Primary sclerosing cholangitis in children: a single-center experience and evaluation of prognostic markers

Introduction

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by progressive biliary strictures and fibrosis, which may potentially lead to end-stage liver disease and the need for liver transplantation (1). In the pediatric population, its incidence is estimated as 0.2 cases per 100,000 children, although this is likely underestimated due to limited epidemiological data and the typically mild and variable early symptoms (2,3). Although the exact pathogenetic mechanism of PSC has not yet been fully elucidated, it is thought to result from a complex interplay of genetic, immune, and environmental factors. In recent years, increasing attention has been given to the potential role of gut microbiome dysregulation in this multifactorial process (4,5).

PSC with features of autoimmune hepatitis (AIH), also referred to as autoimmune sclerosing cholangitis, affects up to 33% of pediatric patients, a higher proportion than in adults (6). In children under 6 years of age with very early onset inflammatory bowel disease (VEO-IBD), the incidence is even higher, with up to 92% of VEO-IBD cases reported PSC with features of AIH, according to a recent retrospective study (7). Additionally, PSC in children is often associated with IBD, particularly ulcerative colitis (UC), with reported co-occurrence rates ranging from 43% to 93% (6,8-14).

Recent pediatric studies suggest that a 25% reduction or normalization of gamma-glutamyl transferase (GGT) within 1 year of diagnosis may serve as a favorable prognostic marker (15,16). In contrast, elevated levels of total bilirubin, aspartate aminotransferase (AST), and the AST-to-platelet ratio index (APRI), as well as high GGT at diagnosis, have been associated with poorer long-term outcomes (6). The Sclerosing Cholangitis Outcomes in Pediatrics (SCOPE) index has been proposed as a prognostic tool to predict long-term outcomes in children with PSC (17). While it has shown promise in some national studies, its predictive utility remains inconsistent and has not yet been evaluated in an independent multinational setting (9,18).

This retrospective study aimed to identify clinical and biochemical markers associated with a severe disease course and to evaluate the prognostic value of the SCOPE index at diagnosis and GGT normalization within 1 year. A secondary aim was to characterize the clinical course of pediatric PSC. We present this article in accordance with the STROBE reporting checklist (available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-57/rc).

Methods

Study population

All pediatric patients (<19 years) diagnosed with PSC and followed at Motol University Hospital in Prague, a tertiary liver transplant center, between January 1, 2011 and June 30, 2023 were included in this study. The date of PSC diagnosis was used as the inclusion date. Patients were followed until June 2023 or until the last documented visit at our center or an affiliated adult center (in case of transition to adult care), whichever occurred first. For patients referred to external centers, follow-up information was obtained either from medical records provided by the adult transplant center and through direct communication with the patient or their family (e.g., via phone interview). Patients who had already developed severe complications at the time of diagnosis were excluded from the analysis. A detailed patient selection process is outlined in the patient flowchart (Figure S1).

Diagnostic criteria

PSC was diagnosed based on a cholestatic biochemical profile and characteristic findings on magnetic resonance cholangiopancreatography (MRCP), following the diagnostic recommendations established by the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and after the exclusion of secondary sclerosing cholangitis (1,19,20).

Patients with typical MRCP findings, such as multiple focal strictures or dilatations of the biliary tree, were classified as having large duct PSC. In contrast, those with normal MRCP but abnormal liver histology consistent with PSC were classified as having small duct PSC. Characteristic histologic features of small duct PSC include periductal fibrosis (often referred to as “onion skinning”) surrounding interlobular bile ducts, as well as secondary changes like periductal edema, concentric inflammation, bile duct epithelial injury, ductular reaction, and neutrophilic infiltration within the bile ducts (20,21).

Suspicion of PSC with features of AIH arose from elevated immunoglobulin G (IgG) levels, positive autoantibodies, and histologic features consistent with AIH (interface hepatitis) (1,19,20). This diagnosis was confirmed by liver biopsy. We utilized the simplified criteria for AIH, with a score of ≥7 indicating probable and ≥8 indicating definitive AIH (19).

