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Pediatric PSC outcomes still poor; effective treatment needed

Nearly half of pediatric patients with primary sclerosing cholangitis developed an adverse liver outcome within 10 years of diagnosis, according to a recent retrospective review.

“Pediatric PSC has a chronic, progressive, and relentless course,” Mark R. Deneau, MD, from the University of Utah, and colleagues wrote. “The identification of a portal hypertensive or biliary complication represents a tipping point in the natural history, with a subsequent median survival with native liver of only 3 years. These outcomes occurred despite treatment of the vast majority of patients with chronic ursodeoxycholic acid therapy. Effective treatments are needed to change the course of this disease.”

Patients with elevated bilirubin, gamma-glutamyl transferase and aspartate aminotransferase-to-platelet ratio index at diagnosis appear to have the highest risk, whereas small duct PSC and PSC-inflammatory bowel disease are more favorable disease phenotypes.

To determine the disease characteristics and long-term outcomes of pediatric PSC, the researchers retrospectively reviewed the cases of 781 children with PSC from 36 international institutions. Median age at diagnosis was 12 years (range, 8-15 years), 571 had IBD, 260 had autoimmune hepatitis (AIH) and 98 had small duct PSC.

Long-term outcomes included portal hypertension in 163 patients (5% at diagnosis and 38% at 10 years), biliary complications in 95 patients (5% at diagnosis and 25% at 10 years), and cholangio-carcinoma in 8 patients (median 6 years after diagnosis). All patients with cholangio-carcinoma had AIH, which was significantly higher than the rest of the cohort (100% vs. 67%; P = 0.04).

Median survival with native liver after developing portal hypertension was 2.8 years and was 3.5 years for biliary complication. Three patients with cholangio-carcinoma died under palliative care within 5 months of metastatic cancer diagnosis and five were alive at last known follow-up (median, 2.5 years after cancer diagnosis). Overall, 221 patients experienced at least one adverse liver-related outcome. Event-free survival was 70% at 5 years (95% CI, 66-74) and 53% at 10 years (95% CI, 47-59).

Of the 83% of patients with available data, those with higher values of AST ratio index (1.33 vs. 0.49; P < .001), gamma-glutamyl transferase (309 vs. 142; P = .001) and bilirubin (0.86 vs. 0.41; P < .001) had the most significant risk for worse long-term outcomes.

Patients with small duct PSC were younger at diagnosis than those with large duct PSC (10.5 vs. 11.7 years; P < .01). Most patients with IBD and PSC were male (64% vs. 52%; P < .01), less likely to have overlapping autoimmune hepatitis (28% vs. 51%; P < .01), had lower AST ratio index (0.68 vs. 1.57; P < .001) and MELD scores (0 vs. 4; P < .001), and had better rates of event-free survival (P < .01) than those without IBD.

Those with autoimmune hepatitis and PSC were more often female (45% vs. 36%; P < .01), more likely to have non-IBD autoinflammatory disease (10% vs. 5%; P < .01) and had higher AST ratio index (1.25 vs. 0.71; P < .001) than those without AIH.

On multivariate analysis, small duct PSC (HR = 0.69; 95% CI, 0.5-0.96) and the presence of IBD (HR = 0.63; 95% CI, 0.47-0.86) were correlated with more favorable outcomes.

“Despite a comparable degree of presumed fibrosis, small duct PSC patients progressed more slowly to end-stage disease complications,” the researchers wrote. “PSC-IBD carried a more favorable prognosis in our cohort as well. PSC patients with IBD had a lower rate of cirrhosis and higher survival with native liver in children.”

In a related editorial, Giorgina Mieli-Vergani, MD, PhD, FRCP, FRCPCH, FAASLD, and Diego Vergani, MD, PhD, FRCPath, FRCP, FAASLD, from King’s College Hospital, London, recognized the importance of the study’s multicenter collaboration to collect data from dedicated registries. They were concerned with the uneven diagnostic protocols and lack of accurate information on IBD treatment prior to sclerosing cholangitis in retrospective studies, however.

“Juvenile [sclerosing cholangitis] is the result of different pathologies, with a high proportion of patients having associated IBD and/or autoimmune features,” they wrote. “Multicenter prospective studies are needed for dening [sclerosing cholangitis] phenotype and diagnostic criteria and for exploring pathogenic mechanisms with the aim of devising more effective treatment for this unrelenting condition.” – by Talitha Bennett

Disclosure: Deneau reports no relevant financial disclosures. Please see the full study for the other researchers’ relevant financial disclosures.