Abstract
Background
The elucidation of differences between adult and pediatric-onset primary sclerosing cholangitis (PSC) may inform clinical decision making, and whether results of adult PSC clinical trials can be extrapolated to pediatric subjects.
Methods
A single-center retrospective analysis of PSC subjects diagnosed during the epoch 2000–13 was conducted. Demographic, clinical, and laboratory data were compared between PSC subjects diagnosed between 0–18 (pediatric) and 19+ (adult) years of age. An adverse outcome was defined as PSC-related death, liver transplant, or malignancy. Survival without any of these was defined as event-free survival.
Results
Analyses of 28 pediatric-diagnosed and 59 adult-diagnosed subjects revealed that incidence of early portal hypertension (PHT; P = 0.2), laboratory parameters of liver disease severity, and fibrosis grade at diagnosis were comparable between adult and pediatric PSC subjects. Adult-diagnosed PSC subjects had higher incidences of adverse outcomes compared to pediatric-diagnosed PSC subjects (P = 0.02). The age group 0–18 years (n = 30) had significantly better event-free survival compared to the age group more than 40 years (n = 25; P = 0.03). The prevalence of PHT in adult PSC subjects was 2.6 that of pediatric PSC subjects. PHT adversely affected outcomes in both adult (P < 0.001) and pediatric (P = 0.01) subjects. Adult PSC subjects were more likely to develop biliary complications (BCs; P = 0.001), ascites (P = 0.004), and variceal bleed (P = 0.03). Adult PSC subjects were more likely to have extra-hepatic co-morbidities (P < 0.001). Adult subjects had a longer follow-up duration compared to pediatric subjects (P = 0.06).
Conclusion
Despite having a comparable clinical, laboratory, and histologic biomarkers of liver disease severity at the time of diagnosis, adult PSC subjects had a worse outcome compared to pediatric PSC subjects. Possible reasons for this finding include higher incidence of PHT, BCs, extra-hepatic co-morbidities, and longer duration of follow-up.
Keywords: primary, sclerosing, cholangitis, outcome, age
Abbreviations: AIH, autoimmune hepatitis; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ERCP, endoscopic cholangiopancreatography; GGT, gamma-glutamyl transferase; GI, gastrointestinal; IBD, inflammatory bowel disease; INR, international normalized ratio; MR imaging, magnetic resonance imaging; MRCP, magnetic resonance cholangiopancreatography; PHT, portal hypertension; PSC, primary sclerosing cholangitis; x ULN, times upper limit of normal
Primary sclerosing cholangitis (PSC) is characterized by chronic inflammatory damage to intra- and extra-hepatic bile ducts.1 PSC is associated with inflammatory bowel disease (IBD) in 60–80% of subjects.2 PSC may be accompanied by clinical, serological, and pathologic features of autoimmune hepatitis (AIH), a condition known as PSC/AIH overlap.3 The diagnosis of PSC is based on the presence of cholestasis on laboratory analysis, demonstration of characteristic bile duct on imaging studies, and exclusion of secondary causes of sclerosing cholangitis.4 Small-duct PSC refers to a condition where-in the histologic changes of PSC are present in the absence of typical radiologic findings of PSC.5
Although the incidence of PSC in children is lower than in adults, it accounts for approximately 2–3% of all pediatric liver transplants.6, 7, 8 Multiple past studies have attempted to characterize pediatric PSC subjects.9, 10, 11 Recently published large multi-center retrospective analyses of PSC subjects have elucidated phenotypic differences between adult and pediatric subjects diagnosed with PSC, and hence demonstrated that pediatric PSC has distinct characteristics compared to adult PSC.12,13 The hypotheses explaining such differences include the following: (a) adult and pediatric PSC have distinct phenotypes, or (b) adult PSC presents at a more advanced stage compared to pediatric-onset disease.14,15
There is a paucity of studies directly comparing adult and pediatric PSC subjects.16 Such a comparison could potentially help elucidate differences in the natural history of adult versus pediatric-onset PSC. In addition, such efforts could help to potentially inform whether medications and therapeutic end-points used in adult PSC clinical trials could be extrapolated to pediatric PSC subjects.17 In the present study, we aimed at elucidating the differences in the clinical and laboratory characteristics, outcomes, and predictors of outcomes between adult- and pediatric-diagnosed PSC over a recent time epoch at an adult and pediatric liver transplant center.