Liver biopsy was performed when clinically indicated, particularly if small duct PSC or PSC with features of AIH was suspected, in accordance with current recommendations (20).

IBD was diagnosed according to the Porto criteria (22).

Monitored variables and endpoints

We collected demographic, laboratory, and liver-specific immunological data at the time of diagnosis, and at 3- and 12-month post-diagnosis. At diagnosis, we calculated the Model for End-Stage Liver Disease (MELD)/Pediatric End-Stage Liver Disease (PELD) score (used in children under 12 years old), the APRI, and the SCOPE index (17). We also recorded the presence of coexisting autoimmune diseases and documented medications used during follow-up. All data were retrieved from patients’ medical records.

Patients were stratified into two groups based on GGT levels within the first year after diagnosis: those who achieved full normalization and those with persistently elevated levels, adjusted for age and sex.

Severe complications of interest were defined as follows: (I) portal hypertensive complications (ascites, hepatic encephalopathy, esophageal varices with or without bleeding); (II) biliary complications (acute cholangitis, dominant biliary stricture requiring intervention); (III) cholangiocarcinoma; (IV) placement on the liver transplant waiting list; and (V) death due to liver disease.

Statistical analysis

All data were analyzed using R statistical software (version 4.3.1; https://www.r-project.org/). Continuous variables are presented as medians and interquartile ranges (IQRs), and categorical variables as frequencies and percentages. Missing data were excluded from the specific analysis. A significance level of P<0.05 was used.

Kaplan-Meier curves were generated to describe the occurrence of complications during follow-up. Patients were censored at the last follow-up or at the earliest occurrence of a defined endpoint. Survival differences between laboratory terciles and markers were assessed using the long-rank test. Cox proportional hazard regression was used to evaluate associations with outcomes. Both univariate and multivariate Cox regression models were performed, adjusting for GGT, total bilirubin, APRI, age at diagnosis, and sex. The following variables were assessed for association with severe outcomes: sex, age at PSC diagnosis, presence of IBD, large duct PSC, features of AIH, and GGT normalization within 1 year.

Ethical approval

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Institutional Ethics Board of the Motol University Hospital, Prague, on December 28, 2022 (No. EK-1457/22). Individual consent for this retrospective analysis was waived.

Results

Demographics and clinical characteristics

A total of 62 pediatric patients with PSC were initially enrolled in the study. Two were excluded due to the presence of severe complications at the time of diagnosis, leaving a final cohort of 60 patients. Among these, 33 had isolated PSC, and 26 met diagnostic criteria for AIH, thus classified as PSC with features of AIH. One patient fulfilled the diagnostic criteria for PSC and was included in the overall analysis, but could not be classified regarding concomitant AIH due to incomplete data.

IBD was confirmed in 49 children, including 4 with IBD-Unclassified, 5 with Crohn’s disease, and 40 with UC. In the remaining 11 patients, IBD was ruled out based on normal fecal calprotectin levels or negative endoscopic findings.

MRCP confirmed large duct PSC in 45 patients. Fourteen patients with negative MRCP findings but cholestasis features on liver biopsy were classified as having small duct PSC. One patient declined liver biopsy and could not be definitively subtyped.

Eight children were diagnosed with another autoimmune disease, the most common autoimmune thyroiditis, followed by celiac disease, type 1 diabetes mellitus, and autoimmune polyglandular syndrome. Demographic and clinical data are summarized in Table 1 (detailed demographic and clinical data for each subtype can be found in Table S1).

The cohort was followed for a total of 306 person-years, with a median follow-up of 3.8 years (IQR, 1.5–8.7 years). No significant differences in laboratory values at diagnosis were observed across PSC subtypes (isolated PSC vs. PSC with IBD or AIH; large vs. small duct PSC).

Treatment

Fifty-one patients (85%) received ursodeoxycholic acid (UDCA) at a median dose of 12.8 mg/kg (IQR, 7.8–16.1 mg/kg).

