A clinical staging system for SDB based on palate position, tonsil size, and body mass index is presented. It appears to be a valuable predictor of the success of UPPP. Additional studies and wider use of the staging system will ultimately define its role in the treatment of SDB.

Objectives To prospectively assess the value of serum total bilirubin (TB) within 3 months of hepatoportoenterostomy (HPE) in infants with biliary atresia (BA) as a biomarker predictive of clinical sequelae of liver disease in the first two years of life. Study design Infants with BA undergoing HPE between June 2004-January 2011 were enrolled in a prospective, multicenter study. Complications were monitored until 2 years of age or the earliest of liver transplant (LT), death, or study withdrawal. TB below 2 mg/dL (34.2 μM) at any time in the first 3 months (TB<2.0, all others = TB≥2) after HPE was examined as a biomarker, using Kaplan-Meier survival and logistic regression. Results Fifty percent (68/137) of infants had TB<2.0 in the first 3 months after HPE. Transplant-free survival at 2 years was significantly higher in the TB<2.0 group vs. TB≥2 (86% vs. 20%, p<0.0001). Infants with TB≥2 had diminished weight gain (p<0.0001), greater probability of developing ascites (OR 6.4, 95% CI 2.9–14.1, p<0.0001), hypoalbuminemia (OR 7.6, 95% CI 3.2–17.7, p< 0.0001), coagulopathy (OR 10.8, 95% CI 3.1–38.2, p=0.0002), LT (OR 12.4, 95% CI 5.3–28.7, p<0.0001), or LT or death (OR 16.8, 95% CI 7.2–39.2, p<0.0001). Conclusions Infants whose TB does not fall below 2.0 mg/dL within 3 months of HPE were at high risk for early disease progression, suggesting they should be considered for LT in a timely fashion. Interventions increasing the likelihood of achieving TB <2.0 mg/dL within 3 months of HPE may enhance early outcomes.

Biliary atresia (BA) is notable for marked ductular reaction and rapid development of fibrosis. Activation of the Hedgehog (Hh) pathway promotes the expansion of populations of immature epithelial cells that coexpress mesenchymal markers and may be profibrogenic. We examined the hypothesis that in BA excessive Hh activation impedes ductular morphogenesis and enhances fibrogenesis by promoting accumulation of immature ductular cells with a mesenchymal phenotype. Livers and remnant extrahepatic ducts from BA patients were evaluated by quantitative reverse‐transcription polymerase chain reaction (QRT‐PCR) and immunostaining for Hh ligands, target genes, and markers of mesenchymal cells or ductular progenitors. Findings were compared to children with genetic cholestatic disease, age‐matched deceased donor controls, and adult controls. Ductular cells isolated from adult rats with and without bile duct ligation were incubated with Hh ligand‐enriched medium ± Hh‐neutralizing antibody to determine direct effects of Hh ligands on epithelial to mesenchymal transition (EMT) marker expression. Livers from pediatric controls showed greater innate Hh activation than adult controls. In children with BA, both intra‐ and extrahepatic ductular cells demonstrated striking up‐regulation of Hh ligand production and increased expression of Hh target genes. Excessive accumulation of Hh‐producing cells and Hh‐responsive cells also occurred in other infantile cholestatic diseases. Further analysis of the BA samples demonstrated that immature ductular cells with a mesenchymal phenotype were Hh‐responsive. Treating immature ductular cells with Hh ligand‐enriched medium induced mesenchymal genes; neutralizing Hh ligands inhibited this. Conclusion: BA is characterized by excessive Hh pathway activity, which stimulates biliary EMT and may contribute to biliary dysmorphogenesis. Other cholestatic diseases show similar activation, suggesting that this is a common response to cholestatic injury in infancy. (HEPATOLOGY 2011;)

Objectives Biliary atresia (BA) frequently results in portal hypertension (PHT), complications of which lead to significant morbidity and mortality. The Childhood Liver Disease Research and Education Network (ChiLDREN) was utilized to perform a cross-sectional multi-centered analysis of PHT in children with BA. Methods BA subjects receiving medical management at a ChiLDREN site were enrolled. A priori, clinically evident PHT was defined as “definite” when there was either 1) history of a complication of PHT or 2) clinical findings consistent with PHT (both splenomegaly and thrombocytopenia). PHT was denoted as “possible” if one of the findings was present in the absence of a complication, while PHT was “absent” if none of the criteria were met. Results 163 subjects were enrolled between May 2006 and December 2009. At baseline, definite PHT was present in 49%, possible in 17% and absent in 34% of subjects. Demographics, growth and anthropometrics were similar amongst the 3 PHT categories. ALT, GGTP, and sodium levels were similar, while there were significant differences in AST, AST/ALT, albumin, total bilirubin, PT, WBC, platelet count and AST/platelet between definite and absent PHT. Thirty-four percent of those with definite PHT had either PT > 15s or albumin < 3 g/L. Conclusions Clinically definable PHT is present in two thirds of North American long-term BA survivors with their native livers. The presence of PHT is associated with measures of hepatic injury and dysfunction, although in this selected cohort the degree of hepatic dysfunction is relatively mild and growth is preserved.