Methods
Subjects were identified from a list of patients who attended pediatric (St. Louis Children's Hospital) and adult (Barnes Jewish Hospital and associated clinics) hepatology clinics between January 2000 and December 2013 at Washington University in St. Louis. Subjects were initially identified using the International Classification of Diseases, Ninth Revision, diagnosis code 576.1 and data were extracted from physician notes, laboratory values, as well as radiologic and histopathologic reports. Subjects were selected after applying the following inclusion and exclusion criteria after a detailed chart review. Subjects with characteristic radiologic or histologic (liver biopsy) features of PSC were included in the analysis. The characteristic radiologic features of sclerosing cholangitis were identified either on magnetic resonance cholangiopancreatography (MRCP), or endoscopic cholangiopancreatography (ERCP). Exclusion criteria included the following: (1) subjects with diagnoses associated with secondary sclerosing cholangitis (5 pediatric and 15 adult subjects), and (2) subjects with incomplete data vis-a-vis the variables mentioned below (15 pediatric and 24 adult subjects). Identified subjects meeting the inclusion criteria were followed through in 2018.
Subjects were stratified based on their age at the time of diagnosis with pediatric diagnoses being made at age 18 years or younger and adult diagnoses being made at age 19 years and older. They were further stratified into the following categories: 0–18 years of age, 19–40 years of age, and more than 40 years of age. Demographic variables included gender, year of diagnosis, and year of the latest follow-up visit. Clinical information collected included presenting symptoms at diagnosis; concomitant diagnosis of IBD, including year of diagnosis, IBD subtype, and history of colectomy; subtype of PSC (large duct, small duct, or AIH/PSC overlap); co-morbid conditions; presence of esophageal varices; occurrences of variceal bleeding; presence of ascites; episodes of cholangitis; and occurrences of biliary strictures requiring endoscopic therapy. We collected laboratory data at the time of diagnosis. Laboratory variables collected included alanine aminotransferase (ALT), aspartate aminotransferase (AST), biliary markers (gamma-glutamyl transferase [GGT] for pediatric subjects, and alkaline phosphatase [ALP] for adult subjects), platelet count, bilirubin, albumin, international normalized ratio, and creatinine. To look at the trend of these values, we recorded values of the aforementioned laboratory variables between 1 and 3 years after diagnosis. ALP and GGT levels were expressed as “times upper limit of normal (x ULN)” for specific age and gender of the subject. Histologic data were collected from subjects who had a liver biopsy performed at the time of diagnosis. Subjects were classified based on the degree of fibrosis found on this liver biopsy using METAVIR score.
The outcomes recorded included biliary complications (BCs), portal hypertension (PHT), liver transplant, hepatic malignancy, and liver-related death. There were no subjects with liver-unrelated causes of death in our study. An adverse event was defined as PSC-related death, liver transplant, or hepatic malignancy. Survival without any of these events was termed as “event-free survival.” Biliary complication was defined as either a diagnosis of cholangitis treated with intravenous antibiotics, or endoscopic therapy of biliary stricture. PHT was defined by presence of esophageal varices, presence of ascites, or evidence of persistent hypersplenism (splenomegaly and thrombocytopenia).
The data were analyzed using SPSS version 25.0 (SPSS Inc, Chicago, IL). We compared categorical data using the Chi-square test or the Fisher exact test. We compared numerical data using the t-test. Kaplan–Meier analyses were used to analyze time to outcomes. Log-rank analysis was used to compare survival curves. Binary logistic regression analysis was used to investigate predictors of outcomes. In all of the above, we considered P values less than 0.05 as significant.
Results
There were 87 subjects analyzed in our study. Of these, 28 (32%) were pediatric (less than 18 years) at the time of initial diagnosis. During the study period, 20 pediatric subjects (72%) underwent magnetic resonance (MR) imaging at the time of diagnosis, whereas 8 (28%) had ERCP at the time of diagnosis. In 5 of 8 patients, ERCP was performed for both diagnostic and therapeutic purposes, whereas 3 of 8 patients had an ERCP only for diagnostic purposes. Among adult-diagnosed PSC subjects, 42 subjects (73%) underwent MR imaging at the time of diagnosis, whereas 16 (27%) had ERCP at the time of diagnosis. In our study, 68% of pediatric subjects and 72% of the adult subjects had an established diagnosis of IBD at the time of PSC diagnosis.
