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. 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. 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. 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. 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, 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. 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, as recommended for pediatric patients, 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 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, in studies that performed liver biopsy or magnetic resonance cholangiopancreatography on all UC patients regardless of laboratory results, and in a retrospective series that had access to 45 years of follow-up data.
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, 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.