Primary sclerosing cholangitis, autoimmune hepatitis, and overlap in utah children: Epidemiology and natural history


  • Potential conflict of interest: Nothing to report.

  • The project described in this article was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences (National Institutes of Health) through grant 8UL1TR000105 (formerly UL1RR025764). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Address reprint requests to: Mark Deneau, M.D., M.S., Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Utah, 100 North Mario Capecchi Drive, Suite 2650, Salt Lake City, UT 84113. E-mail:; fax: 801-662-2912; or Stephen L. Guthery, M.D., M.Sc., Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Utah, 100 North Mario Capecchi Drive, Suite 2650, Salt Lake City, UT 84113. E-mail:


The epidemiology and natural history of pediatric primary sclerosing cholangitis (PSC), autoimmune sclerosing cholangitis (ASC), and autoimmune hepatitis (AIH) are not well characterized. Using multiple, overlapping search strategies followed by a detailed records review, we identified all cases of pediatric PSC, ASC, AIH, and inflammatory bowel disease (IBD) in a geographically isolated region of the United States. We identified 607 cases of IBD, 29 cases of PSC, 12 cases of ASC, and 44 cases of AIH. The mean age at diagnosis was 13.0 years for PSC, 11.3 years for ASC, and 9.8 years for AIH. The incidence and prevalence of PSC, ASC, and AIH were 0.2 and 1.5 cases, 0.1 and 0.6 cases, and 0.4 and 3.0 cases per 100,000 children, respectively. The mean duration of follow-up was 5.9 years. The probability of developing complicated liver disease within 5 years of the diagnosis of liver disease was 37% [95% confidence interval (CI) = 21%-58%] for PSC, 25% (95% CI = 7%-70%) for ASC, and 15% (95% CI = 7%-33%) for AIH. The 5-year survival rates with the native liver were 78% (95% CI = 54%-91%) for PSC, 90% (95% CI = 47%-99%) for ASC, and 87% (95% CI = 71%-95%) for AIH. Cholangiocarcinoma developed in 2 of the 29 PSC patients (6.9%). PSC occurred in 9.9% of patients with ulcerative colitis (UC) and in 0.6% of patients with Crohn's disease (CD). ASC occurred in 2.3% of UC patients and 0.9% of CD patients. AIH occurred in 0.4% of UC patients and in 0.3% of CD patients. Liver disease occurred in 39 of 607 IBD patients (6.4%) overall. Conclusion: Immune-mediated liver diseases are important sources of morbidity in children. Using a population-based design, this study quantifies the burden and natural history of immune-mediated liver disease in children. (Hepatology 2013;58:1392–1400)


autoimmune hepatitis


anti-nuclear antibody


anti-nuclear cytoplasmic antibody


autoimmune sclerosing cholangitis


Crohn's disease


confidence interval


inflammatory bowel disease


International Classification of Diseases, Ninth Revision, Clinical Modification


immune-mediated liver disease


liver-kidney microsomal antibody


not significant


primary sclerosing cholangitis


soluble liver antigen


smooth muscle antibody


ulcerative colitis.

Primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) are the major immune-mediated liver diseases (IMLDs) that occur in children beyond infancy. Both diseases occur at an increased frequency in patients with inflammatory bowel disease (IBD).[1-3] PSC is primarily a cholestatic disorder characterized by inflammation and periductal fibrosis of the intrahepatic and/or extrahepatic bile ducts, whereas AIH is characterized by inflammation of the portal tract that may extend into the hepatic lobule. Many patients, particularly children, have PSC-AIH overlap with features of both diseases, and this is termed autoimmune sclerosing cholangitis (ASC).[4] Both PSC and AIH can progress to cirrhosis and portal hypertension and ultimately require liver transplantation. There is currently no treatment that alters the natural history of PSC,[5] whereas immunosuppression can lead to long-term remission of AIH.[6]

The epidemiology of PSC, ASC, and AIH in children is not well characterized.[5, 7] To date, 11 population-based studies of PSC have been performed. Only four of these were of sufficient quality to be included in a recent systematic review,[8] and collectively, they included fewer than 10 pediatric cases.[9-12] Data for AIH are similarly sparse, with few pediatric reports.[13-15] There are significant gaps in our knowledge of the natural history of PSC, ASC, and AIH.