Corticosteroids (CS) were administered to 50 patients (83%), primarily those with features of AIH, with 25 out of 26 patients (96%) of this group receiving CS therapy. The median induction dose was 0.8 mg/kg (IQR, 0.53–1 mg/kg). A second course of CS was required in 14 patients, with median interval of 531 days (IQR, 310.7–1,286 days) between the two courses.

Azathioprine was prescribed in 90% of patients, either because of IBD or presence of AIH features, at a median dose of 1 mg/kg (IQR, 0.96–1.47 mg/kg). Immunosuppressive therapy was modified in four patients: three were switched to mycophenolate mofetil and one to mercaptopurine. The median time to treatment change was 72 days (IQR, 42.3–313.8 days).

Among the 49 patients with IBD, 94% were treated with mesalazine at a median dose of 46 mg/kg (IQR, 23.6–57.5 mg/kg), and only 18% received biological treatment.

None of the patients in the cohort was treated with vancomycin.

Severe complications

Severe complications occurred in 10 patients (17%), with some experienced more than one event (Table 2). Event-free survival was 88.3% [95% confidence interval (CI): 78.6–99.1%] at 5 years and 71.5% (95% CI: 56.3–90.9%) at 10 years (Figure 1).

Figure 1 Ten-year event-free survival showing the proportion of patients without severe complications, defined as biliary and portal complications, cholangiocarcinoma, liver transplant listing, or liver-related death.

Portal hypertension-related complications were observed in 5 patients (8%), all of whom developed esophageal varices; one of these patients also had ascites. Biliary complications occurred in 4 patients (7%), all presenting with episodes of acute cholangitis.

Liver transplantation was performed in 4 patients (7%): three due to chronic liver failure and one due to cholangiocarcinoma. Two of these patients later required re-transplantation. All transplanted patients had large duct PSC associated with UC, and one also had features of AIH. Transplantation occurred at a median of 8 years (IQR, 6–10 years) after PSC diagnosis, at a median age of 19 years (IQR, 15.5–23.3 years).

Cholangiocarcinoma developed in a 22-year-old with large duct PSC and UC, 5 years after diagnosis. No liver-related deaths were observed in the cohort.

Predictors of severe complications

None of the laboratory parameters at diagnosis (GGT, total bilirubin, or APRI) were significantly associated with the development of severe complications. The hazard ratio (HR) and 95% CI were as follows: GGT, HR =1.22 (95% CI: 0.84–1.79); total bilirubin, HR =1.04 (95% CI: 0.93–1.16); and APRI, HR =0.86 (95% CI: 0.56–1.32). There was also no significant association between sex or age at diagnosis and occurrence of severe complications (P=0.18 and P=0.28, respectively; Table 3). Similarly, no phenotypic characteristics, including the presence of IBD, features of AIH, or PSC subtype, were associated with an increased risk of severe complications.

Furthermore, there was no significant difference in outcomes between patients who achieved GGT normalization within the first year and those with persistently elevated GGT levels (HR =4.33; 95% CI: 0.50–37.73; Figure 2).

Figure 2 Five-year event-free survival comparing patients with persistent GGT elevation to those GGT normalization within the first year after diagnosis. GGT, gamma-glutamyl transferase.

SCOPE index

Patients were stratified by the SCOPE index as follows: 10 (17%) were categorized as high-risk (≥6 points), 29 (48%) as medium-risk (4–5 points), and 15 (25%) as low-risk (≤3 points). Six patients had insufficient data for scoring (17).

The SCOPE index at diagnosis did not significantly predict severe complications. When comparing the high-risk group to the low-risk group, HR was 2.10 (95% CI: 0.35–12.61; Figure 3). Among high-risk patients, only one underwent liver transplantation, and three developed complications (esophageal varices or cholangiocarcinoma). Overall, SCOPE-based risk stratification did not reach statistical significance.

Figure 3 Liver-related outcomes stratified by the SCOPE index: (I) low-risk group (≤3 points); (II) medium-risk group (4–5 points); and (III) high-risk group (≥6 points). SCOPE, Sclerosing Cholangitis Outcome in Pediatrics.