To evaluate the efficacy of non-transplant surgery for pediatric cholestasis, 58 clinically diagnosed children, including 20 Alagille syndrome (ALGS), 16 Familial Intrahepatic Cholestasis-1 (FIC1), 18 Bile Salt Export Pump (BSEP) disease, & 4 others with low γ-glutamyl transpeptidase disease (levels <100 U/L), were identified across 14 Childhood Liver Disease Research Network (ChiLDReN) centers. Data were collected retrospectively from individuals who collectively had 39 partial external biliary diversions (PEBD), 11 ileal exclusions (IE) and 7 gallbladder-to-colon diversion (GBC). Serum total bilirubin decreased after PEBD in FIC1 (8.1±4.0 vs. 2.9±4.1 mg/dL, preop vs. 12–24 months postop respectively, p=0.02) but not in ALGS or BSEP. Total serum cholesterol decreased after PEBD in ALGS patients (695±465 vs. 457±319 mg/dL; preop vs. 12–24 months postop respectively; p=0.0001). Alanine aminotransferase levels increased in ALGS after PEBD (182±70 vs. 260±73 IU/L, preop vs. 24 mos. p=0.03) but not in FIC1 or BSEP. ALGS, FIC1, and BSEP patients experienced less severely scored pruritus after PEBD (ALGS: 100% vs. 9% severe, FIC1: 64% vs. 10%; BSEP: 50% vs. 20%, preop vs. >24 mos. postop respectively, p<0.001). ALGS patients experienced a trend toward greater freedom from xanthomata after PEBD. There was a trend toward decreased pruritus in FIC1 after IE and GBC. Vitamin K supplementation increased in ALGS after PEBD (33% vs. 77%, p=0.03. Overall, there were 15 major complications after surgery. 12 patients (3 ALGS, 3 FIC1, 6 BSEP) subsequently underwent liver transplantation. Conclusion This is the first multi-center analysis of non-transplant surgical approaches to intrahepatic cholestasis. Approaches vary, are well tolerated, and generally although not uniformly result in improvement of pruritus and cholestasis.

Medically refractory, severe, cholestasis‐induced pruritus in Alagille syndrome may be improved by surgical interruption of the enterohepatic circulation. This multicenter trial (NCT02057692) tested the hypothesis that the intestinal bile acid transport inhibitor maralixibat would similarly reduce pruritus in Alagille syndrome. Thirty‐seven children with Alagille syndrome were randomly assigned to double‐blinded administration of placebo, 70, 140, or 280 µg/kg/day of maralixibat for 13 weeks. Pruritus was assessed by caregiver (itch‐reported outcome instrument [ItchRO]) and clinician report (range, 0‐4 [severe]). Liver chemistries and serum bile acids were measured. The primary outcome was the change from baseline to week 13 in ItchRO relative to placebo. In the a priori first analysis of the primary efficacy endpoint, the mean adjusted difference between participants receiving 140 or 280 µg/kg/day and placebo was –0.47 (95% confidence interval [CI], –1.14, 0.20; P = 0.16). Statistically significant decreases were observed with doses of 70 and 140 µg/kg/day (mean adjusted difference, –0.89; 95% CI, –1.70, –0.08; P = 0.032; and mean adjusted difference, –0.91; 95% CI, –1.62, –0.19; P = 0.014) but not 280 µg/kg/day (mean adjusted difference, –0.04; 95% CI, –0.94, 0.86; P = 0.44) or all doses combined (mean adjusted difference, –0.61; 95% CI, –1.24, 0.20; P = 0.055). A 1‐point reduction in pruritus was more common in maralixibat‐treated versus placebo‐treated participants (caregiver ItchRO, 65% versus 25%; P = 0.06; clinician score, 76% versus 25%; P = 0.01). There were no significant changes in liver chemistries or bile acids relative to placebo. Adverse and serious adverse events were similar between maralixibat and placebo. Conclusion: Although the prespecified primary analyses of ItchRO were not all statistically significant, the data suggest that maralixibat is safe and may reduce pruritus in Alagille syndrome.

Objective Alpha-1-antitrypsin deficiency (A1AT) is a common genetic disease with unpredictable and highly variable course. The Childhood Liver Disease Research and Education Network (ChiLDREN) is an NIH, multi-center, longitudinal consortium studying pediatric liver diseases, with the objective of prospectively defining natural history and identifying disease modifiers. Methods Longitudinal, cohort study of A1AT patients birth through 25 years diagnosed with liver disease, type PIZZ or PISZ. Medical history, physical exam, laboratory, imaging, and standardized survey tool data were collected during the provision of standard of care. Results In this report of the cohort at baseline, 269 subjects were enrolled between Nov. 2008 and Oct. 2012 (208 with their native livers and 61 post-liver transplant). Subjects with mild disease (native livers and no portal hypertension [PHT]) compared to severe disease (with PHT or post-liver transplant) were not different in age at presentation. 57% of subjects with mild disease and 76% with severe disease were jaundiced at presentation (p=0.0024). 29% of subjects with native livers had PHT, but age at diagnosis and growth were not different between the no PHT and PHT groups (p>0.05). Subjects with native livers and PHT were more likely to have elevated bilirubin, ALT, AST, INR, and GGTP than the no PHT group (p≪0.001), but overlap was large. Chemistries alone could not identify PHT. Conclusion Many A1AT subjects presenting with elevated liver tests and jaundice improve spontaneously. Subjects with PHT have few symptoms and normal growth. Longitudinal cohort follow up will identify genetic and environmental disease modifiers. NCT00571272.

Few children can accurately recall the episodes of AP. Children commonly recall a lower frequency of AP than that assessed by prospective diary reports. Reported recall does not reflect a shorter recollection period. Recall is not related to intensity of pain. Adolescents have worse recall of symptoms.