The comparison of clinical characteristics of adult- versus pediatric-diagnosed PSC subjects is shown in Table 1. The median age at diagnosis of PSC in pediatric subjects was 12.9 years (interquartile range [IQR] 11.1–14.1 years), as compared to 37.4 years (IQR 34.5–40.3 years) in adults. Eighty-five percent of pediatric subjects had concomitant IBD, as compared to 83% of adult subjects. Twenty pediatric PSC-IBD subjects (83%) had ulcerative colitis, 3 (13%) had Crohn's disease, whereas 1 (4%) had indeterminate colitis at the time of final follow-up. Among adult PSC-IBD subjects, 69% had ulcerative colitis, 26% had Crohns disease, whereas the rest had indeterminate colitis at the time of final follow-up. The follow-up period for adult PSC subjects was longer than pediatric PSC subjects, although this comparison did not reach statistical significance (P = 0.06). Pediatric subjects were more likely to present with luminal symptoms like abdominal pain, vomiting, diarrhea, and blood in stools. In contrast, adult PSC subjects were more likely to present with hepatic symptoms like jaundice, pruritus, and asymptomatic elevation of liver enzymes. Among a subset of pediatric PSC-IBD subjects, the diagnosis of IBD preceded the diagnosis of PSC by a median of 1 year (0–2 years), as compared to a median of 3.5 years (1–9.8 years) in 40 adult PSC-IBD subjects where IBD preceded PSC (P = 0.008).
Table 1.
Comparison of Demographic and Clinical Characteristics Between Pediatric and Adult-Onset PSC.
| Pediatric N (%) = 28 | Adult N (%) = 59 | P-value | |
|---|---|---|---|
| Female gender | 9 (32.1%) | 25 (42.3%) | 0.48 |
| PSC-IBD | 24 (85.7%) | 49 (83.1%) | 1.00 |
| Age (years) | 12.9 (11.1–14.1) | 37.4 (34.5–40.3) | <0.001 |
| Follow-up (years) | 7.4 (6.6–9.2) | 9.7 (8.8–10.8) | 0.06 |
| GI complaint as initial presentation | 18 (64.3%) | 20 (33.9%) | 0.02 |
| Elevated liver enzymes at initial diagnosis | 21 (75%) | 51 (86.4%) | 0.2 |
| Small-duct PSC | 2 (7.1%) | 3 (5.0%) | 0.14 |
| AIH-PSC | 10 (35.7%) | 5 (8.5%) | 0.004 |
| Duration of IBD before PSC (years)∗ | 1 (0–2) | 3.5 (0–9.8) | 0.008 |
| Subjects with other co-morbid conditions | 4 (14.3) | 47 (79.6%) | <0.001 |
| Co-existent liver diseases | 0 (0%) | 4 (6.8%) | 0.3 |
| Esophageal varices | 5 (17.9%) | 12 (20.3%) | 0.5 |
| Biliary complication | 6 (25.0%) | 39 (66.1%) | 0.001 |
| Ascites | 1 (3.6%) | 17 (28.8%) | 0.004 |
| Variceal bleed | 0 (0%) | 9 (15.3%) | 0.03 |
| PHT | 9 (32.1%) | 25 (42.4%) | 0.48 |
| Complicated PHT | 5 (17.9%) | 19 (32.2%) | 0.16 |
| PHT within 3 years of diagnosis | 2 (7.1%) | 11 (18.6%) | 0.2 |
Only for PSC-IBD patients. AIH, autoimmune hepatitis; GI, gastrointestinal; IBD, inflammatory bowel disease; PHT, portal hypertension; PSC, primary sclerosing cholangitis.
Only 4 pediatric PSC subjects (14%) had extra-hepatic (not counting IBD) co-morbidities, as compared to 47 adult PSC subjects (80%) (P < 0.001). The most commonly reported extra-hepatic co-morbidities included hypertension, obesity, diabetes mellitus, hypothyroidism, renal insufficiency, headache disorders, asthma, and depression. None of the pediatric subjects had other co-existent liver diseases, as compared to 4 adults; 3 of whom had metabolic-associated fatty liver disease and 1 had a hepatic hemangioma. Pediatric PSC subjects were more likely to have overlap with AIH compared to adult subjects (36% vs. 8%, P = 0.004). Six of 10 pediatric subjects and 2 of 5 adult subjects with AIH-PSC overlap had a predominant AIH phenotype. Adult PSC subjects were more likely to have BCs (P = 0.001), ascites (P = 0.004), and variceal bleed (P = 0.03).
