Background and Aims Disease progression in children with primary sclerosing cholangitis (PSC) is variable. Prognostic and risk-stratification tools exist for adult-onset PSC, but not for children. We aimed to create a tool that accounts for the biochemical and phenotypic features and early disease stage of pediatric PSC. Approach and Results We used retrospective data from the Pediatric PSC Consortium. The training cohort contained 1,012 patients from 40 centers. We generated a multivariate risk index (Sclerosing Cholangitis Outcomes in Pediatrics [SCOPE] index) that contained total bilirubin, albumin, platelet count, gamma glutamyltransferase, and cholangiography to predict a primary outcome of liver transplantation or death (TD) and a broader secondary outcome that included portal hypertensive, biliary, and cancer complications termed hepatobiliary complications (HBCs). The model stratified patients as low, medium, or high risk based on progression to TD at rates of <1%, 3%, and 9% annually and to HBCs at rates of 2%, 6%, and 13% annually, respectively (P < 0.001). C-statistics to discriminate outcomes at 1 and 5 years were 0.95 and 0.82 for TD and 0.80 and 0.76 for HBCs, respectively. Baseline hepatic fibrosis stage was worse with increasing risk score, with extensive fibrosis in 8% of the lowest versus 100% with the highest risk index (P < 0.001). The model was validated in 240 children from 11 additional centers and performed well. Conclusions The SCOPE index is a pediatric-specific prognostic tool for PSC. It uses routinely obtained, objective data to predict a complicated clinical course. It correlates strongly with biopsy-proven liver fibrosis. SCOPE can be used with families for shared decision making on clinical care based on a patient's individual risk, and to account for variable disease progression when designing future clinical trials.

Our aim was to analyze the outcomes in children with short-bowel syndrome (SBS), parenteral nutrition dependence (PND), and intestinal failure-associated liver disease (IFALD) treated in our Intestinal Rehabilitation Program (IRP) during 2007-2018. We retrospectively reviewed charts of 135 patients with SBS-PND at the time of enrollment in IRP; of these, 89 (66%) had IFALD, defined as conjugated bilirubin (CB) of ≥2 mg/dl at enrollment and/or abnormal liver biopsy showing stage 2-4 fibrosis. Outcomes included resolution of CB, enteral autonomy, laboratory parameters (platelets, aspartate aminotransferase to platelet ratio index), growth trends, transplant rates, and mortality. Of the 89 patients, 74 had elevated CB at enrollment; the other 15 had normalized CB but had fibrosis on liver biopsy. Thirty-eight patients had liver biopsies: 36 (95%) had fibrosis, including 21/36 with bridging fibrosis/cirrhosis. The median proportion of residual small bowel was 23% (interquartile range, 13%-38%) of the expected length for age and median, daily energy requirement by PN was 100%. Two received a transplant, three died (one posttransplant), and the remaining 85 survived; 69 (81%) achieved enteral autonomy. Seventy-three (99%) of the 74 patients with hyperbilirubinemia normalized their CB with medical treatment. In a subset of eight of 89 patients with initial platelet count of <100,000/μl(median 50,500/μl) and median CB of 21 mg/dl, seven achieved CB normalization and had improved platelet count. Overall survival was 97% (censored 96.3%). We demonstrate high transplant-free survival and enteral autonomy rates among children with SBS-IFALD relying on low-dose soybean lipid emulsion.

Carnitine palmitoyltransferase 1A (CPT1A) deficiency is a rare disorder of hepatic long-chain fatty acid oxidation. Most patients with CPT1A deficiency present with hypoketotic hypoglycemia and hepatic encephalopathy. We describe an atypical case of an 8-year-old male with CPT1A deficiency presenting with chronic liver steatosis and cirrhosis. He also had a history of developmental delay, autism spectrum disorder, and mild dysmorphic features of unknown cause. His newborn screening test suggested CPT1A deficiency, but confirmatory biochemical testing was not conclusive. The patient never experienced a metabolic crisis. At age six, hepatomegaly was detected. Further investigations showed transaminitis, hepatosteatosis and cirrhosis. Repeat acylcarnitine profile and total/free carnitine were consistent with CPT1A deficiency. The CPTI enzyme activity was 18% of normal on fibroblast enzyme assay. A novel homozygous variant in the CPT1A gene, c.1394G> A (p. Gly465Glu) was identified from whole-exome sequencing. To our knowledge, the patient is the first reported individual with CPT1A deficiency and chronic liver steatosis and fibrosis. Developmental delay and autistic spectrum disorder are not typical features of CPT1A deficiency, given that the patient never experienced any metabolic decompensation.

