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Chen Y, Chen R, Li H, Shuai Z. Clinical management of autoimmune liver diseases: juncture, opportunities, and challenges ahead. Immunol Res 2025; 73:67. [PMID: 40195209 PMCID: PMC11976385 DOI: 10.1007/s12026-025-09622-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Accepted: 03/14/2025] [Indexed: 04/09/2025]
Abstract
The three major autoimmune liver diseases are autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC).These conditions are assumed to result from a breakdown in immunological tolerance, which leads to an inflammatory process that causes liver damage.The self-attack is started by T-helper cell-mediated identification of liver autoantigens and B-cell production of autoantibodies,and it is maintained by a reduction in the number and activity of regulatory T-cells.Infections and environmental factors have been explored as triggering factors for these conditions, in addition to a genetic predisposition.Allelic mutations in the HLA locus have been linked to vulnerability, as have relationships with single nucleotide polymorphisms in non-HLA genes.Despite the advances in the management of these diseases, there is no curative treatment for these disorders, and a significant number of patients eventually progress to an end-stage liver disease requiring liver transplantation.In this line, tailored immune-therapeutics have emerged as possible treatments to control the disease.In addition, early diagnosis and treatment are pivotal for reducing the long-lasting effects of these conditions and their burden on quality of life.Herein we present a review of the etiology, clinical presentation, diagnosis, and challenges on ALDs and the feasible solutions for these complex diseases.
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MESH Headings
- Humans
- Hepatitis, Autoimmune/therapy
- Hepatitis, Autoimmune/diagnosis
- Hepatitis, Autoimmune/immunology
- Hepatitis, Autoimmune/etiology
- Cholangitis, Sclerosing/therapy
- Cholangitis, Sclerosing/diagnosis
- Cholangitis, Sclerosing/immunology
- Liver Cirrhosis, Biliary/therapy
- Liver Cirrhosis, Biliary/diagnosis
- Liver Cirrhosis, Biliary/immunology
- Animals
- Immunotherapy/methods
- Autoimmune Diseases/therapy
- Autoimmune Diseases/diagnosis
- Disease Management
- Genetic Predisposition to Disease
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Affiliation(s)
- Yangfan Chen
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Ruofei Chen
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Haiyan Li
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Zongwen Shuai
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, 230032, China.
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Zhao X, Naghibzadeh M, Sun Y, Rahmani A, Lilly L, Selzner N, Tsien C, Jaeckel E, Vyas MP, Krishnan R, Hirschfield G, Bhat M. Machine Learning Prediction Model of Waitlist Outcomes in Patients with Primary Sclerosing Cholangitis. Transplant Direct 2025; 11:e1774. [PMID: 40166627 PMCID: PMC11957646 DOI: 10.1097/txd.0000000000001774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Accepted: 01/01/2025] [Indexed: 04/02/2025] Open
Abstract
Background Liver transplantation is essential for many people with primary sclerosing cholangitis (PSC). People with PSC are less likely to receive a deceased donor liver transplant compared with other causes of chronic liver disease. This disparity may stem from the inaccuracy of the model for end-stage liver disease (MELD) in predicting waitlist mortality or dropout for PSC. The broad applicability of MELD across many causes comes at the expense of accuracy in prediction for certain causes that involve unique comorbidities. We aimed to develop a model that could more accurately predict dynamic changes in waitlist outcomes among patients with PSC while including complex clinical variables. Methods We developed 3 machine learning architectures using data from 4666 patients with PSC in the Scientific Registry of Transplant Recipients (SRTR) and tested our models on our institutional data set of 144 patients at the University Health Network (UHN). We evaluated their time-dependent concordance index (C-index) for mortality prediction and compared it against MELD-sodium and MELD 3.0. Results Random survival forest (RSF), a decision tree-based survival model, outperformed MELD-sodium and MELD 3.0 in both the SRTR and the UHN test data set using the same bloodwork variables and readily available demographic data. It achieved a C-index of 0.868 (SD 0.020) and 0.771 (SD 0.085) on the SRTR and UHN test data, respectively. Training a separate RSF model using the UHN data with PSC-specific achieved a C-index of 0.91. In addition to high MELD score, increased white blood cells, time on the waiting list, platelet count, presence of Autoimmune hepatitis-PSC overlap, aspartate aminotransferase, female sex, age, history of stricture dilation, and extremes of body weight were the top-ranked features predictive of the outcomes. Conclusions Our RSF model offers more accurate waitlist outcome prediction in PSC. The significant performance improvement with the inclusion of PSC-specific variables highlights the importance of disease-specific variables for predicting trajectories of clinically distinct presentations.
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Affiliation(s)
- Xun Zhao
- Ajmera Transplant Program, University Health Network, Toronto, ON, Canada
| | - Maryam Naghibzadeh
- Ajmera Transplant Program, University Health Network, Toronto, ON, Canada
| | - Yingji Sun
- Ajmera Transplant Program, University Health Network, Toronto, ON, Canada
| | - Arya Rahmani
- Ajmera Transplant Program, University Health Network, Toronto, ON, Canada
| | - Leslie Lilly
- Ajmera Transplant Program, University Health Network, Toronto, ON, Canada
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Toronto, Toronto, ON, Canada
| | - Nazia Selzner
- Ajmera Transplant Program, University Health Network, Toronto, ON, Canada
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Toronto, Toronto, ON, Canada
| | - Cynthia Tsien
- Ajmera Transplant Program, University Health Network, Toronto, ON, Canada
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Toronto, Toronto, ON, Canada
| | - Elmar Jaeckel
- Ajmera Transplant Program, University Health Network, Toronto, ON, Canada
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Toronto, Toronto, ON, Canada
| | | | - Rahul Krishnan
- Department of Computer Science, University of Toronto, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Gideon Hirschfield
- Ajmera Transplant Program, University Health Network, Toronto, ON, Canada
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Toronto, Toronto, ON, Canada
| | - Mamatha Bhat
- Ajmera Transplant Program, University Health Network, Toronto, ON, Canada
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Toronto, Toronto, ON, Canada
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Kahan T, Marenco-Flores A, Amaris NR, Barba R, Goyes D, Medina-Morales E, Sierra L, Patwardhan VR, Bonder A. Performance of the Mayo Risk Score in Predicting Transplant and Mortality in a Single-Center U.S. Cohort of Primary Sclerosing Cholangitis. J Clin Med 2025; 14:2098. [PMID: 40142906 PMCID: PMC11942813 DOI: 10.3390/jcm14062098] [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: 01/16/2025] [Revised: 03/03/2025] [Accepted: 03/17/2025] [Indexed: 03/28/2025] Open
Abstract
Background: The Mayo Risk Score (MRS) predicts short-term mortality in primary sclerosing cholangitis (PSC) using the age, bilirubin, albumin, aspartate aminotransferase (AST), and variceal bleeding history. While the MRS has been validated in end-stage PSC, its ability to predict liver transplantation (LT) and outcomes in newly diagnosed patients without advanced disease remains unclear. This study evaluated the effectiveness of the MRS in predicting LT and mortality in this patient population. Methods: We analyzed data from 109 adults with PSC enrolled in a prospective registry (2018-2024) with ≥4 years of follow-up. Logistic regression identified the predictors of LT or death, and the model performance was assessed using the area under the receiver operating characteristic curve (AUROC). Multicollinearity was evaluated using the variance inflation factor (VIF). Results: Among the 109 patients (mean age 45 ± 15 years, 51% female), 85% remained alive without LT, 12% underwent LT, and 3% died over a median follow-up of 4.63 years. The MRS was significantly associated with LT or death (OR 3.08, p < 0.001) and demonstrated excellent predictive performance (AUROC 0.99, p < 0.001). The model achieved 95.45% sensitivity, 98.85% specificity, and a correct classification rate of 98.17%, supporting its clinical utility. Conclusion: The MRS is a robust tool for risk stratification in PSC, predicting LT and mortality. These findings highlight its broader applicability beyond end-stage PSC and underscore its potential for guiding clinical management and early intervention strategies.
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Affiliation(s)
- Tamara Kahan
- Division of Gastroenterology, Hepatology, and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (T.K.); (A.M.-F.); (N.R.A.); (V.R.P.)
| | - Ana Marenco-Flores
- Division of Gastroenterology, Hepatology, and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (T.K.); (A.M.-F.); (N.R.A.); (V.R.P.)
| | - Natalia Rojas Amaris
- Division of Gastroenterology, Hepatology, and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (T.K.); (A.M.-F.); (N.R.A.); (V.R.P.)
| | - Romelia Barba
- Department of Internal Medicine, Texas Tech University System, Lubbock, TX 79430, USA;
| | - Daniela Goyes
- Division of Digestive Diseases, Yale School of Medicine, New Haven, CT 06520, USA
| | - Esli Medina-Morales
- Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, USA;
| | - Leandro Sierra
- Department of Medicine, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
| | - Vilas R. Patwardhan
- Division of Gastroenterology, Hepatology, and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (T.K.); (A.M.-F.); (N.R.A.); (V.R.P.)
| | - Alan Bonder
- Division of Gastroenterology, Hepatology, and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (T.K.); (A.M.-F.); (N.R.A.); (V.R.P.)
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Abdulrasak M, Someili AM, Mohrag M. Cytopenias in Autoimmune Liver Diseases-A Review. J Clin Med 2025; 14:1732. [PMID: 40095848 PMCID: PMC11900928 DOI: 10.3390/jcm14051732] [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: 01/26/2025] [Revised: 02/22/2025] [Accepted: 03/01/2025] [Indexed: 03/19/2025] Open
Abstract
Autoimmune liver diseases (AiLDs), including autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC), are immune-mediated conditions associated with significant hepatic and systemic manifestations. Among these, cytopenias-defined as reductions in blood cell counts affecting single or multiple lineages-represent a clinically important, though often under-recognized, complication. Cytopenias in AiLDs arise from diverse mechanisms, including immune-mediated destruction, hypersplenism due to portal hypertension, bone marrow suppression, and nutritional deficiencies. These abnormalities can exacerbate bleeding, infections, or fatigue, complicating the disease course and impacting therapeutic strategies. Immune-mediated cytopenias, such as autoimmune hemolytic anemia (AIHA), immune thrombocytopenic purpura (ITP), and autoimmune neutropenia (AIN), are more frequently associated with AIH, whereas cytopenias in PBC and PSC are largely attributed to hypersplenism. Diagnostic evaluation involves a systematic approach combining clinical history, laboratory testing (e.g., complete blood counts, Coombs tests, and nutritional assessments), imaging studies, and bone marrow evaluation in complex cases. Treatment strategies aim to address the underlying cause of cytopenias, including immunosuppressive therapy for autoimmune mechanisms, beta-blockers or splenectomy for hypersplenism, and supplementation for nutritional deficiencies. Challenges include distinguishing between immune- and hypersplenism-related cytopenias, managing drug-induced cytopenias, and optimizing care in transplant candidates. The recently recognized IgG4-related disease, often mimicking cholestatic AiLDs, adds another layer of complexity, given its association with autoimmune cytopenias and hypersplenism. This review aims to act as a guide for the clinician dealing with patients with AiLDs with respect to the occurrence of cytopenias, with a specific focus on pathophysiology and management of these cytopenias. Furthermore, there need to be enhanced multidisciplinary discussions about those patients between the hematologists and hepatologists, with a maintenance of a high index of suspicion for the rarer causes of cytopenias in AiLDs on the part of the treating physician, and there is a need for further studies to elucidate the mechanisms behind the occurrence of cytopenias in AiLDs.
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Affiliation(s)
- Mohammed Abdulrasak
- Department of Gastroenterology and Nutrition, Skane University Hospital, 214 28 Malmo, Sweden
- Department of Clinical Sciences, Lund University, 221 00 Malmo, Sweden
| | - Ali M. Someili
- Department of Medicine, Faculty of Medicine, Jazan University, Jazan 45142, Saudi Arabia; (A.M.S.); (M.M.)
| | - Mostafa Mohrag
- Department of Medicine, Faculty of Medicine, Jazan University, Jazan 45142, Saudi Arabia; (A.M.S.); (M.M.)
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Zheng D, Xu Q, Wu J, Gu Z, Chen J, Liu Y. Prevalence and bidirectional association between primary sclerosing cholangitis and Crohn's disease: A systematic review and meta-analysis. GASTROENTEROLOGIA Y HEPATOLOGIA 2025:502346. [PMID: 39832533 DOI: 10.1016/j.gastrohep.2025.502346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 01/05/2025] [Accepted: 01/06/2025] [Indexed: 01/22/2025]
Abstract
PURPOSE This meta-analysis aimed to evaluating the prevalence of Crohn's disease in primary sclerosing cholangitis (PSC) and the incidence of primary sclerosing cholangitis in Crohn's disease (CD), along with their interrelation. METHODS An extensive search was conducted in the PubMed and Embase to identify available publications up to December 2023. Studies were included if they reported the prevalence of CD in PSC patients, or vice versa. Proportions were assessed using the DerSimonian and Laird method, followed by transformation via the Freeman-Tukey double inverse sine transformation. The quality of the included studies utilizing the Joanna Briggs Institute Critical Appraisal Checklist. RESULTS Based on quantitative analysis of 61 studies, the prevalence of PSC in patients with CD was 0.88% (95% CI: 0.53-1.30%). The prevalence of PSC in male CD patients was 0.45% (95% CI: 0.03-1.16%). In female CD patients, the prevalence was 0.51% (95% CI: 0.09-1.14%). The prevalence of CD with PSC was 11.27% (95% CI: 9.56-13.10%). The prevalence of CD in male PSC patients was 10.71% (95% CI: 7.42-14.50%). Among female PSC patients, the pooled prevalence of CD was 13.05% (95% CI: 11.05-15.19%). CONCLUSIONS We found a significant bidirectional association between PSC and CD, with a higher prevalence of CD in female with PSC compared to male. These findings provide important epidemiological data for clinical practice.
