomes between patients with PSC, IBD, and neither. Methods Patients with malignancy were separated into cohorts by the presence of PSC and IBD. Data regarding demographics, clinical presentation, therapeutic regimens, and survival were collected. Statistical analysis was carried out using GraphPad and R‐Studio. Results Of 946 patients, 22 had PSC, and 18 had isolated IBD. PSC and IBD patients were younger than controls (P < 0.001, P = 0.01). Cholangiocarcinoma prevalence was estimated at 0.01% for IBD patients, 0.6% for PSC patients, and 0.002% for all other patients. All cohorts most often presented at stage 4. PSC patients presented more often at stage 3 (P = 0.04) and with perihilar disease (P = 0.001). Patients with PSC or IBD received less chemotherapy (P = 0.004, 0.01). Median overall survivals were 15 months (PSC), 11 months (IBD), and 10 months (controls) (P = 0.79). Patients with intrahepatic tumors had longer survival (P < 0.001). Curative intent resection improved survival in all cohorts (P < 0.001). Multivariate regression identified resection as a predictor of improved survival. Extrahepatic, perihilar, gallbladder, and unspecified biliary tumors were predictors of death. Conclusions Cholangiocarcinoma presents at a late stage and portends dismal survival regardless of PSC or IBD status. Survival was dependent on tumor location and surgical resection. These data suggest that efforts should focus on developing protocols that are able to detect and treat cholangiocarcinoma in high‐risk populations (PSC) at an early stage.
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Affiliation(s)
- Daljeet Chahal
- Division of Gastroenterology University of British Columbia Vancouver British Columbia Canada.,Department of Medicine University of British Columbia Vancouver British Columbia Canada
| | - Chris Shamatutu
- Department of Medicine University of British Columbia Vancouver British Columbia Canada
| | - Bill Salh
- Division of Gastroenterology University of British Columbia Vancouver British Columbia Canada.,Department of Medicine University of British Columbia Vancouver British Columbia Canada
| | - Janine Davies
- Department of Medicine University of British Columbia Vancouver British Columbia Canada.,Division of Medical Oncology BC Cancer Vancouver British Columbia Canada
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Weismüller TJ, Zhou T, Kalthoff S, Lenzen H, Manns MP, Strassburg CP. Genetic variants of UDP-glucuronosyltransferase 1A genes are associated with disease presentation and outcome in primary sclerosing cholangitis. Liver Int 2020; 40:1645-1654. [PMID: 32378294 DOI: 10.1111/liv.14487] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 04/09/2020] [Accepted: 04/17/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS Primary sclerosing cholangitis (PSC) is a progressive cholestatic liver disease without a curative medical therapy. The human UDP-glucuronosyltransferases 1A play a major role in the detoxification and elimination of bilirubin, bile acids and xenobiotics. Whether genetic UGT1A variants determine course and outcome of PSC has not yet been described. METHODS A large cohort of German PSC patients with a long-term-follow-up was genotyped for UGT1A variants including UGT1A1*28, UGT1A3-66 T>C and UGT1A7 p.N129K/p.R131K using TaqMan 5'-nuclease assays. Results were correlated with clinical characteristics and transplant-free survival. RESULTS About 331 patients with PSC were included in the study (69.9% male, mean age at diagnosis 32.6 years). Median transplant-free survival was 14.9 years. Patients with wild-type alleles of all three UGT1A genes had a longer transplant-free survival (17.2 vs. 14.4 years, P = .048) than patients carrying a homozygous or heterozygous SNP variant in at least one of the UGT1A1, UGT1A3 or UGT1A7 genes. Additionally, we found that patients carrying wild-type alleles of all three UGT1A genes had lower serum bilirubin (25 vs. 38 µmol/L, P = .02) and serum cholesterol (195 vs. 223 mg/dL), P = .035) at first presentation. Furthermore, inflammatory bowel disease was found to be associated with wild-type UGT1A alleles (82.2% vs. 68.4%, P = .046). CONCLUSIONS This large cohort shows an association with single nucleotide polymorphisms of the UGT1A1, UGT1A3 and UGT1A7 genes and outcome in PSC. Thus, UGT1A variants may represent a tool for the prognostic stratification of PSC patients and establish a link between disease progression and the regulation of detoxification by glucuronidation in PSC.
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Affiliation(s)
| | - Taotao Zhou
- Department of Internal Medicine 1, University of Bonn, Bonn, Germany
| | - Sandra Kalthoff
- Department of Internal Medicine 1, University of Bonn, Bonn, Germany
| | - Henrike Lenzen
- Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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Little R, Wine E, Kamath BM, Griffiths AM, Ricciuto A. Gut microbiome in primary sclerosing cholangitis: A review. World J Gastroenterol 2020; 26:2768-2780. [PMID: 32550753 PMCID: PMC7284173 DOI: 10.3748/wjg.v26.i21.2768] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 03/27/2020] [Accepted: 05/26/2020] [Indexed: 02/06/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by biliary inflammation and stricturing. Exploration of the pathogenesis of PSC in light of its association with inflammatory bowel disease (IBD) and the “gut-liver” axis is an emerging area of interest. A growing number of studies have begun to elucidate the role of the gut microbiota, its metabolites and its influence on host immune responses in the development of PSC and PSC-IBD. Studies of the fecal microbiota have highlighted enriched levels of certain species, including Veillonella, Streptococcus and Enterococcus, among others. A heightened immune response to enteric dysbiosis and bacterial translocation have also been implicated. For example, Klebsiella pneumoniae strains derived from gnotobiotic mice transplanted with PSC-IBD microbiota were found to induce pore formation in human intestinal epithelial cells and enhanced Th17 responses. Gut microbes have additionally been hypothesized to be implicated in PSC pathogenesis through their role in the synthesis of various metabolites, including bile acids (BAs), which function as signaling molecules with important gut and hepatic effects. An expanded knowledge of the gut microbiome as it relates to PSC offers critical insight into the development of microbe-altering therapeutic interventions, such as antibiotics, nutritional interventions and fecal microbial transplantation. Some of these have already shown some preliminary evidence of benefit. Despite exciting progress in the field, much work remains to be done; areas that are particularly lacking include functional characterization of the microbiome and examination of pediatric populations. In this review, we summarize studies that have investigated the microbiome in PSC and PSC-IBD as well as putative mechanisms, including the potential role of metabolites, such as BAs. We then briefly review the evidence for interventions with microbe-altering properties for treating PSC.
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Affiliation(s)
- Rebecca Little
- Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
| | - Eytan Wine
- Division of Pediatric Gastroenterology and Nutrition, 7-142H Katz Group – Rexall Centre, University of Alberta, Edmonton, AB T6G 1C9, Canada
| | - Binita M Kamath
- Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
| | - Anne M Griffiths
- Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
| | - Amanda Ricciuto
- Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
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