AIMS:In RCT of adults with decompensated cirrhosis, GCSF mobilizes hematopoietic stem cells HSC and improves short-term outcome. An FDA-IND for sequential Kasai-GCSF treatment in biliary atresia BA was approved. This phase 1 study examines GCSF safety in Kasai subjects. Preliminary short-term outcome was evaluated. METHODS:GCSF (Neupogen) at 5 or 10 μg/kg (n = 3/group) was given in 3 daily doses starting on day 3 of Kasai surgery (NCT03395028). Serum CD34+ HSC cell counts, and 1-month of GCSF-related adverse events were monitored. The 6-months Phase 1 clinical outcome was compared against 10 subsequent post Phase 1 Kasai patients who did not receive GCSF. RESULTS:With GCSF, WBC and platelet count transiently increased, LFT and serum creatinine remained stable. Reversible splenic enlargement (by 8.5-20%) occurred in 5/6 subjects. HSC count increased 12-fold and 17.5-fold for the 5 μg/kg and10 ug/kg dose respectively; with respective median total bilirubin levels for GCSF vs no-GCSF groups of 55 vs 91 μM at 1 month, p = 0.05; 15 vs 37 μM at 3 months, p = 0.24); and the 6-months cholangitis frequency of 40% vs 90%, p = 0.077. CONCLUSIONS:GCSF safely mobilizes HSC in Kasai infants and may improve short-term biliary drainage and cholangitis. Phase 2 efficacy outcome of GCSF adjunct therapy for sequential Kasai and GCSF is pending.

BACKGROUND:Natural history models for primary sclerosing cholangitis (PSC) are derived from adult patient data, but have never been validated in children. It is unclear how accurate such models are for children with PSC.METHODS:We utilized the pediatric PSC consortium database to assess the Revised Mayo Clinic, Amsterdam-Oxford, and Boberg models. We calculated the risk stratum and predicted survival for each patient within each model using patient data at PSC diagnosis, and compared it with observed survival. We evaluated model fit using the c-statistic.RESULTS:Model fit was good at 1 year (c-statistics 0.93, 0.87, 0.82) and fair at 10 years (0.78, 0.75, 0.69) in the Mayo, Boberg, and Amsterdam-Oxford models, respectively. The Mayo model correctly classified most children as low risk, whereas the Amsterdam-Oxford model incorrectly classified most as high risk. All of the models underestimated survival of patients classified as high risk. Albumin, bilirubin, AST, and platelets were most associated with outcomes. Autoimmune hepatitis was more prevalent in higher risk groups, and over-weighting of AST in these patients accounted for the observed versus predicted survival discrepancy.CONCLUSIONS:All 3 models offered good short-term discrimination of outcomes but only fair long-term discrimination. None of the models account for the high prevalence of features of autoimmune hepatitis overlap in children and the associated elevated aminotransferases. A pediatric-specific model is needed. AST, bilirubin, albumin, and platelets will be important predictors, but must be weighted to account for the unique features of PSC in children.

In 1989, a collaboration between the Centers for Disease Control (CDC) and a California biotechnology company identified the hepatitis C virus (HCV, formerly known as non-A, non-B hepatitis virus) as the causative agent in the epidemic of silent posttransfusion hepatitis resulting in cirrhosis. We now know that, the HCV genome is a 9.6 kb positive, single-stranded RNA. A single open reading frame encodes a 3011 amino acid residue polyprotein that undergoes proteolysis to yield 10 individual gene products, consisting of 3 structural proteins (core and envelope glycoproteins E1 and E2) and 7 nonstructural (NS) proteins (p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B), which participate in posttranslational proteolytic processing and replication of HCV genetic material. Less than 25 years later, a new class of medications, known as direct-acting antivirals (DAAs) which target these proteins, were introduced to treat HCV infection. These highly effective antiviral agents are now approved for use in children as young as 3 years of age and have demonstrated sustained virologic responses exceeding 90% in most genotypes. Although tremendous scientific progress has been made, the incidence of acute HCV infections has increased by 4-fold since 2005, compounded in the last decade by a surge in opioid and intravenous drug use. Unfortunately, awareness of this deadly hepatotropic virus among members of the lay public remains limited. Patient education, advocacy, and counseling must, therefore, complement the availability of curative treatments against HCV infection if this virus is to be eradicated.