We sought to characterize the spectrum of IMLDs in children in a population-based fashion with a focus on disease epidemiology and natural history and on IBD as a comorbidity. Because population-based estimates in children are lacking, our first goal was to measure the prevalence and incidence of IMLDs in children. Our second goal was to determine the natural history of IMLDs and to test the hypothesis that clinical outcomes are similar for the subtypes of IMLDs that affect children and adolescents.

Patients and Methods


In Utah, all pediatric gastroenterologists, most adult gastroenterologists, and all hepatologists practice in one of two large hospital systems that have adopted the widespread use of one of two electronic medical records systems. These hospital systems provide all pediatric liver and gastroenterology subspecialty care to a geographically isolated region of the western United States, with a referral area extending into southern Idaho, western Wyoming, and eastern Nevada. All three tertiary-referral hospitals, all three liver transplantation programs, and many community hospitals and health centers are within these two hospital systems.

We examined electronic records from all inpatient, outpatient, and procedure encounters for patients who represented possible incident or prevalent cases born between January 1, 1986 and December 31, 2011. Records were reviewed from both hospital systems for every individual patient. Multiple, overlapping search strategies were used to maximize the ascertainment of cases of IBD and IMLD.

IBD Case Identification

Because IMLDs and IBD frequently occur in the same patient, we first identified all pediatric IBD patients in the referral area. Patients with at least one encounter containing the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9) code for Crohn's disease (CD; 555.x) or ulcerative colitis (UC; 556.x) underwent a detailed records review. A diagnosis of IBD was based on established criteria requiring chronicity of symptoms (longer than 8 weeks), exclusion of infections, and objective evidence of chronic inflammation on endoscopy and histology.[16]

PSC, ASC, and AIH Case Identification

We identified patients suspected to have liver disease through reviews of patient records with at least one encounter containing the ICD-9 code for liver biopsy (50.1x), AIH (571.42), or cholangitis (576.1). Using Oracle Text software (Oracle, Redwood Shores, CA), we also searched 99 million documents in the electronic data warehouses for the phrase sclerosing cholangitis and numerous misspellings. Patients flagged in any one of these four ways, along with all patients with a confirmed diagnosis of IBD, underwent further chart review. We excluded patients who were more than 18 years old at the time of the diagnosis of liver disease. We examined all clinical documentation for symptoms (right upper quadrant abdominal pain, fatigue, pruritus, jaundice, and weight loss) as well as laboratory values for biochemical evidence of hepatitis, cholestasis, bile ductular injury, and hypergammaglobulinemia. We included available serum titers for anti-nuclear antibody (ANA), anti-nuclear cytoplasmic antibody (ANCA), smooth muscle antibody (SMA), soluble liver antigen (SLA), and liver-kidney microsomal antibody (LKM); histology results from liver biopsy; and results of endoscopic retrograde cholangiopancreatography and/or magnetic resonance cholangiopancreatography.

We defined PSC as the presence of a cholestatic biochemical profile and either cholangiography showing multifocal strictures and segmental dilations[5] or liver histology showing fibro-obliterative cholangitis or consistent with a primary ductular involvement.[17, 18] We excluded one patient with secondary sclerosing cholangitis from Langerhans cell histiocytosis. We defined AIH with a simplified adult diagnostic scoring tool[19] that has been validated in children,[20] as shown in Table 1. We excluded one patient with de novo posttransplant alloimmune hepatitis. We classified patients as having ASC if they met the diagnostic criteria for both PSC and AIH.

Table 1. Simplified Scoring System for AIH
  1. The maximum number of points for all autoantibodies is 2; the total number of possible points is 8. Six points indicates probable AIH, and 7 or more points indicates definite AIH.

  2. a

    Chronic hepatitis with lymphocytic infiltration without all of the features considered typical.

  3. b

    Interface hepatitis, lymphoplasmocytic infiltrates in the portal tract extending into the lobule, emperipolesis, and hepatic rosette formation.

ANA or SMA1:401
Immunoglobulin G or globulin fraction>Upper limit of normal1
 >1.1 × upper limit of normal2
Liver histologyCompatible with AIHa1
 Typical of AIHb2
Absence of viral hepatitisYes2


The incidence and the prevalence were estimated with US Census population estimates for Utah. Annual population counts between formal, measured census years (2000 and 2010) were interpolated with the US Census Bureau's Population Estimate Program. For 2011, for which no such estimates existed, the 2010 counts were carried forward. There were 801,365 patients less than 18 years old at risk in 2005, and 909,435 were at risk in 2011. Utah residents were approximately 80% Caucasian, 13% Hispanic, 2% Asian, 1% black, and 1% Pacific Islander, with 3% from other groups. Only patients with a permanent Utah mailing address during the studied year were included as cases for incidence and prevalence calculations. We limited calculations of epidemiology to 2005-2011 because we had the greatest ability to electronically confirm the location of residence in the health record in multiple places during those years. The incidence was calculated annually for each of the 7 years in the study period and then averaged. The point prevalence was calculated on December 31 of each year and then averaged.