The comparison of the laboratory parameters at the time of diagnoses between adult and pediatric PSC subjects is shown in Table 2. Biliary marker at the time of diagnosis was higher in pediatric subjects as compared to adult subjects (P = 0.02). The ALT and AST levels at diagnosis were comparable between the two groups. Serum bilirubin at the time of diagnosis was higher in adult subjects compared to pediatric subjects (P = 0.02). Data regarding ALT and AST levels (and trend) at 1–3 years post-diagnosis were available for 25 children and 47 adults, respectively. Data regarding platelet count (and trend) at 1–3 years post-diagnosis were available for 28 children and 54 adults, respectively. Data regarding biliary markers (and trend) at 1–3 years post-diagnosis were available for 22 children and 44 adults, respectively. There were no differences in the ALT level (P = 0.48), AST level (P = 0.19), biliary markers (P = 1.0), and platelet count (P = 0.66) at 1–3 years post-diagnosis between adult and pediatric age groups. There was no difference in the proportion of subjects with increase in ALT (P = 0.51), increase in AST (P = 0.96), increase in biliary marker (P = 0.07), and decrease in platelet count (P = 0.96) between adult and pediatric subjects.
Table 2.
Comparison of the Laboratory and Histologic Parameters Between Pediatric- and Adult-Diagnosed PSC.
| Pediatric (N = 28) Median (1st–3rd IQR) | Adult (N = 59) Median (1st–3rd IQR) | P-value | |
|---|---|---|---|
| Biliary marker at diagnosis (x ULN) | 5.8 (3.3–8.1) | 2.7 (1.9–3.3) | 0.02 |
| ALT at diagnosis | 87 (52.5–117.5) | 97 (43.3–184.3) | 0.6 |
| AST at diagnosis | 66 (42.5–118) | 77 (30–145.5) | 0.4 |
| Platelet count at diagnosis | 274 (217.3–357.8) | 242 (157–352) | 0.2 |
| Bilirubin year of diagnosis | 0.4 (0.25–0.5) | 0.8 (0.4–1.8) | 0.02 |
| Albumin year of diagnosis | 4.2 (3.9–4.3) | 3.8 (3.3–4.3) | 0.2 |
| INR year of diagnosis | 1.01 (0.95–1.11) | 1.05 (1–1.1) | 0.14 |
| Creatinine year of diagnosis | 0.7 (0.5–0.8) | 0.8 (0.6–0.9) | 0.8 |
| Grade of fibrosis on liver biopsy (METAVIR)∗ | 2 (2–2.75) | 2 (2–3) | 0.6 |
Liver biopsy was performed in 18 pediatric subjects and 14 adult subjects at the time of diagnosis. ULN, upper limit of normal; ALT, alanine aminotransferase; AST, aspartate aminotransferase; INR, international normalized ratio.
Pediatric subjects were more likely to be on ursodeoxycholic acid compared to adult subjects (68% vs. 29%, P < 0.001). The median dose of ursodeoxycholic acid was 14 mg/kg (IQR 10.3–19.5 mg/kg). The median dose in pediatric subjects was 12 mg/kg (IQR 8–15.5 mg/kg) as compared to 15 mg/kg (IQR 13.5–19.5 mg/kg) in adult subjects (P = 0.13). Eight pediatric subjects and 4 adult subjects with AIH-PSC overlap were treated with corticosteroids, whereas 6 pediatric subjects and 4 adult subjects received azathioprine. Each one of the 12 of 15 AIH-PSC subjects who received immunosuppression had a decrease in serum transaminases. A higher percentage of pediatric subjects were on azathioprine compared to adult subjects (36% vs. 22%, P = 0.17). Of these, 6 pediatric subjects (21%) and 4 adult subjects (7%) were on azathioprine for AIH-PSC overlap, whereas the rest were on azathioprine for the treatment of IBD. Liver biopsy was performed in 18 pediatric subjects (64%) and 14 adult subjects (24%) at the time of diagnosis. There was no difference between the degrees of fibrosis at the time of diagnosis between pediatric and adult subjects (P = 0.6).