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Affiliation(s)
- Dongyuan Zheng
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Qinke Xu
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Jin Wu
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Zhouyue Gu
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Jieya Chen
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yingchao Liu
- The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China.
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Horio R, Kato J, Taida T, Ohta Y, Saito K, Oyama Y, Nakazawa H, Mamiya Y, Goto C, Takahashi S, Ouchi M, Kurosugi A, Sonoda M, Kan M, Kaneko T, Nagashima H, Akizue N, Takahashi K, Okimoto K, Ohyama H, Matsumura T, Ohno I, Kato N. Clinical outcomes and reintervention after endoscopic retrograde cholangiopancreatography in primary sclerosing cholangitis in absence of cholangitis. Indian J Gastroenterol 2024; 43:1021-1029. [PMID: 38995523 PMCID: PMC11464613 DOI: 10.1007/s12664-024-01630-1] [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: 02/19/2024] [Accepted: 06/10/2024] [Indexed: 07/13/2024]
Abstract
BACKGROUND AND AIM Endoscopic retrograde cholangiopancreatography (ERCP) may help detect cholangiocarcinoma in patients with primary sclerosing cholangitis (PSC), but it may be associated with complications. This study was aimed at determining the prognostic impact of ERCP on patients with PSC without cholangitis. METHODS Patients with PSC without cholangitis were divided into two groups: those who underwent ERCP within three years after diagnosis (ERCP-performed group) and those who did not (non-ERCP group). These groups were compared in terms of clinical outcomes (liver-related death or liver transplantation, endoscopic treatment requirement and repeated cholangitis) and the composite outcome. RESULTS Of 99 patients with PSC with detailed medical history, 49 were included in the ERCP-performed group and 21 in the non-ERCP group. In Kaplan-Meier analysis, the non-ERCP group was less likely to achieve the three outcomes and the composite outcome, showing statistical significance (endoscopic treatment requirement; p = 0.017 and composite outcome; p = 0.014). A Cox proportional hazards model indicated that ERCP in the asymptomatic state was a significant predictor of endoscopic treatment requirement (hazard ratio [HR]: 4.37, 95% confidence interval [CI]: 1.03-18.59) and the composite outcome (HR: 4.54, 95% CI: 1.07-19.28). CONCLUSION ERCP in patients with PSC without cholangitis is likely to require further endoscopic treatment and may be associated with poor prognosis.
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Affiliation(s)
- Ryosuke Horio
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Jun Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan.
| | - Takashi Taida
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Yuki Ohta
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Keiko Saito
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Yuhei Oyama
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Hayato Nakazawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Yukiyo Mamiya
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Chihiro Goto
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Satsuki Takahashi
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Mayu Ouchi
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Akane Kurosugi
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Michiko Sonoda
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Motoyasu Kan
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Tatsuya Kaneko
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Hiroki Nagashima
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Naoki Akizue
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Koji Takahashi
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Kenichiro Okimoto
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Hiroshi Ohyama
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Tomoaki Matsumura
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Izumi Ohno
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Naoya Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
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Färkkilä M, Åberg F, Alfthan H, Jokelainen K, Puustinen L, Kautiainen H, Tenca A. Surrogate markers of bile duct disease progression in primary sclerosing cholangitis - A prospective study with repeated ERCP examinations. JHEP Rep 2024; 6:101161. [PMID: 39290402 PMCID: PMC11405802 DOI: 10.1016/j.jhepr.2024.101161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 06/14/2024] [Accepted: 06/25/2024] [Indexed: 09/19/2024] Open
Abstract
Background & Aims Validated prognostic tools for estimating short-term bile duct disease progression in primary sclerosing cholangitis (PSC) are lacking. We evaluated the predictive value of serum and biliary biochemistry for the progression of bile duct disease in PSC using repeated endoscopic retrograde cholangiopancreatography (ERCP) examinations to identify surrogate markers for more personalized surveillance. Methods We conducted a prospective analysis including patients with PSC who underwent ERCP for confirmation of diagnosis, monitoring of disease progression, or dysplasia surveillance. ERCP findings were scored, and dilatation was performed if a dominant stricture was diagnosed or if a cytology brush could not be passed. Bile samples were aspirated for biliary IL8 and calprotectin. We analysed optimal cut-off values and AUCs for 20 laboratory markers and evaluated their association with the time to an ERCP score increase of ≥2 points or first dilatation, whichever came first. Of the 1,002 patients, 653 had ≥2 ERCP examinations and ≥3 years of follow-up. After excluding patients with PSC-overlap syndrome or initial dilatation, 398 patients were included. Results Of the patients included, 62% had mild or moderate and 38% had advanced bile duct disease. During follow-up, 41% of patients demonstrated progression of disease. Biliary calprotectin (AUC 0.76; 95% CI 0.69 to 0.82) and IL8 (AUC 0.76; 95% CI 0.69 to 0.84) were the only variables that demonstrated predictive value for disease progression and/or need for dilatation. Conclusions Biliary calprotectin and IL8 are promising surrogate markers for identifying patients with PSC at risk of progression and determining the timing for subsequent imaging. Conventional liver function tests may not be sensitive or specific enough to monitor PSC progression, particularly in the short term. Impact and implications Validated prognostic tools for estimating short-term bile duct disease progression in primary sclerosing cholangitis are lacking. In this prospective study, based on sequential endoscopic retrograde cholangiopancreatography examinations, biliary calprotectin and IL8 levels turned out to be more sensitive for predicting bile duct progression than traditional liver function tests, such as alkaline phosphatase, in the short term. These findings could lead to more personalized patient surveillance and improve clinical practice by providing a more accurate method for monitoring disease progression and treatment responses. Additionally, these markers have potential as surrogate endpoints in clinical drug trials. The limitation is that measurement of biliary IL8 and calprotectin requires endoscopic retrograde cholangiopancreatography with bile sampling.
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Affiliation(s)
- Martti Färkkilä
- Helsinki University, Finland
- Department of Gastroenterology, Helsinki University Hospital, Abdominal Center, Helsinki, Finland
| | - Fredrik Åberg
- Transplantation and Liver Surgery, Abdominal Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Henrik Alfthan
- Department of Clinical Chemistry, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Kalle Jokelainen
- Department of Gastroenterology, Helsinki University Hospital, Abdominal Center, Helsinki, Finland
| | - Lauri Puustinen
- Department of Gastroenterology, Helsinki University Hospital, Abdominal Center, Helsinki, Finland
| | - Hannu Kautiainen
- Folkhälsan Research Center, Helsinki, Finland and Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - Andrea Tenca
- Department of Gastroenterology, Helsinki University Hospital, Abdominal Center, Helsinki, Finland
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8
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Berg T, Aehling NF, Bruns T, Welker MW, Weismüller T, Trebicka J, Tacke F, Strnad P, Sterneck M, Settmacher U, Seehofer D, Schott E, Schnitzbauer AA, Schmidt HH, Schlitt HJ, Pratschke J, Pascher A, Neumann U, Manekeller S, Lammert F, Klein I, Kirchner G, Guba M, Glanemann M, Engelmann C, Canbay AE, Braun F, Berg CP, Bechstein WO, Becker T, Trautwein C. S2k-Leitlinie Lebertransplantation der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) und der Deutschen Gesellschaft für Allgemein- und Viszeralchirurgie (DGAV). ZEITSCHRIFT FUR GASTROENTEROLOGIE 2024; 62:1397-1573. [PMID: 39250961 DOI: 10.1055/a-2255-7246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/11/2024]
Affiliation(s)
- Thomas Berg
- Bereich Hepatologie, Medizinischen Klinik II, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - Niklas F Aehling
- Bereich Hepatologie, Medizinischen Klinik II, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - Tony Bruns
- Medizinische Klinik III, Universitätsklinikum Aachen, Aachen, Deutschland
| | - Martin-Walter Welker
- Medizinische Klinik I Gastroent., Hepat., Pneum., Endokrin. Universitätsklinikum Frankfurt, Frankfurt, Deutschland
| | - Tobias Weismüller
- Klinik für Innere Medizin - Gastroenterologie und Hepatologie, Vivantes Humboldt-Klinikum, Berlin, Deutschland
| | - Jonel Trebicka
- Medizinische Klinik B für Gastroenterologie und Hepatologie, Universitätsklinikum Münster, Münster, Deutschland
| | - Frank Tacke
- Charité - Universitätsmedizin Berlin, Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Campus Virchow-Klinikum (CVK) und Campus Charité Mitte (CCM), Berlin, Deutschland
| | - Pavel Strnad
- Medizinische Klinik III, Universitätsklinikum Aachen, Aachen, Deutschland
| | - Martina Sterneck
- Medizinische Klinik und Poliklinik I, Universitätsklinikum Hamburg, Hamburg, Deutschland
| | - Utz Settmacher
- Klinik für Allgemein-, Viszeral- und Gefäßchirurgie, Universitätsklinikum Jena, Jena, Deutschland
| | - Daniel Seehofer
- Klinik für Viszeral-, Transplantations-, Thorax- und Gefäßchirurgie, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - Eckart Schott
- Klinik für Innere Medizin II - Gastroenterologie, Hepatologie und Diabetolgie, Helios Klinikum Emil von Behring, Berlin, Deutschland
| | | | - Hartmut H Schmidt
- Klinik für Gastroenterologie und Hepatologie, Universitätsklinikum Essen, Essen, Deutschland
| | - Hans J Schlitt
- Klinik und Poliklinik für Chirurgie, Universitätsklinikum Regensburg, Regensburg, Deutschland
| | - Johann Pratschke
- Chirurgische Klinik, Charité Campus Virchow-Klinikum - Universitätsmedizin Berlin, Berlin, Deutschland
| | - Andreas Pascher
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Universitätsklinikum Münster, Münster, Deutschland
| | - Ulf Neumann
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Universitätsklinikum Essen, Essen, Deutschland
| | - Steffen Manekeller
- Klinik und Poliklinik für Allgemein-, Viszeral-, Thorax- und Gefäßchirurgie, Universitätsklinikum Bonn, Bonn, Deutschland
| | - Frank Lammert
- Medizinische Hochschule Hannover (MHH), Hannover, Deutschland
| | - Ingo Klein
- Chirurgische Klinik I, Universitätsklinikum Würzburg, Würzburg, Deutschland
| | - Gabriele Kirchner
- Klinik und Poliklinik für Chirurgie, Universitätsklinikum Regensburg und Innere Medizin I, Caritaskrankenhaus St. Josef Regensburg, Regensburg, Deutschland
| | - Markus Guba
- Klinik für Allgemeine, Viszeral-, Transplantations-, Gefäß- und Thoraxchirurgie, Universitätsklinikum München, München, Deutschland
| | - Matthias Glanemann
- Klinik für Allgemeine, Viszeral-, Gefäß- und Kinderchirurgie, Universitätsklinikum des Saarlandes, Homburg, Deutschland
| | - Cornelius Engelmann
- Charité - Universitätsmedizin Berlin, Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Campus Virchow-Klinikum (CVK) und Campus Charité Mitte (CCM), Berlin, Deutschland
| | - Ali E Canbay
- Medizinische Klinik, Universitätsklinikum Knappschaftskrankenhaus Bochum, Bochum, Deutschland
| | - Felix Braun
- Klinik für Allgemeine Chirurgie, Viszeral-, Thorax-, Transplantations- und Kinderchirurgie, Universitätsklinikum Schlewswig-Holstein, Kiel, Deutschland
| | - Christoph P Berg
- Innere Medizin I Gastroenterologie, Hepatologie, Infektiologie, Universitätsklinikum Tübingen, Tübingen, Deutschland
| | - Wolf O Bechstein
- Klinik für Allgemein- und Viszeralchirurgie, Universitätsklinikum Frankfurt, Frankfurt, Deutschland
| | - Thomas Becker
- Klinik für Allgemeine Chirurgie, Viszeral-, Thorax-, Transplantations- und Kinderchirurgie, Universitätsklinikum Schlewswig-Holstein, Kiel, Deutschland
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9
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Li M, Pai RA, Gomel R, Vyas M, Callif SC, Hatchett J, Bowlus CL, Lai JC. Patient-focused drug development in primary sclerosing cholangitis: Insights on patient priorities and involvement in clinical trials. Hepatol Commun 2024; 8:e0433. [PMID: 38727680 PMCID: PMC11093571 DOI: 10.1097/hc9.0000000000000433] [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: 10/24/2023] [Accepted: 02/16/2024] [Indexed: 05/16/2024] Open
Abstract
BACKGROUND According to the new AASLD Practice Guidance, all patients with primary sclerosing cholangitis (PSC) should be considered for participation in clinical trials. However, PSC's rarity has posed challenges to characterizing patient interest in trial participation and identifying predictors of patient willingness to participate in drug trials. METHODS PSC Partners Seeking a Cure developed the "Our Voices" survey to inform the development of the Externally-Led Patient-Focused Drug Development Forum, an FDA initiative to capture patient experiences and perspectives on drug development. RESULTS Of 797 survey respondents from over 30 countries, 536 (67%) identified slowing disease progression as the most important outcome. Eighty-nine percent identified their hepatologist/gastroenterologist as someone they would approach for advice about trials. Although 61% reported being willing to participate in drug trials, only 26% had ever been asked to participate. Notable barriers to trial involvement included unknown long-term risks (71%), long travel times to the study center (32%), and a liver biopsy requirement (27%). On multivariable logistic regression, pruritus (OR 1.62, 95% CI: 1.09-2.40, p = 0.017) was positively associated with willingness to participate in disease-modifying therapy trials, while jaundice (OR 0.34, 95% CI: 0.19-0.61, p < 0.001) and inflammatory bowel disease (OR 0.64, 95% CI: 0.42-0.98, p = 0.038) were negatively associated. Pruritus (OR 2.25, 95% CI: 1.50-3.39, p < 0.001) was also independently associated with willingness to participate in symptom treatment trials. CONCLUSIONS Most patients with PSC report interest in participating in clinical trials, but few have been asked to participate. Referral of patients with PSC by their hepatologist/gastroenterologist to clinical trials and patient education on trial participation are vital to closing the gap between trial interest and participation. Pruritus may serve as a key indicator of patient interest in trial participation.