For natural history analyses, only patients with permanent addresses in the immediate referral area of Utah, southern Idaho, western Wyoming, and eastern Nevada were included. We created a retrospective cohort of all PSC, ASC, and AIH patients and followed them to the endpoints of clinical portal hypertension, obstructive cholangitis, liver transplantation, and death. We defined clinical portal hypertension as splenomegaly and/or a platelet count less than 150,000/μL and at least one of the following: hepatic encephalopathy (based on a subspecialist's subjective impression and the initiation of therapy), ascites on imaging, and endoscopic evidence of esophageal varices and/or portal gastropathy. We defined obstructive cholangitis as fever and/or worsened jaundice, an increased serum white blood cell count, and a cholestatic biochemical profile that was worse than the baseline in a patient with new or known bile duct stricturing on cholangiography. We defined complicated liver disease as a composite endpoint consisting of one or more of the following: clinical portal hypertension, obstructive cholangitis, cholangiocarcinoma, liver transplantation, and death. All observations were censored at the end of the review period (December 1, 2012) or at the date of the last known encounter for patients who were lost to follow-up.

Statistical Methods

We used the Kaplan-Meier method to determine 5-year outcome probabilities. The time variable was calculated from the date of the liver disease diagnosis. The log-rank test was used to test for statistical differences among groups. The Kruskal-Wallis test and an analysis of variance were used to compare continuous variables, and chi-squared and Fisher exact tests were used to analyze categorical variables as appropriate. All calculations were performed with Stata 11 (StataCorp, College Station, TX). All research activities were approved by the institutional review boards of both health care systems.



We identified 1070 unique patients with at least one encounter associated with an ICD-9 code for IBD. We identified 987 unique patients with at least one encounter associated with an ICD-9 code for liver biopsy, AIH, or cholangitis or via a text search for sclerosing cholangitis. A diagnosis of IBD was confirmed in 607 patients. CD was found in 317 (52%), UC was found in 262 (43%), and indeterminate colitis was found in 28 (5%). The overall incidence and prevalence of IBD per 100,000 children in Utah were 5.7 and 22.3, respectively.

The mean duration of follow-up for patients with liver disease was 5.9 years (range = 0.4-17.8 years). Demographic, laboratory, and comorbid illness data for the patients are detailed in Table 2. The intersection of IBD, PSC, and AIH is shown in Fig. 1. Comparisons of survival with the native liver and progression to complicated liver disease between subtypes of IMLD are shown in Figs. 2 and 3.

Table 2. Demographic and Laboratory Characteristics of Patients With Liver Disease
 PSC (n = 29)ASC (n = 12)AIH (n = 44)P Value
  1. a

    The data are presented as means and ranges.

  2. b

    The data are presented as medians and interquartile ranges.

  3. c

    Some patients had more than one diagnosis.