Discussion

We conducted a single-center observational study to evaluate predictors of severe liver-related complications in children with PSC. No significant associations were found between adverse outcomes and laboratory markers at diagnosis (GGT, total bilirubin, or APRI), nor with clinical characteristics such as PSC subtype (large vs. small duct), presence of IBD or features of AIH, sex, or age at diagnosis.

The SCOPE index, developed as a prognostic tool, also failed to reliably identify high-risk patients at the time of diagnosis in our cohort. Notably, some patients classified as low-risk developed complications earlier than those in the medium- or high-risk groups. This unexpected result may be explained by the small number of severe complications (17%) observed in our study. In contrast, a large retrospective Swedish study demonstrated that the SCOPE index was predictive of liver transplantation or death at the end of follow-up. Another recent study suggested that calculating the SCOPE index 5 years after diagnosis may better predict outcomes. These findings highlight the need for further research to clarify the role of the SCOPE index in routine clinical practice (9,18).

GGT normalization within 12 months of diagnosis may still serve as a useful marker for identifying at-risk patients, although our analysis did not reach statistical significance, likely due to the small number of severe complications. Thus, our findings do not argue against the continued use of GGT monitoring as an integral part of follow-up care (15,16,23).

The 10-year event-free survival in our cohort, estimated using the Kaplan-Meier method, was 71.5%. This is comparable to recent Swedish (77%) and English (75%) data, and more favorable than outcomes reported in the largest multicentric pediatric study (53%) (6,9,18). Portal hypertension was the most common severe complication, consistent with previous studies (6,13). During the observed follow-up period (median 3.8 years, maximum 12.5 years), 17% of patients developed severe complications. This observed complication rate is lower than previously reported cumulative rates, which have ranged from 27% to 39% (3,6,9,13). It’s important to note that the Kaplan-Meier estimate accounts for varying follow-up durations and projects the probability of remaining free of complications over time, whereas the observed complication rate reflects the actual proportion of patients who experienced events during the available follow-up. The fact that such complications occurred in only a small proportion of patients, even within this timeframe, is a meaningful finding. It suggests that in most children, severe outcomes may be less frequent in the early disease course than previously assumed, which may help guide clinical expectations and patient counseling.

Cholangiocarcinoma, although rare in pediatric PSC, may develop in early adulthood, usually before the age of 30 years, as confirmed by our study of one patient who developed cholangiocarcinoma at the age of 22 years (6,9). In our cohort, transplant-free survival was similarly favorable, with only 7% of patients undergoing liver transplantation, closely aligning with recent Swedish data (13%) (9).

Treatment options for PSC remain limited. In our study, 85% of patients were treated with UDCA, consistent with previous reports (11). Only 5% of our patients were on ≥10 mg/day of prednisolone at 1 year, compared to 28% reported by Valentino et al. (13). Immunosuppressive therapy was used in 92% of our cohort, a higher proportion than the 24–61% reported in other studies, likely reflecting the high prevalence of concomitant IBD in our patients (82%, most with UC) (9,13,18). Biological therapy was used in 13% of our IBD patients, compared to 20–21% in other studies, possibly due to differing treatment protocols (9,18). It is important to note that this was a retrospective study and that treatment strategies may have evolved over the study period. Management decisions were often individualized, based on physician discretion and shared decision-making with the patients and families.

The main limitations of our study include its retrospective design, historical variability in treatment approaches, and limited follow-up duration. While our cohort of 60 pediatric PSC patients represents a substantial number for a single-center study on a rare disease, this sample size may have limited the statistical power for detecting subtle associations. However, we believe it is unlikely that we missed a major predictor with a substantial clinical impact.

Conclusions

In conclusion, the prognostic value of SCOPE index at diagnosis remains uncertain. GGT normalization within 1 year did not predict the development of severe complications. None of the evaluated clinical factors, including sex, age at diagnosis, IBD presence, features of AIH, or PSC subtype, nor laboratory markers at diagnosis (GGT, total bilirubin, or APRI) reliably predicted a severe liver disease course.