The comparison of outcomes among pediatric- and adult-diagnosed PSC subjects is shown in Figure 1(a and b). Adult-diagnosed PSC subjects had worse outcomes compared to pediatric-diagnosed PSC subjects (42% vs. 18%, P = 0.02). Kaplan–Meier analyses showed higher event-free survival in pediatric-diagnosed subjects as compared to adult-diagnosed subjects, but this failed to reach statistical difference (P value by log-rank analyses = 0.11). The median survival in pediatric subjects was 15 years (IQR 12.7–17.3 years) as compared to 14 years (IQR 12.4–15.6 years) in adult subjects. These worse outcomes were predominantly related to higher proportion of PSC-related death in adult subjects compared to pediatric subjects (15.3% vs. 0%, P = 0.02). Nine adult patients in the cohort died during the study period. All these deaths were related to complications from the subjects’ liver disease. Using Kaplan–Meier analyses, we did not find any differences in event-free survival between adult and pediatric subjects without AIH overlap (P = 0.13), subjects without small-duct PSC (P = 0.17), and subjects without both overlap and small-duct PSC (P = 0.2). In our study, Kaplan–Meier analyses did not reveal a beneficial effect on adverse outcomes of the use of ursodeoxycholic acid in adult (P = 0.9) or pediatric subjects (P = 0.49).
Figure 1.
The Kaplan–Meier survival curve showing the comparison of (A) event-free survival (%) between adult PSC and pediatric PSC and (B) event-free survival between age groups 0–18 years, 19–40 years, and over 40 years at the time of PSC diagnosis.
We further wished to study the effect of age at diagnosis on outcome. Hence, we stratified subjects into 3 age strata 0–18 years or pediatric age group (n = 28), 19–40 years (n = 34), and more than 40 years (n = 25). Subjects in the age group 0–18 years had significantly higher event-free survival compared to subjects in the over 40 years age group (P = 0.04). Subjects in the age group 0–18 years had similar event-free survival compared to subjects in the age group 19–40 years (P = 0.3). Similarly, individuals diagnosed between ages 19–40 years had comparable event-free survival compared to those diagnosed at more than 40 years (P = 0.17). We saw a trend toward better event-free survival in subjects who were aged less than or equal to 40 years compared to subjects aged more than 40 years at the time of diagnosis (P = 0.06).
The effects of sentinel events like PHT and BCs on event-free survival in adult and pediatric subjects are shown in Figure 2 and further summarized in Table 3. Adult PSC subjects had a higher percentage of subjects with PHT compared to pediatric subjects, although this did not reach statistical significance (42% vs. 32%, P = 0.48). Kaplan–Meier analyses showed that both adult (P < 0.001) and pediatric subjects (P = 0.01) with PHT had worse event-free survival compared to subjects without PHT. PHT developed after a median of 5.5 years (IQR 3.8–7.3 years) after diagnoses in pediatric subjects and a median of 5 years (IQR 2–7.8 years) in adult subjects. PHT predated an adverse outcome (death, liver transplant, or malignancy) by a median of 2.5 years (IQR 1–7.8 years) in pediatric subjects and 1.5 years (IQR 1–7 years) in adult subjects. Kaplan–Meier analyses showed that adult subjects with BCs had similar event-free survival compared to subjects without BCs (P = 0.58). In contrast, Kaplan–Meier analyses showed that pediatric subjects with BCs had worse event-free survival compared to pediatric subjects without BCs (P = 0.04). The median event-free survival within subjects with BCs is shown in Figure 2. Biliary complications preceded an adverse outcome by 2.5 years (IQR 1.75–3.25 years). Pearson correlation analyses revealed a significant correlation between PHT and BCs in pediatric PSC (P = 0.04), but not in adult PSC (P = 0.42).
Figure 2.
Kaplan–Meier curves showing event-free survival (%) of adult and pediatric subjects with and without portal hypertension.
Table 3.