  4. Abbreviation: NS, not significant.

Age at diagnosis (years)a13.0 (5.3-18.0)11.3 (3.1-17.6)9.8 (0.7-17.6)0.002
Follow-up duration (years)a5.6 (0.4-14.0)6.4 (0.6-13.3)5.9 (1.0-17.8)NS
Male [% (n/N)]75.9 (22/29)50.0 (6/12)34.1 (15/44)0.002
Race/ethnicity [% (n/N)]    
Caucasian96.6 (28/29)91.7 (11/12)86.4 (38/44)NS
Hispanic13.6 (6/44)NS
Asian8.3 (1/12)NS
Middle Eastern3.4 (1/29)NS
Labs at diagnosisb    
White blood cell count (K/μL)7.9 (6.8-10.7)7.4 (5.7-10.1)6.6 (5.5-9.4)NS
Hemoglobin (g/dL)13.8 (11.8-15.3)12.5 (11.4-14.2)12.9 (12-13.7)NS
Platelet count (×109/L)318 (244-359)405 (214-462)300 (171-363)NS
International normalized ratio1.1 (1-1.2)1.1 (1-1.2)1.3 (1-1.5)0.045
Total protein (g/dL)7.9 (7.4-8.3)8.2 (8-9.1)7.8 (7-8.5)NS
Albumin (g/dL)4.0 (3.7-4.4)4.1 (3.6-4.3)3.9 (3.4-4.2)NS
Globulin fraction (g/dL)3.9 (3.6-4.3)4.3 (4.1-5.3)3.9 (3.2-4.8)NS
Conjugated bilirubin (mg/dL)0 (0-0.1)0 (0-0)0.5 (0-5.0)0.002
Alanine aminotransferase (U/L)72 (52-172)160 (76-368)702 (235-1363)<0.001
Aspartate aminotransferase (U/L)76 (47-162)167 (97-306)583 (176-1252)<0.001
Alkaline phosphatase (U/L)316 (188-838)292 (207-823)323 (216-490)NS
Gamma-glutamyl transpeptidase (U/L)221 (160-656)275 (174-414)90 (50-161)<0.001
Autoantibodies [% (n/N)]    
ANA-positive36.4 (8/22)77.7 (7/9)56.8 (21/37)NS
ANCA-positive80 (16/20)80 (8/10)42.8 (6/14)0.002
SMA-positive14.3 (1/7)33.3 (2/6)47.8 (11/23)NS
F-actin–positive35.7 (6/16)85.7 (6/7)57.1 (20/35)NS
LKM-positive0 (0/12)16.7 (1/6)12.1 (4/33)NS
AIH [% (n/N)]    
Probable16.7 (2/12)13.6 (6/44)NS
Definite, type 175 (9/12)77.3 (34/44)NS
Definite, type 28.3 (1/12)9.1 (4/44)NS
Comorbid diseases    
IBD [% (n/N)]96.6 (28/29)75 (9/12)4.5 (2/44)<0.001
Additional autoimmune disease excluding IBD [% (n/N)]c6.9 (2/29)16.7 (2/12)22.7 (10/44)NS
Hypothyroidism (n)213 
Celiac disease (n)013 
Type I diabetes (n)002 
Autoimmune hemolytic anemia (n)002 
Immune thrombocytopenic purpura (n)100 
Systemic vasculitis (n)101 
Scleroderma (n)001 
Vitiligo (n)100 
Figure 1.

Proportional-area Venn diagram depicting the overlap of IBD, PSC, and AIH in Utah (ASC numbers are included in both AIH and PSC totals).

Figure 2.

Progression to complicated liver disease (log-rank test P = 0.025). *The groups were statistically different.

Figure 3.

Survival with the native liver from the time of the liver disease diagnosis (log-rank test P = not significant).


We identified 29 cases of PSC. The incidence and prevalence of PSC per 100,000 children in Utah were 0.2 and 1.5, respectively. Complicated liver disease developed in 11 of the 29 PSC patients (38%) during follow-up. Three individual patients developed ascites, six developed esophageal varices, and three developed cholangitis and required biliary stent placement. Two of the 29 PSC patients (6.9%) developed cholangiocarcinoma, and their characteristics are detailed in Table 3. One died of metastatic cholangiocarcinoma, and one was successfully treated with chemotherapy, radiation, and liver transplantation.[21] Five additional patients required liver transplantation. The probability of developing complicated liver disease within 5 years of the diagnosis of PSC was 37% [95% confidence interval (CI) = 21%-58%; Fig. 2]. The 5-year survival rate with the native liver from the time of the PSC diagnosis was 78% (95% CI = 54%-91%; Fig. 3).

Table 3. Characteristics of Patients Diagnosed With Cholangiocarcinoma
 Case 1Case 2
  1. a


  2. b


  3. c


Age at cancer diagnosis (years)17.918
Time since diagnosis of PSC (years)64.2
Underlying IBDUCUC
PresentationProgressive, painless jaundice after a complete loss to follow-up for 5 yearsObstructive cholangitis with a dominant stricture
Cancer antigen 19-9 (U/mL)a88,979324
Carcinoembryonic antigen (ng/mL)b14.61.1
AFP (ng/mL)c8.22.3
OutcomeDied 5 months after the diagnosisRemained alive 3 years after chemotherapy, radiation, and liver transplantation


We identified 12 patients with ASC. The incidence and prevalence of ASC per 100,000 children in Utah were 0.1 and 0.6, respectively. Complicated liver disease developed in 5 of the 12 ASC patients (42%) during follow-up. Two individual patients developed ascites, one developed esophageal varices, one developed hepatic encephalopathy, and one developed cholangitis and required biliary stent placement. One patient underwent liver transplantation. One patient died from sepsis and complications of portal hypertension while awaiting liver transplantation. The probability of developing complicated liver disease within 5 years of the diagnosis of ASC was 25% (95% CI = 7%-70%; Fig. 2). The 5-year survival rate with the native liver from the time of the ASC diagnosis was 90% (95% CI = 47%-99%; Fig. 3).