Despite these findings, the overall prognosis in our pediatric cohort was generally favorable, with event-free survival rates of 88.3% (95% CI: 78.6–99.1%) at 5 years and 71.5% (95% CI: 56.3–90.9%) at 10 years. Larger studies with longer follow-up are needed to refine predictive tools and support individualized management. Pediatric PSC remains a heterogeneous disease with an unpredictable course, and optimal treatment strategies have yet to be defined.

Acknowledgments

We sincerely thank all colleagues and staff who contributed to this study, with special thanks to Ondřej Fabián for his valuable support.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-57/rc

Data Sharing Statement: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-57/dss

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-57/prf

Funding: This work was supported by Charles University (Project GA UK No. 71124 to E.V.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-57/coif). E.V. reports the funding from Charles University (Project GA UK No. 71124) and the congress fee from Ewopharma. O.H. reports payments for presentations from MSD, AbbVie, Takeda, Pfizer, Lilly, Nutricia; congress fees from AbbVie, Takeda, Pfizer, Lilly, Ferring; participation on the advisory board of AbbVie, Pfizer, and the leadership or fiduciary role in AbbVie. M.D. reports the financial support for travel and congress fee from Nutricia and PRO.MED.CS. D.K. reports the lecture payment from Vitabalans Oy and financial support for attending a single national meeting in 2021 from Takeda. T.L. reports the financial support for the congress fee from Ferring, Nutricia, Biocodex, and AbbVie. J.B. reports the payment for lectures from Nutricia, Nestlé, AbbVie, MSD, Sanofi, Pfizer, Vitabalans, and congress support from Nutricia, Nestlé, and AbbVie. K.M. reports lecture fees from AbbVie, Eli Lilly, Takeda, Johnson, and congress support from Celltrion and Johnson. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Institutional Ethics Board of the Motol University Hospital, Prague, on December 28, 2022 (No. EK-1457/22). Individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Mieli-Vergani G, Vergani D, Baumann U, et al. Diagnosis and Management of Pediatric Autoimmune Liver Disease: ESPGHAN Hepatology Committee Position Statement. J Pediatr Gastroenterol Nutr 2018;66:345-60. [Crossref] [PubMed]
2. Fagundes EDT, Ferreira AR, Hosken CC, et al. Primary sclerosing cholangitis in children and adolescents. Arq Gastroenterol 2017;54:286-91. [Crossref] [PubMed]
3. Deneau M, Jensen MK, Holmen J, et al. Primary sclerosing cholangitis, autoimmune hepatitis, and overlap in Utah children: epidemiology and natural history. Hepatology 2013;58:1392-400. [Crossref] [PubMed]
4. Ricciuto A, Kamath BM, Hirschfield GM, et al. Primary sclerosing cholangitis and overlap features of autoimmune hepatitis: A coming of age or an age-ist problem? J Hepatol 2023;79:567-75. [Crossref] [PubMed]
5. Trivedi PJ, Hirschfield GM, Adams DH, et al. Immunopathogenesis of Primary Biliary Cholangitis, Primary Sclerosing Cholangitis and Autoimmune Hepatitis: Themes and Concepts. Gastroenterology 2024;166:995-1019. [Crossref] [PubMed]
6. Deneau MR, El-Matary W, Valentino PL, et al. The natural history of primary sclerosing cholangitis in 781 children: A multicenter, international collaboration. Hepatology 2017;66:518-27. [Crossref] [PubMed]