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Affiliation(s)
- Michael Li
- Department of Medicine, Division of Gastroenterology and Hepatology, University of California, San Francisco, California, USA
| | - Ruth-Anne Pai
- PSC Partners Seeking a Cure, Greenwood Village, Colorado, USA
| | - Rachel Gomel
- PSC Partners Seeking a Cure, Greenwood Village, Colorado, USA
| | - Mary Vyas
- PSC Partners Seeking a Cure Canada, Toronto, ON, Canada
| | | | - Joanne Hatchett
- PSC Partners Seeking a Cure, Greenwood Village, Colorado, USA
| | - Christopher L. Bowlus
- Department of Medicine, Division of Gastroenterology and Hepatology, University of California Davis Health, Sacramento, California, USA
| | - Jennifer C. Lai
- Department of Medicine, Division of Gastroenterology and Hepatology, University of California, San Francisco, California, USA
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10
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Lee SH, Song SY. Recent Advancement in Diagnosis of Biliary Tract Cancer through Pathological and Molecular Classifications. Cancers (Basel) 2024; 16:1761. [PMID: 38730713 PMCID: PMC11083053 DOI: 10.3390/cancers16091761] [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: 02/23/2024] [Revised: 04/24/2024] [Accepted: 04/29/2024] [Indexed: 05/13/2024] Open
Abstract
Biliary tract cancers (BTCs), including intrahepatic, perihilar, and distal cholangiocarcinomas, as well as gallbladder cancer, are a diverse group of cancers that exhibit unique molecular characteristics in each of their anatomic and pathological subtypes. The pathological classification of BTCs compromises distinct growth patterns, including mass forming, periductal infiltrating, and intraductal growing types, which can be identified through gross examination. The small-duct and large-duct types of intrahepatic cholangiocarcinoma have been recently introduced into the WHO classification. The presentation of typical clinical symptoms, as well as the extensive utilization of radiological, endoscopic, and molecular diagnostic methods, is thoroughly detailed in the description. To overcome the limitations of traditional tissue acquisition methods, new diagnostic modalities are being explored. The treatment landscape is also rapidly evolving owing to the emergence of distinct subgroups with unique molecular alterations and corresponding targeted therapies. Furthermore, we emphasize the crucial aspects of diagnosing BTC in practical clinical settings.
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Affiliation(s)
- Sang-Hoon Lee
- Department of Internal Medicine, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul 05030, Republic of Korea;
| | - Si Young Song
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03772, Republic of Korea
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11
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Mínguez A, Conde I, Montón C, Gonzalez L, Pascual S, Antón MD, Palau A, Forés A, Gisbert C, Ojeda A, Girona E, Di Maira T, Berenguer M. Primary Sclerosing Cholangitis: Gender Effects in Valencia's Low-Prevalence Region. Dig Dis Sci 2024; 69:1863-1871. [PMID: 38517562 DOI: 10.1007/s10620-024-08368-y] [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: 07/19/2023] [Accepted: 02/22/2024] [Indexed: 03/24/2024]
Abstract
BACKGROUND AND AIMS Recent studies point out to epidemiological changes in primary sclerosing cholangitis (PSC). Our aims were to determine in PSC patients followed in several centers in a Mediterranean geographic area: (i) changes in baseline features and (ii) effect of gender on clinical course. METHODS Retrospective multicenter study of PSC patients treated in 8 hospitals in a Mediterranean area between 2000 and 2021. Charts were reviewed compiling demographic, clinical, radiological, and histological variables. RESULTS Cohort of 112 PSC patients included, 42% women, 70% diagnosed after 2010. Women were increasingly diagnosed in recent cohorts. The median time from diagnosis to the combined endpoint liver transplantation (Lt) and/or death was 6.9 years. Asthenia at diagnosis (p = 0.009) was associated with lower transplant-free survival, while diagnosis before 2005 was associated with greater LT-free survival (p < 0.001). By Cox regression, LT-free survival was not influenced by age, sex, or cirrhosis at the time of diagnosis. Women were found to have less jaundice at diagnosis (2 vs 14%; p = 0.013), higher prevalence of ANA antibodies (43.9 vs 15.7%; p = 0.003), and lower GGT levels at diagnosis (GGT 123 vs 209U/L; p = 0.014) than men. CONCLUSION In an area traditionally considered to have low prevalence, the prevalence of affected women surpasses expectations based on existing literature. There appear to be gender-related variations in the presentation of the condition, highlighting the need for confirmation through larger-scale studies.
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Affiliation(s)
- Alejandro Mínguez
- Universitary and Politecnic Hospital La Fe, 46007, Valencia, CP, Spain.
| | - Isabel Conde
- Universitary and Politecnic Hospital La Fe, 46007, Valencia, CP, Spain
- Hepatology and Liver Transplant Unit, IIS La Fe & CIBER-EHD, Universitary and Politecnic Hospital La Fe, Valencia, Spain
| | - Cristina Montón
- Digestive Disease Department, Clinic University Hospital, INCLIVA Health Research Institute, 46410, Valencia, Spain
| | - Lara Gonzalez
- General University Hospital of Valencia, Valencia, Spain
| | - Sonia Pascual
- Hepatology and Liver Transplant Unit/HGU Dr. Balmis, Alicante, Spain
| | | | - Antonio Palau
- General University Hospital of Castellón, Castellon de La Plana, Spain
| | - Ana Forés
- General University Hospital of Castellón, Castellon de La Plana, Spain
| | - Concha Gisbert
- Digestive Medicine Hospital Arnau de Vilanova, Valencia, Spain
| | - Asunción Ojeda
- Digestive Medicine, General University Hospital of Elche, Alicante, Spain
| | - Eva Girona
- Digestive Medicine, General University Hospital of Elche, Alicante, Spain
| | - Tommaso Di Maira
- Universitary and Politecnic Hospital La Fe, 46007, Valencia, CP, Spain
- Hepatology and Liver Transplant Unit, IIS La Fe & CIBER-EHD, Universitary and Politecnic Hospital La Fe, Valencia, Spain
| | - Marina Berenguer
- Universitary and Politecnic Hospital La Fe, 46007, Valencia, CP, Spain
- Hepatology and Liver Transplant Unit, IIS La Fe & CIBER-EHD, Universitary and Politecnic Hospital La Fe, Valencia, Spain
- Department of Medicina, University of Valencia, Valencia, Spain
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12
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Lange CM, Weismüller TJ, Strassburg CP. [Liver transplantation in viral and autoimmune liver diseases]. INNERE MEDIZIN (HEIDELBERG, GERMANY) 2024; 65:357-364. [PMID: 38446182 DOI: 10.1007/s00108-024-01675-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 02/01/2024] [Indexed: 03/07/2024]
Abstract
BACKGROUND Despite substantial progress in the management of viral and autoimmune liver diseases, these entities remain relevant indications for liver transplantation. AIMS To provide an overview of the current knowledge regarding the management of viral and autoimmune liver diseases before and after liver transplantation. MATERIALS AND METHODS Selective literature search, including current guidelines and abstracts of key scientific meetings. RESULTS AND DISCUSSION Viral and autoimmune liver disease can be effectively treated in most cases, which has resulted in an overall decline in liver transplantations for this indication group. However, hepatitis D infection and primary sclerosing cholangitis remain difficult-to-treat liver diseases in some patients and may progress to end-stage liver disease despite best possible management. Viral or autoimmune hepatitis can lead to fulminant liver failure requiring emergency liver transplantation. In patients who are transplanted due to viral or autoimmune liver disease, specific measures to prevent recurrence of these diseases after transplantation are mandatory. In view of effective treatment modalities for chronic hepatitis B and C, even liver grafts from donors infected with these viruses can be considered for liver transplantation under certain circumstances.
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Affiliation(s)
- Christian M Lange
- Klinik und Poliklinik für Innere Medizin II, LMU Klinikum der Universität München, Marchioninistr. 15, 81337, München, Deutschland.
| | - Tobias J Weismüller
- Klinik für Innere Medizin - Gastroenterologie und Hepatologie, Vivantes Humboldt-Klinikum, Berlin, Deutschland
| | - Christian P Strassburg
- Medizinische Klinik und Poliklinik I, Universitätsklinikum Bonn, Venusberg-Campus 1, Gebäude 26, 53127, Bonn, Deutschland.
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13
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Dong X, Gong LL, Hong MZ, Pan JS. Investigating the shared genetic architecture between primary sclerosing cholangitis and inflammatory bowel diseases: a Mendelian randomization study. BMC Gastroenterol 2024; 24:77. [PMID: 38373892 PMCID: PMC10875759 DOI: 10.1186/s12876-024-03162-6] [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: 11/10/2023] [Accepted: 02/07/2024] [Indexed: 02/21/2024] Open
Abstract
BACKGROUND Several studies have found that primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) are closely associated. However, the direction and causality of their interactions remain unclear. Thus, this study employs Mendelian Randomization to explore whether there are causal associations of genetically predicted PSC with IBD. METHODS Genetic variants associated with the genome-wide association study (GWAS) of PSC were used as instrumental variables. The statistics for IBD, including ulcerative colitis (UC), and Crohn's disease (CD) were derived from GWAS. Then, five methods were used to estimate the effects of genetically predicted PSC on IBD, including MR Egger, Weighted median (WM), Inverse variance weighted (IVW), Simple mode, and Weighted mode. Last, we also evaluated the pleiotropic effects, heterogeneity, and a leave-one-out sensitivity analysis that drives causal associations to confirm the validity of the analysis. RESULTS Genetically predicted PSC was significantly associated with an increased risk of UC, according to the study (odds ratio [OR] IVW= 1.0014, P<0.05). However, none of the MR methods found significant causal evidence of genetically predicted PSC in CD (All P>0.05). The sensitivity analysis results showed that the causal effect estimations of genetically predicted PSC on IBD were robust, and there was no horizontal pleiotropy or statistical heterogeneity. CONCLUSIONS Our study corroborated a causal association between genetically predicted PSC and UC but did not between genetically predicted PSC and CD. Then, we identification of shared SNPs for PSC and UC, including rs3184504, rs9858213, rs725613, rs10909839, and rs4147359. More animal experiments and clinical observational studies are required to further clarify the underlying mechanisms of PSC and IBD.
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Affiliation(s)
- Xuan Dong
- Department of Hepatology, the First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
- Hepatology Research Institute, Fujian Medical University, Fuzhou, Fujian, China
- Department of Hepatology, National Regional Medical Center, Binhai Campus of the First Affiliated Hosptial, Fujian Medical University, Fuzhou, Fujian, China
- Fujian Clinical Research Center for Hepatopathy and Intestinal Diseases, Fuzhou, Fujian, China
| | - Li-Li Gong
- Department of General Practice, Zhongshan Hospital, Xiamen University, Xiamen, Fujian, China
| | - Mei-Zhu Hong
- Department of Traditional Chinese Medicine, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, China.
| | - Jin-Shui Pan
- Department of Hepatology, the First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China.
- Hepatology Research Institute, Fujian Medical University, Fuzhou, Fujian, China.
- Department of Hepatology, National Regional Medical Center, Binhai Campus of the First Affiliated Hosptial, Fujian Medical University, Fuzhou, Fujian, China.
- Fujian Clinical Research Center for Hepatopathy and Intestinal Diseases, Fuzhou, Fujian, China.
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14
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Sohal A, Kayani S, Kowdley KV. Primary Sclerosing Cholangitis: Epidemiology, Diagnosis, and Presentation. Clin Liver Dis 2024; 28:129-141. [PMID: 37945154 DOI: 10.1016/j.cld.2023.07.005] [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: 11/12/2023]
Abstract
Primary sclerosing cholangitis (PSC) is considered an immunologically mediated disease. However, some of its features are not consistent with the typical profile of autoimmune conditions. PSC is characterized by progressive biliary fibrosis that may ultimately result in the eventual development of cirrhosis. In recent years, multiple studies have reported that the incidence and prevalence of this disease are on the rise. Consequently, patients are often diagnosed without symptoms or signs of advanced liver disease, although many still present with signs of decompensated liver disease. This article discusses the epidemiology, clinical presentation, and diagnostic workup in patients with PSC.
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Affiliation(s)
- Aalam Sohal
- Liver Institute Northwest, , 3216 Northeast 45th Place, Suite 212, Seattle, WA 98105, USA
| | - Sanya Kayani
- Avera McKennan Hospital and University Health Center, Sioux Falls, SD, USA
| | - Kris V Kowdley
- Liver Institute Northwest, , 3216 Northeast 45th Place, Suite 212, Seattle, WA 98105, USA; Elson Floyd College of Medicine, Spokane, WA, USA.