We identified 44 patients with AIH. The incidence and prevalence of AIH per 100,000 children in Utah were 0.4 and 3.0, respectively. Complicated liver disease developed in 8 of the 44 AIH patients (18%) during follow-up. Three patients developed ascites, five developed esophageal varices, and three developed hepatic encephalopathy. Four patients required liver transplantation. There were no deaths. The probability of developing complicated liver disease within 5 years of the diagnosis of AIH was 15% (95% CI = 7%-33%; Fig. 2). The 5-year survival rate with the native liver from the time of the AIH diagnosis was 87% (95% CI = 71%-95%; Fig. 3).


PSC, ASC, or AIH occurred in 39 of the 607 IBD patients (6.4%) overall. Liver disease was diagnosed a median of 1 month after the diagnosis of IBD (interquartile range = −35 to +48 months), as early as 10.2 years before IBD, and as late as 6.6 years after IBD (see Fig. 4 for details). PSC occurred in 28 of 607 IBD patients (4.6%), in 26 of 262 UC patients (9.9%), and in 2 of 317 CD patients (0.6%). ASC occurred in 9 of 607 IBD patients (1.5%), in 6 of 262 UC patients (2.3%), and in 3 of 317 CD patients (0.9%). AIH occurred in 2 of 607 IBD patients (0.3%), in 1 of 262 UC patients (0.4%), and in 1 of 317 CD patients (0.3%).

Figure 4.

Time elapsing between the diagnosis of IMLD and the diagnosis of IBD (39 patients had both IMLD and IBD).


In summary, we identified all cases of pediatric IBD, PSC, ASC, and AIH in Utah and described the intersection and co-occurrence of these related diseases in a population-based cohort of children. Our study has four major findings. First, we measured the incidence and prevalence of pediatric PSC, ASC, and AIH in Utah and provided estimates of disease frequency that were previously unreported. Second, we described the natural history and provided data on progression to complicated liver disease, and we added data to an area with data derived mostly from single-center reports. Third, we described characteristics of ASC patients and compared them to PSC and AIH populations, and we provided new insight into this subtype of liver disease. Fourth, we identified a high proportion of UC patients who progressed to complicated liver disease, and this has implications for the clinical care of UC patients.


We calculated the incidence and point prevalence of the major immune-mediated diseases affecting children beyond the neonatal period. Our results largely mirror the incidence and prevalence from the few existing studies with pediatric data. The incidence of PSC was estimated to be 0.23 per 100,000 children in the Calgary, Canada area (0.2 in our study), although this was based on only 3 pediatric cases.[9] We identified no published reports of the prevalence of pediatric PSC. Estimates for adults vary, with the incidence and prevalence ranging from 0 to 1.3 and from 0 to 16.2 per 100,000, respectively.[8] We identified no published reports of the incidence or prevalence of ASC. The incidence of AIH was estimated to be 0.1 per 100,000 children (0.4 in our study) in a multicenter survey in Canada.[15] The prevalence was estimated to be 2.3 per 100,000 in British Columbia, Canada (3.0 in our study) on the basis of data from a hospital registry.[14] Adult estimates vary, with the incidence and prevalence ranging from 1.7 to 1.9 and from 16.9 to 42.9 per 100,000, respectively.[10, 12, 22] In contrast to a previous study of PSC,[8] we did not find an increasing incidence of PSC or an increasing incidence of ASC or AIH over the 7 years.

Incidence and prevalence estimates allow extrapolation to the number of cases of pediatric IMLD in the United States. Using census data, we estimate that 155 children are diagnosed with PSC annually, and 1200 children are living with PSC. For ASC, we estimate 80 new pediatric cases annually and 460 prevalent cases. For AIH, we estimate 310 new pediatric cases annually and 2310 prevalent cases. These data indicate that individually and as a group, IMLDs satisfy the Office of Rare Disease Research definition of a rare disease, with fewer than 4000 children affected in the United States.