7. Catassi G, D'Arcangelo G, Norsa L, et al. Outcome of Very Early Onset Inflammatory Bowel Disease Associated With Primary Sclerosing Cholangitis: A Multicenter Study From the Pediatric IBD Porto Group of ESPGHAN. Inflamm Bowel Dis 2024;30:1662-9. [Crossref] [PubMed]
8. Lee WS, Karthik SV, Ng RT, et al. Characteristics and outcome of primary sclerosing cholangitis associated with inflammatory bowel disease in Asian children. Pediatr Neonatol 2019;60:396-404. [Crossref] [PubMed]
9. Jerregård Skarby A, Casswall T, Bergquist A, et al. Good long-term outcomes of primary sclerosing cholangitis in childhood. JHEP Rep 2024;6:101123. [Crossref] [PubMed]
10. Warner S, Rajanayagam J, Russell E, et al. Biliary disease progression in childhood onset autoimmune liver disease: A 30-year follow-up into adulthood. JHEP Rep 2024;6:100901. [Crossref] [PubMed]
11. Tenca A, Färkkilä M, Arola J, et al. Clinical course and prognosis of pediatric-onset primary sclerosing cholangitis. United European Gastroenterol J 2016;4:562-9. [Crossref] [PubMed]
12. Curci F, Rubino C, Stinco M, et al. Paediatric-onset autoimmune liver disease: Insights from a monocentric experience. Dig Liver Dis 2025;57:494-501. [Crossref] [PubMed]
13. Valentino PL, Wiggins S, Harney S, et al. The Natural History of Primary Sclerosing Cholangitis in Children: A Large Single-Center Longitudinal Cohort Study. J Pediatr Gastroenterol Nutr 2016;63:603-9. [Crossref] [PubMed]
14. Ricciuto A, Kamath BM, Griffiths AM. The IBD and PSC Phenotypes of PSC-IBD. Curr Gastroenterol Rep 2018;20:16. [Crossref] [PubMed]
15. Berhane B, van Rheenen PF, Verkade HJ. Gamma-glutamyl transferase and disease course in pediatric-onset primary sclerosing cholangitis: A single-center cohort study. Health Sci Rep 2023;6:e1086. [Crossref] [PubMed]
16. Deneau MR, Mack C, Abdou R, et al. Gamma Glutamyltransferase Reduction Is Associated With Favorable Outcomes in Pediatric Primary Sclerosing Cholangitis. Hepatol Commun 2018;2:1369-78. [Crossref] [PubMed]
17. Deneau MR, Mack C, Perito ER, et al. The Sclerosing Cholangitis Outcomes in Pediatrics (SCOPE) Index: A Prognostic Tool for Children. Hepatology 2021;73:1074-87. [Crossref] [PubMed]
18. Hensel KO, Kyrana E, Hadzic N, et al. Sclerosing Cholangitis in Pediatric Inflammatory Bowel Disease: Early Diagnosis and Management Affect Clinical Outcome. J Pediatr 2021;238:50-56.e3. [Crossref] [PubMed]
19. Mileti E, Rosenthal P, Peters MG. Validation and modification of simplified diagnostic criteria for autoimmune hepatitis in children. Clin Gastroenterol Hepatol 2012;10:417-21.e1-2.
20. van Rheenen PF, Kolho KL, Russell RK, et al. Primary sclerosing cholangitis in children with inflammatory bowel disease: An ESPGHAN position paper from the Hepatology Committee and the IBD Porto group. J Pediatr Gastroenterol Nutr 2025;80:374-93. [Crossref] [PubMed]
21. Kemme S, Mack CL. Pediatric Autoimmune Liver Diseases: Autoimmune Hepatitis and Primary Sclerosing Cholangitis. Pediatric Clinics of North America 2021;68:1293-1307. [Crossref] [PubMed]
22. Working IBD. Group of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition. Inflammatory bowel disease in children and adolescents: recommendations for diagnosis--the Porto criteria. J Pediatr Gastroenterol Nutr 2005;41:1-7. [Crossref] [PubMed]
23. Deneau M, Perito E, Ricciuto A, et al. Ursodeoxycholic Acid Therapy in Pediatric Primary Sclerosing Cholangitis: Predictors of Gamma Glutamyltransferase Normalization and Favorable Clinical Course. J Pediatr 2019;209:92-96.e1. [Crossref] [PubMed]