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15
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Ahmed W, Joshi D, Huggett MT, Everett SM, James M, Menon S, Oppong KW, On W, Paranandi B, Trivedi P, Webster G, Hegade VS. Update on the optimisation of endoscopic retrograde cholangiography (ERC) in patients with primary sclerosing cholangitis. Frontline Gastroenterol 2024; 15:74-83. [PMID: 38487565 PMCID: PMC10935540 DOI: 10.1136/flgastro-2023-102491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 08/28/2023] [Indexed: 03/17/2024] Open
Affiliation(s)
- Wafaa Ahmed
- Department of Gastroenterology, Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | - Deepak Joshi
- Gastroenterology, King's College Hospital Liver Unit, London, UK
| | - Matthew T Huggett
- Gastroenterology, St James's University Hospital, The Leeds Teaching Hospitals NHS Foundation Trust, Leeds, UK
| | - Simon M Everett
- Gastroenterology, St James's University Hospital NHS Trust, Leeds, UK
| | - Martin James
- Gastroenterology, Nottingham University, Nottingham, UK
| | - Shyam Menon
- Department of Hepatology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | | | - Wei On
- Department of Gastroenterology, Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | - Bharat Paranandi
- Department of Gastroenterology, Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | - Palak Trivedi
- National Institute for Health Research, Centre for Liver Research, University Hospitals Birmingham, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - George Webster
- Department of Gastroenterology, University College London Hospital NHS Foundation Trust, London, UK
| | - Vinod S Hegade
- Leeds Liver Unit, Leeds Teaching Hospitals NHS Trust, Leeds, UK
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16
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Joo SK, Kim W. Sex/Gender Differences in Liver Diseases. SEX/GENDER-SPECIFIC MEDICINE IN CLINICAL AREAS 2024:209-217. [DOI: 10.1007/978-981-97-0130-8_7] [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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17
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Marsool MDM, Vora N, Marsool ADM, Pati S, Narreddy M, Patel P, Gadam S, Prajjwal P. Ulcerative colitis: Addressing the manifestations, the role of fecal microbiota transplantation as a novel treatment option and other therapeutic updates. Dis Mon 2023; 69:101606. [PMID: 37357103 DOI: 10.1016/j.disamonth.2023.101606] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/27/2023]
Abstract
The prevalence and incidence of Ulcerative Colitis (UC), a recurrent and remitting inflammatory condition, are rising. Any part of the colon may be affected, beginning with inflammation of the mucosa in the rectum and continuing proximally continuously. Bloody diarrhea, tenesmus, fecal urgency, and stomach pain are typical presenting symptoms. Many patients present with extraintestinal manifestations (EIMs) including musculoskeletal, ocular, renal, hepatobiliary, and dermatological presentation, among others. Most cases are treated with pharmacological therapy including mesalazine and glucocorticoids. Fecal microbiota transplantation (FMT) is a novel procedure that is increasingly being used to treat UC, however, its use yet remains controversial because of uncertain efficacy. FMT can lower gut permeability and consequently disease severity by boosting short-chain fatty acids production, helping in epithelial barrier integrity preservation. Upadacitinib (JAK Kinase inhibitor) is another newer treatment option, which is an FDA-approved drug that is being used to treat UC. This review article provides a comprehensive review of the EIMs of UC, the role of FMT along with various recent clinical trials pertaining to FMT as well as other diagnostic and therapeutic updates.
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Affiliation(s)
| | - Neel Vora
- B. J. Medical College, Ahmedabad, India
| | | | - Shefali Pati
- St George's University, School of Medicine, Grenada
| | | | - Parth Patel
- Pramukhswami Medical College, Karamsad, India
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18
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Tan N, Lubel J, Kemp W, Roberts S, Majeed A. Current Therapeutics in Primary Sclerosing Cholangitis. J Clin Transl Hepatol 2023; 11:1267-1281. [PMID: 37577219 PMCID: PMC10412694 DOI: 10.14218/jcth.2022.00068s] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Revised: 01/01/2023] [Accepted: 01/20/2023] [Indexed: 07/03/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) is an orphan, cholestatic liver disease that is characterized by inflammatory biliary strictures with variable progression to end-stage liver disease. Its pathophysiology is poorly understood. Chronic biliary inflammation is likely driven by immune dysregulation, gut dysbiosis, and environmental exposures resulting in gut-liver crosstalk and bile acid metabolism disturbances. There is no proven medical therapy that alters disease progression in PSC, with the commonly prescribed ursodeoxycholic acid being shown to improve liver biochemistry at low-moderate doses (15-23 mg/kg/day) but not alter transplant-free survival or liver-related outcomes. Liver transplantation is the only option for patients who develop end-stage liver disease or refractory complications of PSC. Immunosuppressive and antifibrotic agents have not proven to be effective, but there is promise for manipulation of the gut microbiome with fecal microbiota transplantation and antibiotics. Bile acid manipulation via alternate synthetic bile acids such as norursodeoxycholic acid, or interaction at a transcriptional level via nuclear receptor agonists and fibrates have shown potential in phase II trials in PSC with several leading to larger phase III trials. In view of the enhanced malignancy risk, statins, and aspirin show potential for reducing the risk of colorectal cancer and cholangiocarcinoma in PSC patients. For patients who develop clinically relevant strictures with cholestatic symptoms and worsening liver function, balloon dilatation is safer compared with biliary stent insertion with equivalent clinical efficacy.
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Affiliation(s)
- Natassia Tan
- Department of Gastroenterology and Hepatology, Alfred Health; Central Clinical School, Monash University, Melbourne, Australia
| | - John Lubel
- Department of Gastroenterology and Hepatology, Alfred Health; Central Clinical School, Monash University, Melbourne, Australia
| | - William Kemp
- Department of Gastroenterology and Hepatology, Alfred Health; Central Clinical School, Monash University, Melbourne, Australia
| | - Stuart Roberts
- Department of Gastroenterology and Hepatology, Alfred Health; Central Clinical School, Monash University, Melbourne, Australia
| | - Ammar Majeed
- Department of Gastroenterology and Hepatology, Alfred Health; Central Clinical School, Monash University, Melbourne, Australia
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19
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Li X, Wang Y, Chen Z, Ruan M, Yang C, Zhou M, Li N, Xing L, Xu H, Yang L, Shi Q, Wang Y, Chen J, Liang Q. Hepatorenal pathologies in TNF-transgenic mouse model of rheumatoid arthritis are alleviated by anti-TNF treatment. Arthritis Res Ther 2023; 25:188. [PMID: 37784156 PMCID: PMC10544221 DOI: 10.1186/s13075-023-03178-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 09/22/2023] [Indexed: 10/04/2023] Open
Abstract
OBJECTIVE To examine and quantify liver and kidney lesions and their response to anti-tumor necrosis factor (TNF) therapy in a TNF-Tg mouse model of rheumatoid arthritis (RA). METHODS Female TNF-Tg (Tg3647) mice were used as the animal model for chronic RA. Ultrasound, immunofluorescence, histological staining, serology tests, and real-time RT-PCR were used to examine the pathological changes in the liver and kidney. RESULTS TNF-Tg mice showed a significant decrease in the body weight and a dramatic increase in the volumes of the gallbladder, knee cavity, and popliteal lymph nodes. The liver and kidneys of TNF-Tg mice showed increased chronic inflammation and accumulation of immune cells and fibrosis, compared to wild-type (WT) mice. Moreover, upregulation of inflammatory factors and impaired normal function were observed in the liver and kidneys of TNF-Tg mice. Inflammatory infiltration and fibrosis of the liver and kidneys of female TNF-Tg mice were improved after anti-TNF treatment, and better treatment effects were achieved at 4.5-month-old mice when they were received 8 weeks of intervention. CONCLUSIONS We found that TNF drives the development of liver and kidney pathology in female TNF-Tg mice and that there are limitations to the loss of utility of anti-TNF for the prolonged treatment of RA-associated hepatic and renal injury. This study provides a reliable and clinically relevant animal model for further studies exploring the molecular mechanisms and drug discovery for hepatorenal pathologies in RA.
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Affiliation(s)
- Xuefei Li
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, Shanghai, 200032, China
- Spine Institute, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, Shanghai, 200032, China
- Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education (Shanghai University of Traditional Chinese Medicine), 1200 Cailun Road, Shanghai, 201203, China
| | - Yi Wang
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, Shanghai, 200032, China
- Spine Institute, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, Shanghai, 200032, China
- Cardiovascular Department, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, Shanghai, 200032, China
| | - Ziqiang Chen
- Center for Systems Pharmacokinetics, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Ming Ruan
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, Shanghai, 200032, China
- Spine Institute, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, Shanghai, 200032, China
- Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education (Shanghai University of Traditional Chinese Medicine), 1200 Cailun Road, Shanghai, 201203, China
| | - Can Yang
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, Shanghai, 200032, China
- Spine Institute, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, Shanghai, 200032, China
- Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education (Shanghai University of Traditional Chinese Medicine), 1200 Cailun Road, Shanghai, 201203, China
| | - Maolin Zhou
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, Shanghai, 200032, China
- Spine Institute, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, Shanghai, 200032, China
- Cardiovascular Department, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, Shanghai, 200032, China
| | - Ning Li
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, Shanghai, 200032, China
- Spine Institute, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, Shanghai, 200032, China
- Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education (Shanghai University of Traditional Chinese Medicine), 1200 Cailun Road, Shanghai, 201203, China
| | - Lianping Xing
- Center for Musculoskeletal Research, University of Rochester Medical Center, 601 Elmwood Ave, Box 665, Rochester, NY, 14642, USA
- Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA
| | - Hao Xu
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, Shanghai, 200032, China
- Spine Institute, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, Shanghai, 200032, China
- Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education (Shanghai University of Traditional Chinese Medicine), 1200 Cailun Road, Shanghai, 201203, China
| | - Ling Yang
- Center for Systems Pharmacokinetics, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Qi Shi
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, Shanghai, 200032, China
- Spine Institute, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, Shanghai, 200032, China
- Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education (Shanghai University of Traditional Chinese Medicine), 1200 Cailun Road, Shanghai, 201203, China
| | - Yongjun Wang
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, Shanghai, 200032, China
- Spine Institute, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, Shanghai, 200032, China
- Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education (Shanghai University of Traditional Chinese Medicine), 1200 Cailun Road, Shanghai, 201203, China
| | - Jinman Chen
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, Shanghai, 200032, China.
- Spine Institute, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, Shanghai, 200032, China.
- Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education (Shanghai University of Traditional Chinese Medicine), 1200 Cailun Road, Shanghai, 201203, China.
| | - Qianqian Liang
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, Shanghai, 200032, China.
- Spine Institute, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, Shanghai, 200032, China.
- Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education (Shanghai University of Traditional Chinese Medicine), 1200 Cailun Road, Shanghai, 201203, China.
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20
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Russo MW. Noninvasive prognostic models, imaging, and elastography to predict clinical events in primary sclerosing cholangitis: A review. World J Hepatol 2023; 15:1013-1020. [PMID: 37900215 PMCID: PMC10600698 DOI: 10.4254/wjh.v15.i9.1013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 07/17/2023] [Accepted: 08/23/2023] [Indexed: 09/22/2023] Open
Abstract
Surrogate endpoints are needed to estimate clinical outcomes in primary sclerosing cholangitis (PSC). Serum alkaline phosphatase was among the first markers studied, but there is substantial variability in alkaline phosphatase levels during the natural history of PSC without intervention. The Mayo risk score incorporates noninvasive variables and has served as a surrogate endpoint for survival for more than two decades. Newer models have better test performance than the Mayo risk score, including the primary sclerosing risk estimate tool (PREsTo) model and UK-PSC score that estimate hepatic decompensation and transplant free survival, respectively. The c-statistics for transplant-free survival for the Mayo risk model and the long-term UK-PSC model are 0.68 and 0.85, respectively. The c-statistics for hepatic decompensation for the Mayo risk model and PREsTo model are 0.85 and 0.90, respectively. The Amsterdam-Oxford model included patients with large duct and small duct PSC and patients with PSC-autoimmune hepatitis overlap and had a c-statistic of 0.68 for transplant-free survival. Other noninvasive tests that warrant further validation include magnetic resonance imaging, elastography and the enhanced liver fibrosis score. Prognostic models, noninvasive tests or a combination of these surrogate endpoints may not only serve to be useful in clinical trials of investigational agents, but also serve to inform our patients about their prognosis.
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Affiliation(s)
- Mark W Russo
- Division of Hepatology, Atrium Health Wake Forest, Charlotte, NC 28204, United States.
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21
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Lawson KL, Wang HL. Primary Sclerosing Cholangitis, Small Duct Primary Sclerosing Cholangitis, IgG4-Related Sclerosing Cholangitis, and Ischemic Cholangiopathy: Diagnostic Challenges on Biopsy. Surg Pathol Clin 2023; 16:533-548. [PMID: 37536887 DOI: 10.1016/j.path.2023.04.008] [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
Pathologists face many challenges when diagnosing sclerosing biliary lesions on liver biopsy. First, histologic findings tend to be nonspecific with similar to identical features seen in numerous conditions, from benign to outright malignant. In addition, the patchy nature of many of these entities amplifies the inherent limitations of biopsy sampling. The end result often forces pathologists to issue descriptive sign outs that require careful clinical correlation; however, certain clinical, radiologic, and histologic features may be of diagnostic assistance. In this article, we review key elements of four sclerosing biliary processes whose proper identification has significant prognostic and therapeutic implications.
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Affiliation(s)
- Katy L Lawson
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, Ronald Reagan UCLA Medical Center, University of California Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA
| | - Hanlin L Wang
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, Ronald Reagan UCLA Medical Center, University of California Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.