We demonstrated 5-year survival rates with the native liver of 78% for PSC patients, 90% for ASC patients, and 87% for AIH patients. The PSC and ASC outcomes that we reported are similar to those in previously published single-center reports. In two single-center series with similar mean follow-up durations, children with PSC and ASC required liver transplantation in 19% to 21% of cases (17% in our series), and they had a 5-year survival rate with the native liver of approximately 80%. The rates of cholangitis requiring intervention (12%-17% of patients) were similar as well (10% in our study). Varices were identified in 13% of the patients in one of the series (17% in our study).[1, 2] Notably, neither series identified cases of cholangiocarcinoma. Although cholangiocarcinoma has been reported to occur in 8% and 10% of adult PSC patients,[23, 24] the rate of cholangiocarcinoma in a population-based cohort of children with PSC is unreported. For the AIH patients reported here, the outcomes were somewhat better than those previously reported, and this perhaps reflected the population-based nature of our study, which included more cases with mild activity. Prior studies have reported transplantation rates of 15% to 33% for AIH[25, 26] versus 9% in our series. Neither study reported outcomes related to complicated liver disease. Collectively, these data provide the probability of progression to important clinical endpoints such as complications related to liver disease and the need for liver transplantation in children with IMLD. Our outcome data provide population-based confirmation of most findings from prior single-center experiences with PSC and ASC and perhaps a broader view of outcomes from a less severe population with AIH.


We used available histology and cholangiography data to isolate cases of ASC and compare them to their PSC and AIH peers. In ASC patients, the prevalence of comorbid IBD, positive ANCA serology, and elevated gamma-glutamyl transpeptidase levels most closely mirrored that in PSC patients, whereas the prevalence of positive ANA, F-actin, and LKM serologies and non-IBD comorbid autoimmune diseases in ASC patients most closely matched that in AIH patients. Outcomes were similar in the PSC and ASC groups, with 38% and 42% of the patients, respectively, progressing to complicated liver disease. Among AIH patients, only 18% developed these complications. Some of the differences in PSC, ASC, and AIH did not reach statistical significance, however, likely because of the low power from the small sample size, which is inherent in studies of rare pediatric diseases. At a major referral center, cholangiography was performed prospectively in all pediatric patients who met the criteria for AIH, and ASC was diagnosed in 49% of cases.[4] Similarly to our data, ASC patients were more likely to be ANCA-positive and to have IBD than AIH patients. The 10-year transplant-free survival rate was 65% for the ASC patients and 100% for the AIH patients, and this demonstrated a trend toward poorer outcomes in patients with cholangiopathy that was similar to the results of our study. Our outcome data support the hypothesis that the risk of progression to complicated liver disease may depend most on the severity of cholangiopathy present rather than the specific underlying diagnosis.

We feel that the characterization of patients as having ASC rather than PSC with overlap features or AIH with overlap features is important. Few studies of IMLDs have included a separate category of ASC, and a reliable consensus diagnostic definition does not exist.[27, 28] Traditionally, in studies that include patients with overlap features, the diagnosis (PSC or AIH) that is primary and the diagnosis that represents the overlap portion of the phenotype are based on whichever is discovered first. We do not believe that this method is valid. As other authors have shown, screening all patients for cholangiopathy in AIH,[4] as recommended for pediatric patients,[29] or IBD[30-32] reveals cases that are not evident on the basis of laboratory studies or symptoms. This suggests that the sclerosing cholangitis portion of the phenotype may be present from the outset and is not yet clinically apparent. Additionally, we are not aware of a way of distinguishing a patient with AIH and overlap from a patient with both AIH and PSC if the full diagnostic criteria can be met for both diseases. Finally, given the apparent difference in survival outcomes for IMLD depending on the presence of cholangiopathy, we feel that it is important to formally set ASC patients apart from their AIH peers. Still, the classification of IMLD as PSC, ASC, or AIH depends critically on the subjective interpretation of liver histology and cholangiography, which can be quite difficult. We recognize the diagnostic dilemma that exists when the full criteria for both PSC and AIH (our definition of ASC) cannot be met. Valid and reliable criteria for ASC in pediatric patients are needed.