Comparison of Outcomes Between Pediatric- and Adult-Diagnosed PSC Patients.
| (A) Comparison of the total number and percentage pediatric vs. adult patients with overall and specified adverse events during the study period | |||
|---|---|---|---|
| Pediatric N = 28 | Adult N = 59 | P-value (log-rank statistic using Kaplan–Meier analyses) | |
| Overall adverse outcome | 5 (17.9%) | 25 (42.3%) | 0.11 |
| Liver transplant | 4 (14.3%) | 14 (23.7%) | 0.4 |
| Hepatobiliary malignancy | 1 (3.6%) | 5 (8.5%) | 0.21 |
| Liver-related death | 0 (0%) | 9 (15.3%) | 0.03 |
| (B) Comparisons of median years of event-free survival (with IQR) between pediatric- and adult-diagnosed PSC patients with and without PHT and biliary complications, respectively | |||
|---|---|---|---|
| Pediatric subjects | Adult subjects | P-value | |
| PHT | 7.5 (5.8–10.3) | 8.8 (6.6–11) | 0.68 |
| No PHT | 16.8 (14.5–19.1) | 17 (15.2–18.2) | 0.47 |
| Biliary complications | 9 (5.5–12.6) | 13.0 (11–15.1) | 0.36 |
| No biliary complications | 16.5 (14.4–18.5) | 11.4 (9.8–13) | 0.02 |
PHT, potal hypertension.
Discussion
We analyzed pediatric and adult subjects diagnosed at our center over a period of 13 years from 2000 to 2013. We followed up these subjects’ outcomes until the end of the year 2018. Our study showed that adult subjects had a lower incidence of AIH overlap, gastrointestinal symptoms at presentation, and a higher incidence of extra-hepatic co-morbidities and co-existent hepatic conditions. Adult PSC subjects were more likely to have BCs (P = 0.001), ascites (P = 0.004), and variceal bleed (P = 0.03). Adult subjects (especially more than 40 years of age at diagnosis) had worse outcomes compared to pediatric subjects. PHT shortened survival with native liver in all age groups. Apart from bilirubin at presentation (which was higher in adult subjects), and biliary marker at presentation (which was higher in pediatric subjects), the remainder of the laboratory biomarkers (and their trends early in the disease) were comparable between adult- and pediatric-diagnosed PSC subjects. In addition, the proportion of subjects with early (within 3 years of diagnosis) PHT and the degree of fibrosis on a liver biopsy at the time of diagnosis was comparable between groups.
In our study, 36% and 7% of the pediatric subjects had AIH-PSC overlap and small-duct PSC, respectively, as compared to 33% (AIH/PSC overlap) and 13% (small-duct PSC) in a recently published large retrospective analysis of pediatric PSC subjects.12 In adults, 8% had AIH-PSC overlap and 5% small-duct disease as compared to 7% (AIH/PSC overlap) and 4% (small-duct PSC) in a recently published large retrospective cohort.13 The incidence of PHT and BCs in pediatric PSC subjects in our study was similar to the incidence found by the work of Deneau et al. In our study, 85% of pediatric subjects and 83% of adult subjects had associated IBD as compared to incidences of 76% and 70.9% in the large pediatric and adult cohorts. Possible explanations for this difference could be the smaller sample size of our study, and referral of subjects from the large pediatric and adult IBD centers at our institution.
Our study revealed that children had better outcomes compared to adults, which has been supported in the findings of prior studies. In our study, Kaplan–Meier analyses may not have reached statistical significance because of the limited number of subjects (and outcomes) in each group. The 10-year event-free survival in the aforementioned large pediatric and adult cohorts were 83% and 53%, respectively, as compared to 82% and 58% in pediatric and adult subjects in our study.12,13 The median survival without an adverse outcome decreased with advancing age as follows; age groups 0–18 years (15 years [IQR 12.7–17.3 years]), 19–40 years (14 [IQR 9.6–18.4 years]), and 41 years and older (12 years [IQR 7.5–16.5 years]) subjects. Age at diagnosis is a part of the adult predictive risk score.18,19 Recent adult studies have shown that age at diagnosis was predictive of 10-year (post-diagnosis) liver transplant–free survival.13,20
Adult PSC subjects in our study had the following: (a) higher incidence of PHT, (b) higher incidence of BCs, (c) high incidence of PSC with ulcerative colitis, (d) higher incidence of co-existent liver diseases and extra-hepatic co-morbidities, and (e) higher incidence of liver-related mortality. The possible explanations for worse outcomes in adults are a more severe disease phenotype, lead-time bias, association with ulcerative colitis, and contribution by unrelated liver disease and extra-hepatic co-morbidities. A prior study using MRCP analysis in subjects with IBD showed that the prevalence of PSC was 3 times higher than that based on symptoms; and that 65% of all IBD subjects had subclinical PSC.21 This suggests a higher proportion of subclinical disease, which is possibly diagnosed beyond childhood, frequently at the time of occurrence of a complication (biliary obstruction or cholangitis). Early onset of the pathogenesis of an immune-mediated disorder such as PSC may indicate a more severe phenotype.22,23 PSC associated with ulcerative colitis has been shown to be associated with a lower survival with native liver and a higher risk of hepatobiliary malignancy in adult PSC subjects.13 In our study, 58% of all adult PSC subjects had ulcerative colitis, which is greater than the aforementioned adult PSC study. Finally, adult PSC patients had a higher prevalence of co-morbidities (n = 47) and co-existent liver disease (n = 4). Although these co-morbidities and co-existent liver diseases may not be directly related to PSC pathogenesis, these may have indirectly contributed to the progression of liver fibrosis in adult PSC subjects. Medications used for these co-morbid conditions may potentially have covert or overt hepatotoxic adverse effects. The possible reason for a better outcome in children could be a higher incidence of small-duct PSC, which has a better prognosis compared to large-duct PSC.