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22
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Onofrio F, Zheng K, Xu C, Chen S, Xu W, Vyas M, Bingham K, Patel K, Lilly L, Cattral M, Selzner N, Jaeckel E, Tsien C, Gulamhusein A, Hirschfield GM, Bhat M. Living donor liver transplantation can address disparities in transplant access for patients with primary sclerosing cholangitis. Hepatol Commun 2023; 7:e0219. [PMID: 37534935 PMCID: PMC10552969 DOI: 10.1097/hc9.0000000000000219] [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: 01/04/2023] [Accepted: 05/04/2023] [Indexed: 08/04/2023] Open
Abstract
BACKGROUND Liver transplantation (LT) is frequently lifesaving for people living with primary sclerosing cholangitis (PSC). However, patients are waitlisted for LT according to the model for end-stage liver disease-sodium (MELD-Na) score, which may not accurately reflect the burden of living with PSC. We sought to describe and analyze the clinical trajectory for patients with PSC referred for LT, in a mixed deceased donor/living donor transplant program. METHODS This was a retrospective cohort study from November 2012 to December 2019, including all patients with PSC referred for assessment at the University Health Network Liver Transplant Clinic. Patients who required multiorgan transplant or retransplantation were excluded. Liver symptoms, hepatobiliary malignancy, MELD-Na progression, and death were abstracted from chart review. Competing risk analysis was used for timing of LT, transplant type, and death. RESULTS Of 172 PSC patients assessed, 84% (n = 144) were listed of whom 74% were transplanted. Mean age was 47.6 years, and 66% were male. Overall mortality was 18.2% at 2 years. During the follow-up, 16% (n = 23) were removed from the waitlist for infection, clinical deterioration, liver-related mortality or new cancer; 3 had clinical improvement. At listing, 82% (n = 118) had a potential living donor (pLD). Patients with pLD had significantly lower waitlist and liver-related waitlist mortality (HR 0.20, p<0.001 and HR 0.17, p<0.001, respectively), and higher rates of transplantation (HR 1.83, p = 0.05). Exception points were granted to 13/172 (7.5%) patients. CONCLUSIONS In a high-volume North American LT center, most patients with PSC assessed for transplant were listed and subsequently transplanted. However, this was a consequence of patients engaging in living donor transplantation. Our findings support the concern from patients with PSC that MELD-Na allocation does not adequately address their needs.
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Affiliation(s)
- Fernanda Onofrio
- Ajmera Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Katina Zheng
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Cherry Xu
- Ajmera Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Shiyi Chen
- Biostatistics Department, Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada
| | - Wei Xu
- Biostatistics Department, Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada
| | | | | | - Keyur Patel
- Ajmera Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Leslie Lilly
- Ajmera Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Mark Cattral
- Ajmera Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Nazia Selzner
- Ajmera Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Elmar Jaeckel
- Ajmera Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Cynthia Tsien
- Ajmera Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Aliya Gulamhusein
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Toronto, University Health Network, Toronto, Ontario, Canada
| | - Gideon M. Hirschfield
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Toronto, University Health Network, Toronto, Ontario, Canada
| | - Mamatha Bhat
- Ajmera Transplant Program, University Health Network, Toronto, Ontario, Canada
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Toronto, University Health Network, Toronto, Ontario, Canada
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23
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Lee SH, Moon SJ, Woo SH, Ahn G, Kim WK, Lee CH, Hwang JH. CrebH protects against liver injury associated with colonic inflammation via modulation of exosomal miRNA. Cell Biosci 2023; 13:116. [PMID: 37370191 DOI: 10.1186/s13578-023-01065-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 06/05/2023] [Indexed: 06/29/2023] Open
Abstract
BACKGROUND Hepatic liver disease, including primary sclerosing cholangitis (PSC), is a serious extraintestinal manifestations of colonic inflammation. Cyclic adenosine monophosphate (cAMP)-responsive element-binding protein H (CrebH) is a transcription factor expressed mostly in the liver and small intestine. However, CrebH's roles in the gut-liver axis remain unknown. METHODS Inflammatory bowel disease (IBD) and PSC disease models were established in wild-type and CrebH-/- mice treated with dextran sulfate sodium, dinitrobenzene sulfonic acid, and diethoxycarbonyl dihydrocollidine diet, respectively. RNA sequencing were conducted to investigate differential gene expression. Exosomes were isolated from plasma and culture media. miRNA expression profiling was performed using the NanoString nCounter Mouse miRNA Panel. Effects of miR-29a-3p on adhesion molecule expression were investigated in bEnd.3 brain endothelial cells. RESULTS CrebH-/- mice exhibited accelerated liver injury without substantial differences in the gut after administration of dextran sulfate sodium (DSS), and had similar features to PSC, including enlarged bile ducts, enhanced inflammation, and aberrant MAdCAM-1 expression. Furthermore, RNA-sequencing analysis showed that differentially expressed genes in the liver of CrebH-/- mice after DSS overlapped significantly with genes changed in PSC-liver. Analysis of plasma exosome miRNA isolated from WT and CrebH-/- mice indicates that CrebH can contribute to the exosomal miRNA profile. We also identified miR-29a-3p as an effective mediator for MAdCAM-1 expression. Administration of plasma exosome from CrebH-/- mice led to prominent inflammatory signals in the liver of WT mice with inflammatory bowel disease (IBD). CONCLUSIONS CrebH deficiency led to increased susceptibility to IBD-induced liver diseases via enhanced expression of adhesion molecules and concomitant infiltration of T lymphocytes. Exosomes can contribute to the progression of IBD-induced liver injury in CrebH-/- mice. These study provide novel insights into the role of CrebH in IBD-induced liver injury.
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Affiliation(s)
- Sang-Hee Lee
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseoung-gu, Daejeon, 34141, Korea
- Department of Biology, Daejeon University, 62 Daehak-ro, Dong-gu, Daejeon, 34520, Korea
| | - Sung-Je Moon
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseoung-gu, Daejeon, 34141, Korea
- KRIBB School of Bioscience, University of Science and Technology (UST), 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Korea
| | - Seung Hee Woo
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseoung-gu, Daejeon, 34141, Korea
- Department of Biology and Microbiology, Changwon National University, 20 Chanwondaehak-ro, Uichan-gu, Chanwon-si, Gyeonsangnam-do, 51140, Korea
| | - Gwangsook Ahn
- Department of Biology, Daejeon University, 62 Daehak-ro, Dong-gu, Daejeon, 34520, Korea
| | - Won Kon Kim
- KRIBB School of Bioscience, University of Science and Technology (UST), 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Korea
- Metabolic Regulation Research Center, KRIBB, 125 Gwahak-ro, Yuseoung-gu, Daejeon, 34141, Korea
| | - Chul-Ho Lee
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseoung-gu, Daejeon, 34141, Korea.
- KRIBB School of Bioscience, University of Science and Technology (UST), 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Korea.
| | - Jung Hwan Hwang
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseoung-gu, Daejeon, 34141, Korea.
- KRIBB School of Bioscience, University of Science and Technology (UST), 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Korea.
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24
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Hu C, Iyer RK, Juran BD, McCauley BM, Atkinson EJ, Eaton JE, Ali AH, Lazaridis KN. Predicting cholangiocarcinoma in primary sclerosing cholangitis: using artificial intelligence, clinical and laboratory data. BMC Gastroenterol 2023; 23:129. [PMID: 37076803 PMCID: PMC10114387 DOI: 10.1186/s12876-023-02759-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Accepted: 04/06/2023] [Indexed: 04/21/2023] Open
Abstract
BACKGROUND Primary sclerosing cholangitis (PSC) patients have a risk of developing cholangiocarcinoma (CCA). Establishing predictive models for CCA in PSC is important. METHODS In a large cohort of 1,459 PSC patients seen at Mayo Clinic (1993-2020), we quantified the impact of clinical/laboratory variables on CCA development using univariate and multivariate Cox models and predicted CCA using statistical and artificial intelligence (AI) approaches. We explored plasma bile acid (BA) levels' predictive power of CCA (subset of 300 patients, BA cohort). RESULTS Eight significant risk factors (false discovery rate: 20%) were identified with univariate analysis; prolonged inflammatory bowel disease (IBD) was the most important one. IBD duration, PSC duration, and total bilirubin remained significant (p < 0.05) with multivariate analysis. Clinical/laboratory variables predicted CCA with cross-validated C-indexes of 0.68-0.71 at different time points of disease, significantly better compared to commonly used PSC risk scores. Lower chenodeoxycholic acid, higher conjugated fraction of lithocholic acid and hyodeoxycholic acid, and higher ratio of cholic acid to chenodeoxycholic acid were predictive of CCA. BAs predicted CCA with a cross-validated C-index of 0.66 (std: 0.11, BA cohort), similar to clinical/laboratory variables (C-index = 0.64, std: 0.11, BA cohort). Combining BAs with clinical/laboratory variables leads to the best average C-index of 0.67 (std: 0.13, BA cohort). CONCLUSIONS In a large PSC cohort, we identified clinical and laboratory risk factors for CCA development and demonstrated the first AI based predictive models that performed significantly better than commonly used PSC risk scores. More predictive data modalities are needed for clinical adoption of these models.
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Affiliation(s)
- Chang Hu
- Department of Electrical and Computer Engineering, University of Illinois at Urbana-Champaign, Urbana-Champaign, IL, 61801, USA
| | - Ravishankar K Iyer
- Department of Electrical and Computer Engineering, University of Illinois at Urbana-Champaign, Urbana-Champaign, IL, 61801, USA
| | - Brian D Juran
- Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Bryan M McCauley
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, 55905, USA
| | - Elizabeth J Atkinson
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, 55905, USA
| | - John E Eaton
- Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Ahmad H Ali
- Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
- Division of Gastroenterology and Hepatology, University of Missouri School of Medicine, Columbia, MO, 65212, USA
| | - Konstantinos N Lazaridis
- Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
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25
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Abstract
PURPOSE OF REVIEW Magnetic resonance cholangiopancreatography (MRCP) has become the reference examination for the exploration of the biliary tract and has replaced endoscopic cholangiography for the analysis of the biliary tract because of its equivalent performance and its noninvasive character. RECENT FINDINGS Based on the International Primary Sclerosing Cholangitis (PSC) Study Group recommendations for MR imaging in PSC, two protocols can be distinguished for the imaging of biliary tract: a basic protocol and a more complete protocol. It is essential to know the main pitfalls in order not to wrongly describe biliary anomalies. In addition to the excellent performance of MR imaging with MRCP in analyzing the anatomy and the anomalies of the biliary tree, complementary techniques have recently been developed. Several MR prognostic factors have been described. New hepato-specific contrast agents are now available for assessment of the general and segmental liver function. MR Elastography and Diffusion-weighted MR sequences are accurate to evaluate the degree of hepatic fibrosis. Finally, images obtained in MRCP can be postprocessed by a software that will analyze and model the biliary tree in order to quantitatively evaluate the biliary system. SUMMARY Magnetic resonance imaging with its recent developments becomes by now an essential tool for the evaluation of biliary diseases.
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26
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Möller K, Braden B, Culver EL, Jenssen C, Zadeh ES, Alhyari A, Görg C, Ignee A, Hocke M, Dong Y, Sun S, Faiss S, Dietrich CF. Secondary sclerosing cholangitis and IgG4-sclerosing cholangitis - A review of cholangiographic and ultrasound imaging. Endosc Ultrasound 2023; 12:181-199. [PMID: 36588352 PMCID: PMC10237613 DOI: 10.4103/eus-d-22-00208] [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: 11/20/2022] [Accepted: 12/08/2022] [Indexed: 01/01/2023] Open
Abstract
Sclerosing cholangitis (SC) represents a spectrum of chronic progressive cholestatic diseases of the intrahepatic and/or extrahepatic biliary system characterized by patchy inflammation, fibrosis, and stricturing. Primary and secondary SC must be distinguished given the different treatment modalities, risks of malignancy, and progression to portal hypertension, cirrhosis, and hepatic failure. This review focuses on secondary SC and the pathogenic mechanisms, risk factors, clinical presentation, and novel imaging modalities that help to distinguish between these conditions. We explore the detailed use of cholangiography and ultrasound imaging techniques.