Liver Disease in IBD

We found that cholangiopathy from PSC or ASC occurred in 12.2% of UC patients. Many studies have reported a lower prevalence of PSC in UC (between 0.15% and 4%).[33-39] The sources of variation likely include differences in case ascertainment and study design. Methods of case ascertainment have included physician questionnaires[34, 35] and identification within administrative data[37] without confirmation by chart review. Some studies excluded patients with small-duct PSC,[36, 39] included only incident cases from a narrow observation period,[33-35] or used a limited number of laboratory tests as the threshold for further diagnostic evaluation.[3, 39] Additionally, some studies were performed before the widespread use or availability of magnetic resonance cholangiopancreatography,[3, 38, 39] and some were not population-based and may have suffered from referral bias.[3, 33, 34, 36, 38] We believe that our population-based data and multiple strategies for case ascertainment provide a truer representation of the burden of PSC in IBD. More consistent with our results, a higher prevalence of PSC in UC patients (between 8.9% and 25%) has been reported in a study that used a comprehensive laboratory screening program for all UC patients with subsequent liver biopsy and endoscopic retrograde cholangiopancreatography,[31] in studies that performed liver biopsy[30] or magnetic resonance cholangiopancreatography[32] on all UC patients regardless of laboratory results, and in a retrospective series that had access to 45 years of follow-up data.[40]

To the best of our knowledge, this study is the first to identify all IBD, PSC, and ASC patients in a population and follow their outcomes. In our study, most PSC and ASC cases were identified within the same year as the diagnosis of IBD. By coupling our prevalence data with our natural history data, we found that each patient with a new diagnosis of UC had approximately a 5% chance of developing PSC or ASC and progressing to complicated liver disease over the next 5 years (which included a 3% chance of liver transplantation or death). A more commonly discussed complication of UC is colorectal cancer; however, it is exceedingly rare in pediatric patients until at least 8 years after diagnosis,[41, 42] and it may have been overestimated in prior single-center reports.[43, 44] Our data suggest that severe liver disease may be an earlier and more common outcome than colorectal cancer in pediatric UC patients.

We see an opportunity to improve the care of UC patients. Establishing an early diagnosis of PSC in children with UC is controversial. There is no proven therapy to halt the progression to cirrhosis; however, many complications of end-stage liver disease can be effectively managed. The potential impact of an early diagnosis of PSC on the clinical care of children with IBD must be further investigated. We speculate that patients could benefit from an earlier diagnosis of PSC in a number of ways, including counseling on potential liver disease outcomes, avoidance of hepatotoxic medications, earlier recognition and management of the complications of cirrhosis, and, potentially, focused screening strategies for cholangiocarcinoma.

Strengths and Limitations

The strengths of our study include its population-based, multicenter nature. We maximized case ascertainment with multiple, overlapping search strategies and with careful reviews of the medical records of all potential patients. In no case did we rely exclusively on the use of administrative data or ICD-9 codes to include or exclude patients. There were several imitations to our study. First was the retrospective design, which did not allow access to patients or a uniform diagnostic workup. Thus, we cannot exclude the possibility of misclassification bias: the prevalence of ASC may have been higher and the prevalence of PSC and AIH may have been lower had all PSC patients undergone liver biopsy and all AIH patients undergone cholangiography. Second, although our results reflect nearly universal ascertainment of IMLD, we cannot exclude the idea that a small proportion of the true burden of IBD was missed. The general local practice pattern of the minority of gastroenterologists outside the two large hospital systems is to refer all pediatric-aged patients to a pediatric subspecialist, so we believe that almost all of these patients were sampled. Finally, these data are almost exclusively from Caucasian patients of Northern and Western European descent. Utah is not a genetic isolate, and these results are likely generalizable to populations of similar ancestry,[45] but they may not entirely reflect disease epidemiology or behavior in other racial and ethnic groups.

In conclusion, we identified all patients with the major IMLDs of childhood in a population-based manner. We described the epidemiology and natural history of PSC, ASC, and AIH. We identified complications of IMLD as a major source of morbidity and mortality in pediatric UC patients, and we suggested further exploration of the role of an early diagnosis of PSC and ASC in UC patients. Our data suggest the need for improved diagnostic definitions of the spectrum of IMLDs.


The authors thank Luana Micallef, M.S., and Peter Rodgers, Ph.D. (University of Kent, Kent, United Kingdom), for the use of their proportional-area Venn diagram creator, EulerAPE ( They also thank Dr. Greg Stoddard, Dr. Carol Sweeney, and Dr. Steven Bleyl for their research assistance.