We investigated the role of PHT on event-free survival. The development of PHT decreased event-free survival in both pediatric and adult subjects. Our findings were consistent with those of Deneau et al., who demonstrated that the median survival of pediatric PSC subjects after the development of PHT was 2.8 years, compared to 2.5 years in our study. A higher proportion of adult PSC subjects had PHT (1.3 times) compared to pediatric PSC subjects. These differences did not reach statistical significance, probably due to the small sample size of this study. Adult PSC subjects were more likely to develop BCs (P = 0.001), ascites (P = 0.004), and variceal bleed (P = 0.03). Biliary complications such as dominant strictures and cholangitis can potentially predispose to liver fibrosis.24 Biliary complication was an independent predictor of event-free survival in pediatric, but not adult PSC subjects in our study. Prior adult studies have attempted to use clinical and laboratory variables to develop predictive models for PSC subjects.18,25,26 Improvement in biliary marker (while on ursodeoxycholic acid) has been shown to be a favorable prognostic marker in children.27,28 Adult studies have failed to demonstrate similar beneficial effects of ursodeoxycholic acid on PSC prognosis. Our study did not reveal a beneficial effect of the use of ursodeoxycholic acid in adult or pediatric subjects. Likely, the retrospective nature and the limited power of this single-center study limited the investigation of predictors of an adverse outcome in our subjects.29
In conclusion, our study shows that the outcomes of pediatric PSC subjects are better than adult PSC subjects. Our study also demonstrated that the clinical, laboratory, and histologic markers of severity of liver disease at the time of diagnosis (and their early trend) were comparable between adult- and pediatric-diagnosed PSC subjects. Based on the findings of this study, we hypothesize that the differences in outcome are explained by a more complicated course in adult PSC subjects. Incidences of PHT (which adversely impacted event-free survival) and BCs were higher in adults. The higher rate of these complications in adult subjects suggests a lead-time bias. Other contributing factors include higher incidence of PSC-UC, extra-hepatic co-morbidities, co-existent liver conditions, and longer follow-up in adult subjects. The retrospective nature of this study, the limited number of subjects, and variation in diagnostic protocols (use of MRI, ERCP, and liver biopsy) in both groups are the major limitations. The results of these studies need to be validated by comparison of larger adult and pediatric retrospective cohorts.12,13 In addition, analyses of multi-center prospectively collected data of pediatric and adult PSC subjects (like adult and pediatric PSC learning network) may further help confirm or deny our hypothesis, and elucidate differences in pathophysiology between adult- and pediatric-diagnosed PSC.
Credit authorship contribution statement
Stefani Tica—writing, data curation (pediatric and adult subjects), and formal analysis; Saad Alghamdi—data curation (adult subjects) and formal analysis; Christopher Tait M.D.—data curation (adult subjects) and formal analysis; Bonsa Nemara B.A.—data curation (pediatric subjects) and writing; Yumirle Turmelle M.D.—conceptualization, supervision, and writing; Jaqueline Fleckenstein M.D.—conceptualization, supervision, and writing; Janis Stoll M.D.—conceptualization, supervision, and writing; Sakil Kulkarni M.D.—writing, conceptualization, data curation (pediatric subjects), and formal analysis.
Conflicts of interest
The authors have none to declare.
Funding
None.
Data sharing
The raw data (excel sheets) collected from clinical charts of subjects included in this study will be made available to the journal upon request.
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