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Affiliation(s)
- Kathleen Möller
- Medical Department I/Gastroenterology, Sana Hospital Lichtenberg, Berlin, Germany
| | - Barbara Braden
- Translational Gastroenterology Unit, Oxford University Hospitals, Oxford, UK
| | - Emma L. Culver
- Translational Gastroenterology Unit, Oxford University Hospitals, Oxford, UK
| | - Christian Jenssen
- Department of Internal Medicine, Krankenhaus Märkisch Oderland GmbH, Strausberg, Wriezen, Germany
- Brandenburg Institute of Clinical Medicine at Medical University Brandenburg, Neuruppin, Germany
| | - Ehsan Safai Zadeh
- Interdisciplinary Center of Ultrasound Diagnostics, University Hospital Giessen and Marburg, Philipps University Marburg, Marburg, Germany
| | - Amjad Alhyari
- Interdisciplinary Center of Ultrasound Diagnostics, University Hospital Giessen and Marburg, Philipps University Marburg, Marburg, Germany
| | - Christian Görg
- Interdisciplinary Center of Ultrasound Diagnostics, University Hospital Giessen and Marburg, Philipps University Marburg, Marburg, Germany
| | - André Ignee
- Department of Internal Medicine – Gastroenterology and Rheumatology; Klinikum Wuerzburg Mitte, Wuerzburg, Germany
| | - Michael Hocke
- Medical Department II, Helios Klinikum Meiningen, Meiningen, Germany
| | - Yi Dong
- Department of Ultrasound, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Siyu Sun
- Department of Endoscopy Center, Shengjing Hospital of China Medical University, Liaoning Province, China
| | - Siegbert Faiss
- Medical Department I/Gastroenterology, Sana Hospital Lichtenberg, Berlin, Germany
| | - Christoph F. Dietrich
- Department of Internal Medicine (DAIM), Hirslanden Private Hospital, Beau Site, Salem und Permanence, Bern, Switzerland
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27
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Bowlus CL, Arrivé L, Bergquist A, Deneau M, Forman L, Ilyas SI, Lunsford KE, Martinez M, Sapisochin G, Shroff R, Tabibian JH, Assis DN. AASLD practice guidance on primary sclerosing cholangitis and cholangiocarcinoma. Hepatology 2023; 77:659-702. [PMID: 36083140 DOI: 10.1002/hep.32771] [Citation(s) in RCA: 125] [Impact Index Per Article: 62.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 07/26/2022] [Indexed: 01/28/2023]
Affiliation(s)
- Christopher L Bowlus
- Division of Gastroenterology , University of California Davis Health , Sacramento , California , USA
| | | | - Annika Bergquist
- Karolinska Institutet , Karolinska University Hospital , Stockholm , Sweden
| | - Mark Deneau
- University of Utah , Salt Lake City , Utah , USA
| | - Lisa Forman
- University of Colorado , Aurora , Colorado , USA
| | - Sumera I Ilyas
- Mayo Clinic College of Medicine and Science , Rochester , Minnesota , USA
| | - Keri E Lunsford
- Rutgers University-New Jersey Medical School , Newark , New Jersey , USA
| | - Mercedes Martinez
- Vagelos College of Physicians and Surgeons , Columbia University , New York , New York , USA
| | | | | | - James H Tabibian
- David Geffen School of Medicine at UCLA , Los Angeles , California , USA
| | - David N Assis
- Yale School of Medicine , New Haven , Connecticut , USA
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28
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Pathogenesis and Treatment of Pruritus Associated with Chronic Kidney Disease and Cholestasis. Int J Mol Sci 2023; 24:ijms24021559. [PMID: 36675074 PMCID: PMC9864517 DOI: 10.3390/ijms24021559] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 01/07/2023] [Accepted: 01/11/2023] [Indexed: 01/14/2023] Open
Abstract
Itching is an unpleasant sensation that provokes the desire to scratch. In general, itching is caused by dermatologic diseases, but it can also be caused by systemic diseases. Since itching hampers patients' quality of life, it is important to understand the appropriate treatment and pathophysiology of pruritus caused by systemic diseases to improve the quality of life. Mechanisms are being studied through animal or human studies, and various treatments are being tested through clinical trials. We report current trends of two major systemic diseases: chronic kidney disease and cholestatic liver disease. This review summarizes the causes and pathophysiology of systemic diseases with pruritus and appropriate treatments. This article will contribute to patients' quality of life. Further research will help understand the mechanisms and develop new strategies in the future.
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Morgan MA, Khot R, Sundaram KM, Ludwig DR, Nair RT, Mittal PK, Ganeshan DM, Venkatesh SK. Primary sclerosing cholangitis: review for radiologists. Abdom Radiol (NY) 2023; 48:136-150. [PMID: 36063181 PMCID: PMC9852001 DOI: 10.1007/s00261-022-03655-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 08/13/2022] [Accepted: 08/15/2022] [Indexed: 01/22/2023]
Abstract
Primary sclerosing cholangitis is a rare chronic inflammatory disease affecting the bile ducts, which can eventually result in bile duct strictures, cholestasis and cirrhosis. Patients are often asymptomatic but may present with clinical features of cholestasis. Imaging plays an important role in the diagnosis and management. This review covers the pathophysiology, clinical features, imaging findings as well as methods of surveillance and post-transplant appearance.
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Affiliation(s)
- Matthew A. Morgan
- Department of Radiology, University of Pennsylvania Health System, 1 Silverstein, 3400 Spruce Street, Philadelphia, PA, USA
| | - Rachita Khot
- Radiology and Medical Imaging, University of Virginia Health, 1215 Lee Street, Charlottesville, VA, USA
| | - Karthik M. Sundaram
- Department of Radiology, University of Pennsylvania Health System, 1 Silverstein, 3400 Spruce Street, Philadelphia, PA, USA
| | - Daniel R. Ludwig
- Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 S. Kingshighway Blvd, Campus Box 8131, Saint Louis, MO, USA
| | - Rashmi T. Nair
- Department of Radiology, University of Kentucky, 800 Rose Street, Room HX 313B, Lexington, KY 40536-0293, USA
| | - Pardeep K. Mittal
- Medical College of Georgia at Augusta University, 1120 15th street BA −1411, Augusta, GA 30912, USA
| | - Dhakshina M. Ganeshan
- The University of Texas MD Anderson Cancer Center, 1400 Pressler St., Unit 1473, Houston, TX 77030, USA
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Han S, Shah RJ. Benefit of endoscopic stenting for dominant strictures in patients with primary sclerosing cholangitis. Endosc Int Open 2022; 10:E1163-E1168. [PMID: 36118630 PMCID: PMC9473835 DOI: 10.1055/a-1873-0961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 06/09/2022] [Indexed: 11/23/2022] Open
Abstract
Background and study aims Dominant strictures (DS) occur in up to 60 % of patients with primary sclerosing cholangitis (PSC). Data regarding the long-term effects of stenting vs. dilation remain limited. The aim of this study was to compare the two treatment modalities in terms of transplantation-free survival. Patients and methods This single-center, retrospective study examined patients with PSC and DS treated endoscopically with a minimum of 1 year follow-up. Patients were divided into two cohorts: 1) those who received dilation alone; and 2) those who received both dilation and stenting. The primary outcome was transplantation-free survival, defined as time after index ERCP to liver transplantation. Results In all, 169 patients (54 in dilation cohort, 115 in stenting cohort) were included. The stenting cohort had a significantly higher Mayo PSC Risk Score (1.8 ± 1.1 vs. 0.9 ± 1.2) and presented with cholangitis more frequently (22.6 % vs. 1.9 %). During a follow-up period of 1198 person-years, 69 (40.8 %) patients received transplantation at a mean of 3.4 (± 2.9) years. There was no difference in transplantation rate in the stenting cohort [68 (95 % CI 5.2-8.8) per 100 person-years] compared to the dilation cohort [3.7 (95 % CI 2.1-6.0) per 100 person-years] and no difference in risk for transplantation (dilation cohort adjusted hazards ratio 0.67, 95 % CI 0.33-1.32). Conclusions Despite a higher Mayo Risk Score in the stenting group, there was no difference in transplantation-free survival between patients managed with stenting vs. dilation alone. Stenting, therefore, may offer benefit in patients with advanced PSC and DS.
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Affiliation(s)
- Samuel Han
- Division of Gastroenterology, Hepatology, and Nutrition. The Ohio State University Wexner Medical Center, Columbus, Ohio, United States
| | - Raj J. Shah
- Division of Gastroenterology and Hepatology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
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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: 146] [Impact Index Per Article: 48.7] [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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Development of a prognostic MRCP score (DiStrict) for patients with large-duct primary sclerosing cholangitis. JHEP Rep 2022; 4:100595. [DOI: 10.1016/j.jhepr.2022.100595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 09/13/2022] [Accepted: 09/14/2022] [Indexed: 11/19/2022] Open
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Efficacy and safety of immune-modulating therapy for primary sclerosing cholangitis: A systematic review and meta-analysis. Pharmacol Ther 2022; 237:108163. [DOI: 10.1016/j.pharmthera.2022.108163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 02/23/2022] [Accepted: 02/28/2022] [Indexed: 11/17/2022]
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Gleeson D, Walmsley M, Trivedi PJ, Joshi D, Rea B. Surveillance for cholangiocarcinoma in patients with primary sclerosing cholangitis: Can we be more proactive? Frontline Gastroenterol 2022; 14:162-166. [PMID: 36818795 PMCID: PMC9933607 DOI: 10.1136/flgastro-2022-102172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 07/17/2022] [Indexed: 02/24/2023] Open
Affiliation(s)
- Dermot Gleeson
- Liver Unit, Sheffield Teaching Hospitals Sheffield UK, Sheffield, UK
| | | | - Palak J Trivedi
- National Institute for Health Research Birmingham Biomedical Research Centre, Centre for Liver and Gastroenterology Research, University of Birmingham, Birmingham, United Kingdom, Birmingham, UK
| | - Deepak Joshi
- Institute of Liver Studies, King’s College Hospital NHS Foundation Trust, London, UK
| | - Ben Rea
- Department of Clinical Radiology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
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Pria HD, Torres US, Faria SC, Velloni FG, Caiado AH, Tiferes DA, D'Ippolito G. Practical Guide for Radiological Diagnosis of Primary and Secondary Sclerosing Cholangitis. Semin Ultrasound CT MR 2022; 43:490-509. [DOI: 10.1053/j.sult.2022.06.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Sadraei N, Jafari H, Sadraee A, Zeinali-Rafsanjani B, Rastgooyan H, Zahergivar A. Assessment of Three-Phasic CT Scan Findings of Cirrhosis Due to Primary Sclerosing Cholangitis Versus Cryptogenic Cirrhosis. Cureus 2022; 14:e23956. [PMID: 35547407 PMCID: PMC9085709 DOI: 10.7759/cureus.23956] [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] [Accepted: 03/30/2022] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND The CT findings of cirrhosis caused by primary sclerosing cholangitis (PSC) differ from cryptogenic cirrhosis. PSC could become complicated with biliary cirrhosis and cholangiocarcinoma. This study aimed at augmenting the information on the role of the three-phasic-abdominopelvic CT scan in PSC. MATERIAL AND METHODS A total of 185 CT scans were retrospectively reviewed, including 100 patients with cryptogenic cirrhosis and 85 patients with PSC-cirrhosis. Different morphologic criteria were compared, including segmental atrophy/hypertrophy, hepatic contour, portal-hypertension, perihilar lymphadenopathy, biliary tree dilatation, gallbladder appearance. Inflammatory-bowel-disease (IBD) and cholangiocarcinoma frequency, presence of perihilar lymph nodes (LNs), and their size during end-stage PSC cirrhosis are investigated. RESULTS Six findings occur more frequently with PSC than those diagnosed with cryptogenic cirrhosis. Modified caudate/right lobe (m-CRL) ratio >0.73, moderate and severe lobulated liver contour, lateral left lobe atrophy, over distended gallbladder (GB), biliary tree dilatation and wall thickening, and LN sizes were higher in PSC patients as compared to cryptogenic cirrhosis (P < 0.005). Ascites and portosystemic collateral formations were significant in cryptogenic cirrhosis compared to PSC patients (P < 0.005). Cholangiocarcinoma frequency in PSC patients was 14.7%, and the frequency of inflammatory bowel disease (IBD) was 57.6%. Further, 22.4% of the patients were diagnosed with IBD and PSC simultaneously. The LN number and size in PSC patients were not different between those with or without cholangiocarcinoma. CONCLUSION Using three-phasic CT scans and PSC characteristics could be considered as an additional suggestion besides pathology measures. Diagnosis of PSC based on histological findings could be a last resort due to its invasive essence and specific characteristics of PSC in imaging.
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Affiliation(s)
- Nazanin Sadraei
- Department of Radiology, Medical Imaging Research Center, Shiraz University of Medical Sciences, Shiraz, IRN
| | - Hamed Jafari
- Department of Radiology, Medical Imaging Research Center, Shiraz University of Medical Sciences, Shiraz, IRN
| | - Amin Sadraee
- Department of Urology, Nephro-Urology Research Center, Shiraz University of Medical Sciences, Shiraz, IRN
| | | | | | - Aryan Zahergivar
- Department of Radiology, Medical Imaging Research Center, Shiraz University of Medical Sciences, Shiraz, IRN
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Ekanayake LS, Ahmad A, Weyer N, Agrawal S. An Unusual Presentation of Crohn’s Disease and Primary Sclerosing Cholangitis. Cureus 2022; 14:e22797. [PMID: 35399453 PMCID: PMC8980253 DOI: 10.7759/cureus.22797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/03/2022] [Indexed: 11/06/2022] Open
Abstract
Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory gastrointestinal bowel disorders that may affect any part of the alimentary tract. Classically, these two diseases have hallmark associations, such as UC with primary sclerosing cholangitis (PSC). We present a case of a healthy 21-year-old white female with concomitant CD and PSC, complicated by a biliary stricture requiring stent placement. We discuss shared risk factors, disease pathogenesis, and hallmark pathological associations. To the best of our knowledge, there are a limited number of reported cases that demonstrate the dual phenotype of CD and PSC.
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Peerani F, Du L, Lytvyak E, Bain VG, Mason AL, Bailey RJ, Montano-Loza AJ. Serum IgG4 cut-off of 70 mg/dL is associated with a shorter time to cirrhosis decompensation and liver transplantation in primary sclerosing cholangitis patients. CANADIAN LIVER JOURNAL 2022; 5:31-42. [PMID: 35990785 PMCID: PMC9231426 DOI: 10.3138/canlivj-2021-0023] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Accepted: 09/05/2021] [Indexed: 10/11/2023]
Abstract
BACKGROUND Primary sclerosing cholangitis (PSC) is an immune-mediated biliary disorder of unknown etiology with no effective treatment. The purpose of this study was to better prognosticate the development of cirrhosis, decompensation, and requirement for liver transplantation (LT) in PSC patients based on serum immunoglobulin G4 (IgG4) levels. METHODS A retrospective chart review was conducted on PSC patients seen at the University of Alberta Hospital between 2002 and 2017. PSC patients were categorized as high IgG4 group (≥70 mg/dL) or normal IgG4 group (<70 mg/dL). Laboratory parameters, clinical characteristics, and outcomes were compared between the groups. RESULTS One hundred and ten patients were followed over a mean period of 7.3 (SD 5) years. Seventy-two patients (66%) were male, the mean age at diagnosis of PSC was 35 (SD 15) years, and inflammatory bowel disease (IBD) was present in 80 patients (73%). High IgG4 levels were found in 37 patients (34%). PSC patients with high IgG4 had a shorter mean cholangitis-free survival time (5.3 versus 10.4 years, p = 0.02), cirrhosis-free survival time (8.7 versus 13.0 years, p = 0.02), and LT-free survival time (9.3 years versus 18.9 years, p <0.001). IgG4 ≥70 mg/dL was independently associated with liver decompensation and LT-free outcomes. A cut-off IgG4 value of ≥70 mg/dL performed better than a cut-off value of ≥140 mg/dL to predict time to LT (area under the curve [AUC] 0.68, p = 0.03, sensitivity 72%, specificity 78%). CONCLUSIONS Serum IgG4 ≥70 mg/dL in PSC predicts a shorter time to cirrhosis decompensation and LT.
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Affiliation(s)
- Farhad Peerani
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Lillian Du
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Ellina Lytvyak
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Vincent G Bain
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Andrew L Mason
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Robert J Bailey
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Aldo J Montano-Loza
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
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Kim W. Chronic Liver Disease. SEX/GENDER-SPECIFIC MEDICINE IN THE GASTROINTESTINAL DISEASES 2022:209-227. [DOI: 10.1007/978-981-19-0120-1_14] [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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Vitale G, Gitto S, Campani C, Turco L, Baldan A, Marra F, Morelli MC. Biological therapies in patients with liver disease: are they really lifesavers? Expert Opin Biol Ther 2021; 22:473-490. [PMID: 34860629 DOI: 10.1080/14712598.2022.2013799] [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: 10/19/2022]
Abstract
INTRODUCTION The liver plays a key role in the setting of immune tolerance. Targeting antigens for presentation by antigen-presenting cells in the liver can induce immune tolerance to either autoantigens from the liver itself or organs outside of the liver. Despite its non-conventional capacity for tolerance induction, the liver remains a target organ for autoimmune diseases. Whereas chronic inflammation and intra-hepatic immuno-suppressive microenvironment occurring during liver fibrosis lead to hepatocellular carcinoma. Monoclonal antibodies have revolutionized the therapeutic strategies of many autoimmune diseases and some cancers. AREAS COVERED We review data from literature regarding the safety and efficacy of biologics in treating hepatobiliary autoimmune diseases and primary liver cancers. Furthermore, we describe their potential use in the setting of liver transplants and their main immune-related liver adverse events. EXPERT OPINION Biological therapies have changed the natural history of main autoimmune diseases and solid cancers. Compared to other organs and disease settings, the liver lags behind in biologics and their applications. The development of novel diagnostic and therapeutic strategies based on the immunological and antigenic characteristics of the hepatobiliary system could reduce mortality and transplant rates linked to chronic liver diseases.
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Affiliation(s)
- Giovanni Vitale
- Division of Internal Medicine for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
| | - Stefano Gitto
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Claudia Campani
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Laura Turco
- Division of Internal Medicine for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
| | - Anna Baldan
- Division of Internal Medicine for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
| | - Fabio Marra
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Maria Cristina Morelli
- Division of Internal Medicine for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
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Are VS, Vilar-Gomez E, Gromski MA, Akisik F, Lammert C, Ghabril M, Chalasani N, Vuppalanchi R, Nephew LD. Racial differences in primary sclerosing cholangitis mortality is associated with community socioeconomic status. Liver Int 2021; 41:2703-2711. [PMID: 34240538 DOI: 10.1111/liv.15008] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 06/17/2021] [Accepted: 07/05/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIMS Natural history and outcomes data in PSC are mostly derived from cohorts where Blacks have been underrepresented. It is unknown if there are differences in mortality between Blacks and Whites with PSC. METHODS PSC patients seen at our institution from June 1988 to Jan 2019 were identified by merging prospective ERCP hepatology-clinic databases and liver-transplant registry. Data on race, clinical events, and death was obtained through chart review. Data on community health were collected using indices from county health rankings. Cumulative incidence of death was calculated using liver transplant (LT) as a competing risk. RESULTS Of 449 patients, 404 were White and 45 were Black. The median-duration of follow-up was 7 years (IQR:3, 13). Black patients were younger at presentation than White patients (36.3 vs 42.5 years., P = .013). Disease severity as indicated by Mayo Risk Score categories (low 27% vs 31%, intermediate 54% vs 49% and high 19% vs 19%, P = .690), comorbidity burden and frequency of cirrhosis (42% vs 35%, P = .411) were similar between Blacks and Whites. Cumulative incidence of liver-related death, with LT as a competing risk was significantly higher in Blacks compared to Whites (sHR 1.80, 95%CI 1.25, 2.61, P = .002). There was a significant interaction between race and community socioeconomic factors that attenuated the racial difference in mortality (sHR 1.01, 95%CI 0.99, 1.04, P = .345). CONCLUSIONS Blacks with PSC present at a younger age with a similar disease severity as Whites but have higher liver related mortality that is mediated in part through community health.
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Affiliation(s)
- Vijay S Are
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Eduardo Vilar-Gomez
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Mark A Gromski
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Fatih Akisik
- Department of Radiology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Craig Lammert
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Marwan Ghabril
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Naga Chalasani
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Raj Vuppalanchi
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Lauren D Nephew
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN, USA
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Pavic T, Mikolasevic I, Kralj D, Blazevic N, Skrtic A, Budimir I, Lerotic I, Hrabar D. Role of Endoscopic Ultrasound in Liver Disease: Where Do We Stand? Diagnostics (Basel) 2021; 11:2021. [PMID: 34829368 PMCID: PMC8618190 DOI: 10.3390/diagnostics11112021] [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] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 10/25/2021] [Accepted: 10/29/2021] [Indexed: 12/13/2022] Open
Abstract
As the burden of liver disease in the general populace steadily increases, so does the need for both advanced diagnostic and treatment options. Endoscopic ultrasound is a reliable diagnostic and therapeutic method that has an established role, foremost in pancreatobiliary pathology. This paper aims to summarize the growing role of endoscopic ultrasound in hepatology based on the search of the current literature. A number of applications of endoscopic ultrasound are reviewed, including both noninvasive methods and tissue acquisition in focal and diffuse liver disease, portal hypertension measurement, detection and management of gastric and esophageal varices, treatment of focal liver lesions and staging of pancreatobiliary malignancies, treatment of cystic and solid liver lesions, as well as liver abscess drainage. Both hepatologists and endoscopists should be aware of the evolving role of endoscopic ultrasound in liver disease. The inherent invasive nature of endoscopic examination limits its use to a targeted population identified using noninvasive methods. Endoscopic ultrasound is one the most versatile methods in gastroenterology, allowing immediate access with detection, sampling, and treatment of digestive tract pathology. Further expansion of its use in hepatology is immanent.
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Affiliation(s)
- Tajana Pavic
- Department of Gastroenterology and Hepatology, University Hospital Center Sestre Milosrdnice, 10000 Zagreb, Croatia; (D.K.); (N.B.); (I.B.); (I.L.); (D.H.)
| | - Ivana Mikolasevic
- Department of Gastroenterology, University Hospital Center Rijeka, 51000 Rijeka, Croatia;
| | - Dominik Kralj
- Department of Gastroenterology and Hepatology, University Hospital Center Sestre Milosrdnice, 10000 Zagreb, Croatia; (D.K.); (N.B.); (I.B.); (I.L.); (D.H.)
| | - Nina Blazevic
- Department of Gastroenterology and Hepatology, University Hospital Center Sestre Milosrdnice, 10000 Zagreb, Croatia; (D.K.); (N.B.); (I.B.); (I.L.); (D.H.)
| | - Anita Skrtic
- Department of Pathology, Merkur University Hospital, 10000 Zagreb, Croatia;
| | - Ivan Budimir
- Department of Gastroenterology and Hepatology, University Hospital Center Sestre Milosrdnice, 10000 Zagreb, Croatia; (D.K.); (N.B.); (I.B.); (I.L.); (D.H.)
| | - Ivan Lerotic
- Department of Gastroenterology and Hepatology, University Hospital Center Sestre Milosrdnice, 10000 Zagreb, Croatia; (D.K.); (N.B.); (I.B.); (I.L.); (D.H.)
| | - Davor Hrabar
- Department of Gastroenterology and Hepatology, University Hospital Center Sestre Milosrdnice, 10000 Zagreb, Croatia; (D.K.); (N.B.); (I.B.); (I.L.); (D.H.)
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Saffioti F, Mavroeidis VK. Review of incidence and outcomes of treatment of cholangiocarcinoma in patients with primary sclerosing cholangitis. World J Gastrointest Oncol 2021; 13:1336-1366. [PMID: 34721770 PMCID: PMC8529934 DOI: 10.4251/wjgo.v13.i10.1336] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 07/05/2021] [Accepted: 08/23/2021] [Indexed: 02/06/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) is a premalignant condition and a well-documented risk factor for cholangiocarcinoma (CCA) which is the most common malignancy in this setting and the leading cause of deaths in the recent years, with an increasing incidence. PSC-associated CCA has a geographical distribution that follows the incidence of PSC, with an observed ascending gradient from the Eastern to the Western and from the Southern to the Northern countries. It may arise at any location along the biliary tree but is most common in the perihilar area. Patients with PSC and intrahepatic or perihilar CCA are typically not suitable for liver resection, which is otherwise the treatment of choice with curative intent in patients with resectable tumours, providing a radical resection with clear margins can be achieved. This largely relates to the commonly advanced stage of liver disease at presentation, which allows consideration for liver resection only for a very limited number of suitable patients with PSC. On the other hand, remarkable progress has been reached in the last decades with the implementation of a protocol combining neoadjuvant chemoradiation and orthotopic liver transplantation (OLT) for the treatment of perihilar CCA, within specific criteria. Excellent results have been achieved particularly for PSC patients with this cancer, who seem to benefit the most from this treatment, having converted this into an accepted indication for transplantation and the standard of care in several experienced centres. Intrahepatic CCA as an indication for OLT remains controversial and has not been accepted given disappointing previous results. However, as recent studies have shown favourable outcomes in early intrahepatic CCA, it may be that under defined criteria, OLT may play a more prominent role in the future. Distal CCA in the context of PSC requires aggressive surgical treatment with curative intent, when feasible. This review provides insight about particular features of CCA in the setting of PSC, with a main focus on its incidence, considerations relating to its anatomical location and implications to treatment and outcomes, through the viewpoint of historical evolution of management, and future perspectives.
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Affiliation(s)
- Francesca Saffioti
- Department of Gastroenterology and Hepatology, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 9DU, Oxfordshire, United Kingdom
- UCL Institute for Liver and Digestive Health and Sheila Sherlock Liver Unit, Royal Free Hospital, University College London, London NW3 2QG, United Kingdom
| | - Vasileios K Mavroeidis
- Department of Surgery, The Royal Marsden NHS Foundation Trust, London SW3 6JJ, United Kingdom
- Department of Transplant Surgery, North Bristol NHS Trust, Southmead Hospital, Bristol BS10 5NB, United Kingdom
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Rogler G, Singh A, Kavanaugh A, Rubin DT. Extraintestinal Manifestations of Inflammatory Bowel Disease: Current Concepts, Treatment, and Implications for Disease Management. Gastroenterology 2021; 161:1118-1132. [PMID: 34358489 PMCID: PMC8564770 DOI: 10.1053/j.gastro.2021.07.042] [Citation(s) in RCA: 391] [Impact Index Per Article: 97.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Revised: 07/28/2021] [Accepted: 07/28/2021] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel diseases (IBDs) are systemic diseases that manifest not only in the gut and gastrointestinal tract, but also in the extraintestinal organs in many patients. The quality of life for patients with IBD can be substantially affected by these extraintestinal manifestations (EIMs). It is important to have knowledge of the prevalence, pathophysiology, and clinical presentation of EIMs in order to adapt therapeutic options to cover all aspects of IBD. EIMs can occur in up to 24% of patients with IBD before the onset of intestinal symptoms, and need to be recognized to initiate appropriate diagnostic procedures. EIMs most frequently affect joints, skin, or eyes, but can also affect other organs, such as the liver, lung, and pancreas. It is a frequent misconception that a successful therapy of the intestinal inflammation will be sufficient to treat EIMs satisfactorily in most patients with IBD. In general, peripheral arthritis, oral aphthous ulcers, episcleritis, or erythema nodosum can be associated with active intestinal inflammation and can improve on standard treatment of the intestinal inflammation. However, anterior uveitis, ankylosing spondylitis, and primary sclerosing cholangitis usually occur independent of disease flares. This review provides a comprehensive overview of epidemiology, pathophysiology, clinical presentation, and treatment of EIMs in IBD.
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Affiliation(s)
- Gerhard Rogler
- Department of Gastroenterology & Hepatology, Department of Medicine, Zurich University Hospital, Zurich, Switzerland
| | - Abha Singh
- University of California, San Diego, La Jolla, CA, USA
| | | | - David T. Rubin
- University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, IL, USA
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Characteristic features of ulcerative colitis with concomitant primary sclerosing cholangitis. PRZEGLAD GASTROENTEROLOGICZNY 2021; 16:184-187. [PMID: 34584578 PMCID: PMC8456759 DOI: 10.5114/pg.2021.108983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Accepted: 01/30/2021] [Indexed: 11/17/2022]
Abstract
Ulcerative colitis is a chronic inflammatory bowel disease of the colon. The most frequent symptoms include bloody diarrhoea with rectal urgency and tenesmus. It is often complicated by the presence of primary sclerosing cholangitis, a chronic, cholestatic liver disease, characterised by the inflammation and fibrosis of bile ducts. The presence of primary sclerosing cholangitis seems to alter the course of ulcerative colitis, changing its natural course.
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Whole Exome Sequencing Identifies Two Novel Mutations in a Patient with UC Associated with PSC and SSA. Can J Gastroenterol Hepatol 2021; 2021:9936932. [PMID: 34545326 PMCID: PMC8449715 DOI: 10.1155/2021/9936932] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 08/24/2021] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Patients diagnosed with ulcerative colitis (UC) associated with primary sclerosis cholangitis (PSC) and sessile serrated adenoma (SSA) are rare. The present study aimed to identify the potential causative gene mutation in a patient with UC associated with PSC and SSA. METHODS DNA was extracted from the blood sample and tissue sample of SSA, followed by the whole exome sequencing (WES) analysis. Bioinformatics analysis was utilized to predict the deleteriousness of the identified variants. Multiple sequence alignment and conserved protein domain analyses were performed using online software. Sanger sequencing was used to validate the identified variants. Expression and diagnostic analysis of identified mutated genes was performed in the GSE119600 dataset (peripheral blood samples of PSC and UC) and GSE43841 dataset (tumor samples of SSA). RESULTS In the present study, a total of 842 single nucleotide variants (SNVs) in 728 genes were identified in the blood sample. Two variants, integrin beta 4 (ITGB4) (c.C2503G; p.P835A) and a mucin 3A (MUC3A) (c.C1019T; p.P340L), were further analyzed. MUC3A was associated with inflammatory bowel disease. Sanger sequence in blood revealed that the ITGB4 mutation was fully cosegregated with the result of WES in the patient. Additionally, a variant, tumor protein p53 gene (TP53) (c.86delA; p.N29Tfs ∗ 15) was identified in the tissue sample of SSA. Compared to that in normal controls, ITGB4 was upregulated in both UC and PSC, MUC3A was, respectively, upregulated and downregulated in PSC and UC, and TP53 was downregulated in SSA. ITGB4 and TP53 had a potential diagnostic value for UC, PSC and SSA. CONCLUSIONS The present study demonstrated that the ITGB4 (c.C2503G; p.P835A) and MUC3A (c.C1019T; p.P340L) mutations may be the potential causative variants in a patient with UC associated with PSC and SSA. TP53 (c.86delA; p.N29Tfs ∗ 15) mutation may be associated with SSA in this patient.
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Han S, Kahaleh M, Sharaiha RZ, Tarnasky PR, Kedia P, Slivka A, Chennat JS, Joshi V, Sejpal DV, Sethi A, Shah RJ. Probe-based confocal laser endomicroscopy in the evaluation of dominant strictures in patients with primary sclerosing cholangitis: results of a U.S. multicenter prospective trial. Gastrointest Endosc 2021; 94:569-576.e1. [PMID: 33798541 DOI: 10.1016/j.gie.2021.03.027] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 03/21/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Patients with primary sclerosing cholangitis (PSC) and dominant biliary strictures carry increased risk for the development of cholangiocarcinoma. Although ERCP-based techniques including brush cytology and intraductal biopsy sampling represent first-line tissue sampling methods for dominant strictures, sensitivity is low. Probe-based confocal laser endomicroscopy (pCLE) offers microscopic-level imaging of subepithelial biliary mucosa. Because data regarding the use of pCLE in PSC are limited, we aimed to investigate its diagnostic performance in dominant strictures. METHODS This was a multicenter prospective study involving PSC patients with dominant strictures. ERCP with pCLE was performed with use of the Miami classification (2+ criteria for malignant diagnosis) and Paris classification. Final malignant diagnoses required histopathologic confirmation, and benign diagnoses required a minimum of 1 year of follow-up without development of cancer. RESULTS Fifty-nine patients (mean age, 49 years; 59% men) with 63 strictures were included in the study. Stricture locations included the common bile duct (31.7%), bifurcation (22.2%), and common hepatic duct (19%). Seven patients (11.9%) were found to have cholangiocarcinoma. The sensitivity and specificity of pCLE was 85.7% (95% confidence interval [CI], 42.1-99.6) and 73.1% (95% CI, 58.9-84.4), respectively. Within specific stricture locations, the highest sensitivity was seen at the bifurcation (100%; 95% CI, 2.5-100) and the right hepatic duct (100%; 95% CI, 29.2-100). The lowest sensitivities were seen at the common bile duct (25%; 95% CI, 5.5-57.2) and the left hepatic duct (28.6%; 95% CI, 3.7-70.9). CONCLUSIONS In this prospective multicenter study, pCLE had a high sensitivity in detecting cholangiocarcinoma, but technical aspects of the probe may limit evaluation in the common bile duct and left hepatic duct. Further evaluation is needed to elucidate the role of pCLE in the algorithm of excluding neoplasia in biliary strictures associated with PSC. (Clinical trial registration number: NCT02736708.).
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Affiliation(s)
- Samuel Han
- Division of Gastroenterology and Hepatology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Michel Kahaleh
- Division of Gastroenterology, Rutgers Robert Wood Johnson University Hospital, New Brunswick, New Jersey, USA
| | - Reem Z Sharaiha
- Division of Gastroenterology, Weill Cornell Medical Center, New York, New York, USA
| | - Paul R Tarnasky
- Division of Gastroenterology, Dallas Methodist Medical Center, Dallas, Texas, USA
| | - Prashant Kedia
- Division of Gastroenterology, Dallas Methodist Medical Center, Dallas, Texas, USA
| | - Adam Slivka
- Division of Gastroenterology and Hepatology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Jennifer S Chennat
- Division of Gastroenterology and Hepatology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Virendra Joshi
- Division of Gastroenterology, Louisiana State University Health Center, New Orleans, Louisiana, USA
| | - Divyesh V Sejpal
- Division of Gastroenterology, Northwell Health, Manhasset, New York, USA
| | - Amrita Sethi
- Division of Gastroenterology, Columbia University Medical Center, New York, New York, USA
| | - Raj J Shah
- Division of Gastroenterology and Hepatology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
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Alvarenga LR, Sandy NS, Gomez GS, Hessel G, DE Tommaso AMA, Bellomo-Brandão MÂ. SYMPTOMATIC CHOLELITHIASIS AS THE PRESENTATION OF PEDIATRIC PRIMARY SCLEROSING CHOLANGITIS - CASE SERIES AND LITERATURE REVIEW. ARQUIVOS DE GASTROENTEROLOGIA 2021; 58:227-233. [PMID: 34287532 DOI: 10.1590/s0004-2803.202100000-41] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 11/25/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Primary sclerosing cholangitis (PSC) is a rare hepatobiliary disorder, whose etiology remains not fully elucidated. Given how rare PSC is in childhood, until the recent publication of a multicenter international collaboration, even data on its characteristics and natural history were scarce. Symptomatic cholelithiasis has not been previously reported as the presentation of PSC. OBJECTIVE The aim of this study was the diagnosis of PSC following the initial unusual presentation with symptomatic cholelithiasis, that followed an atypical clinical course that could not be explained by cholelithiasis alone. A literature review was also conducted. METHODS We conducted a retrospective chart review of three patients, who were diagnosed and/or followed at the Clinics Hospital, University of Campinas - Sao Paulo/ Brazil, between 2014 and 2020. Data analyzed included gender, age of presentation, past medical history, imaging findings, laboratory results, endoscopic evaluation, response to medical therapy and follow-up. RESULTS Age at time of presentation with cholelithiasis varied from 10 to 12 years. In two of the cases reported, a more subacute onset of symptoms preceded the episode of cholelithiasis. Two patients were managed with cholecystectomy, not followed by any surgical complications, one patient was managed conservatively. Percutaneous liver biopsy was performed in all three cases, showing histological findings compatible with PSC. Associated inflammatory bowel disease (IBD) was not seen in any of the patients. The patients have been followed for a mean time of 3.4 years. CONCLUSION PSC and cholelithiasis are both rare in the pediatric population. This study reports on symptomatic cholelithiasis as a presentation of PSC and raises the importance of suspecting an underlying hepatobiliary disorder in children with cholelithiasis without any known predisposing factors and/or that follow an atypical clinical course for cholelithiasis alone.
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Affiliation(s)
- Lucas Rocha Alvarenga
- Universidade Estadual de Campinas (UNICAMP), Faculdade de Ciências Médicas, Departamento de Pediatria, Campinas, SP, Brasil
| | - Natascha Silva Sandy
- University of Toronto, Hospital for Sick Children, Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Toronto, ON, Canada
| | - Gabriela Souza Gomez
- Universidade Estadual de Campinas (UNICAMP), Faculdade de Ciências Médicas, Departamento de Pediatria, Campinas, SP, Brasil
| | - Gabriel Hessel
- Universidade Estadual de Campinas (UNICAMP), Faculdade de Ciências Médicas, Departamento de Pediatria, Campinas, SP, Brasil
| | - Adriana Maria Alves DE Tommaso
- Universidade Estadual de Campinas (UNICAMP), Faculdade de Ciências Médicas, Departamento de Pediatria, Campinas, SP, Brasil
| | - Maria Ângela Bellomo-Brandão
- Universidade Estadual de Campinas (UNICAMP), Faculdade de Ciências Médicas, Departamento de Pediatria, Campinas, SP, Brasil
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Reporting standards for primary sclerosing cholangitis using MRI and MR cholangiopancreatography: guidelines from MR Working Group of the International Primary Sclerosing Cholangitis Study Group. Eur Radiol 2021; 32:923-937. [PMID: 34363134 DOI: 10.1007/s00330-021-08147-7] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 05/30/2021] [Accepted: 06/06/2021] [Indexed: 12/12/2022]
Abstract
Primary sclerosing cholangitis (PSC) is a chronic inflammatory disorder affecting the bile ducts and is characterized by biliary strictures, progressive liver parenchymal fibrosis, and an increased risk of hepatobiliary malignancies primarily cholangiocarcinoma (CCA). PSC may lead to portal hypertension, liver decompensation, and liver failure with the need for liver transplantation. Magnetic resonance imaging (MRI)/magnetic resonance cholangiopancreatography (MRCP) are considered the imaging standard for diagnosis and follow-up in patients with PSC. Currently, there are no universally accepted reporting standards and definitions for MRI/MRCP features. Controversies exist about the definition of a high-grade stricture and there is no widely agreed approach to their management. The members of the MRI working group of the International Primary Sclerosing Cholangitis Study Group (IPSCSG) sought to define terminologies and reporting standards for describing MRI/MRCP features that would be applied to diagnosis and surveillance of disease progression, and potentially for evaluating treatment response in clinical trials. In this extensive review, the technique of MRI/MRCP and assessment of image quality for the evaluation of PSC is briefly described. The definitions and terminologies for severity and length of strictures, duct wall thickening and hyperenhancement, and liver parenchyma signal intensity changes are outlined. As CCA is an important complication of PSC, standardized reporting criteria for CCA developing in PSC are summarized. Finally, the guidelines for reporting important changes in follow-up MRI/MRCP studies are provided. KEY POINTS: • Primary sclerosing cholangitis is a chronic inflammatory disorder affecting the bile ducts, causing biliary strictures and liver fibrosis and an increased risk of cholangiocarcinoma. • This consensus document provides definitions and suggested reporting standards for MRI and MRCP features of primary sclerosing cholangitis, which will allow for a standardized approach to diagnosis, assessment of disease severity, follow-up, and detection of complications. • Standardized definitions and reporting of MRI/MRCP features of PSC will facilitate comparison between studies, promote longitudinal assessment during management, reduce inter-reader variability, and enhance the quality of care and communication between health care providers.
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Assessment of prognostic value and interreader agreement of ANALI scores in patients with primary sclerosing cholangitis. Eur J Radiol 2021; 142:109884. [PMID: 34380098 DOI: 10.1016/j.ejrad.2021.109884] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Revised: 07/25/2021] [Accepted: 07/27/2021] [Indexed: 11/21/2022]
Abstract
PURPOSE ANALI-scores are two prognostic magnetic resonance imaging (MRI)-based scores developed for patients with primary sclerosing cholangitis (PSC). Our study aims to assess the interreader agreement between expert radiologists of the two ANALI-scores and of the radiological parameters they utilize, and to test the prognostic performance of the scores in our population. METHOD Three radiologists evaluated MRIs of 98 PSC-patients from a prospectively collected cohort with median follow-up of 6.7 years. Each parameter of ANALI-scores was assessed, and the scores were calculated. Interreader agreement was assessed with intraclass correlation coefficient (ICC). After consensus reading was reached, the prognostic value of ANALI-scores was assessed with Cox regression, and outcome-free survival rates were evaluated with Kaplan-Meier estimates. RESULTS The ANALI-score without gadolinium had poor to moderate (ICC = 0.56, 95 %CI: 0.42-0.68) and with gadolinium poor (ICC = 0.30, 95 %CI: 0.16-0.44) agreement. Liver deformity (ICC = 0.28, 95 %CI: 0.13-0.44) and parenchymal enhancement heterogeneity (ICC = 0.24, 95 %CI: 0.12-0.38) had poor agreement. Portal hypertension had poor to moderate (ICC = 0.48, 95 %CI: 0.36-0.59) and dilatation of the intrahepatic ducts had moderate (ICC = 0.64, 95 %CI: 0.54-0.73) agreement. Hazard ratios for liver-related death, transplantation or cirrhosis decompensation of the ANALI-scores with and without gadolinium were 3.53 (95 %CI: 1.40-8.93) and 2.25 (95 %CI: 1.56-3.24), respectively. Outcome-free survival was better for patients with low ANALI-scores. CONCLUSIONS The ANALI-scores show poor to moderate agreement, which challenges their usefulness in clinical practice. They are associated with clinical outcomes, confirming the value of imaging in prognosis of PSC, but need further multicenter evaluation.
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