3 y old boy with deafness, hypotonia, ichthyosis, osteopenia, IF, chronic enteropathy, initially on PN now on J tube feedings, secondary to MEDNIK syndrome. He had IFALD stage 4 fibrosis, now with normal conjugated bilirubin (CB). Liver biopsy with no iron or copper (Cu) deposition, low Cu quantification, presented with feeding intolerance, persistent diarrhea, dehydration, metabolic acidosis and AKI. Treated with high dose of zinc acetate to avoid accumulation of Cu (brain and liver). He had multiple admissions due to enterocolitis, sepsis and severe anemia related to low Cu. His initial target blood Cu level was ~20’s but it was increased to ~40 mcg/dLto minimized complications. He was started on jejunal feeds of amino-acid (aa) based formula; with control of sepsis was able to wean off of PN, now tolerating oral feeds. 10 y old male with SBS, PN and G/J tube dependent due to multiple congenital atresias, TTC7A gene mutation. History of hypogammaglobinemia, bone marrow transplant and IFALD stage 4 fibrosis, now with normal CB. History of multiple surgeries to correct his intestinal (I) obstruction, left with 75 cm of bowel, a Santulli ostomy and a surgical G and J tube due to severe dysmotility. He had multiple I. strictures dilated endoscopically. He has tolerated progressive advances of J tube feedings decreasing PN needs from 100% to 35%. 3y old male with adrenal insufficiency and IF initially on PN, now G tube dependent, secondary to congenital osmotic diarrhea related to PCSK1 mutation. His IGF-1, IGF-BP3, Prolactin, TSH, free T4, and MRI of the pituitary were normal. He had history of multiple CLABSI and diabetes Insipidus needing vasopressin during sepsis episodes; enterocolitis and severe metabolic acidosis due to B2 deficiency. His diarrhea persisted on all formulas and he was placed on PN and on a custom formula (amino acid powder, microlipids, electrolytes), but due to his low B2 this formula was changed for aa based formula via G tube, tolerating progressive advances of enteral nutrition, with PN wean. He now takes >50% of caloric needs via PO and the rest as nighttime GT feeds. Although obesity is observed in PCSK1 his weight is at the 50% and height at the 10%. Patients with complex genetic syndromes and diverse nutritional and electrolyte needs can be successfully managed and transitioned from PN to enteral feeding as was done in our IR program, with a multidisciplinary collaborative approach.

OBJECTIVE:To investigate patient factors predictive of gamma glutamyltransferase (GGT) normalization following ursodeoxycholic acid (UDCA) therapy in children with primary sclerosing cholangitis. STUDY DESIGN:We retrospectively reviewed patient records at 46 centers. We included patients with a baseline serum GGT level ≥50 IU/L at diagnosis of primary sclerosing cholangitis who initiated UDCA therapy within 1 month and continued therapy for at least 1 year. We defined "normalization" as a GGT level <50 IU/L without experiencing portal hypertensive or dominant stricture events, liver transplantation, or death during the first year. RESULTS:We identified 263 patients, median age 12.1 years at diagnosis, treated with UDCA at a median dose of 15 mg/kg/d. Normalization occurred in 46%. Patients with normalization had a lower prevalence of Crohn's disease, lower total bilirubin level, lower aspartate aminotransferase to platelet ratio index, greater platelet count, and greater serum albumin level at diagnosis. The 5-year survival with native liver was 99% in those patients who achieved normalization vs 77% in those who did not. CONCLUSIONS:Less than one-half of the patients treated with UDCA have a complete GGT normalization in the first year after diagnosis, but this subset of patients has a favorable 5-year outcome. Normalization is less likely in patients with a Crohn's disease phenotype or a laboratory profile suggestive of more advanced hepatobiliary fibrosis. Patients who do not achieve normalization could reasonably stop UDCA, as they are likely not receiving clinical benefit. Alternative treatments with improved efficacy are needed, particularly for patients with already-advanced disease.

To evaluate the outcomes of the USBS with < 10 cm or < 10% of the expected bowel length for gestational age enrolled in the IRP at CNMC. 24 USBS patients, who had at least 2 years follow-up over the past 10 years, were included. Outcomes involved death, transplant, time to normalized conjugated bilirubin (CB) and parenteral nutrition (PN) requirement. Platelets, albumin, CB, weight and height Z score were obtained at entrance and end of the study. At entrance, median age was 3 months, mean bowel length 15 cm; 6 had IC valve, 9 had < ½ of colon. Median PN need was 100%. 21 of 24 had liver disease, 19 had a mean CB of 7.5 mg/dl, (liver biopsy in 13/21 showed fibrosis, stage 3–4 in 8). 18/19 (95%) patients with cholestasis normalized their CB with treatment over a median time of 11 weeks. Fourteen patients had 23 lengthening procedures (LP) at CNMC with no complications. 12 had the 1st LP at CNMC; 7 Bianchi; 4 STEP and 1 Bianchi & Step. Median age at 1st LP was 21 months. 8 had a 2nd STEP and 3 had a 3rd STEP (1 had 2 prior STEP in other institution). 2/14 patients with LP were transplanted and 3 weaned off PN (one each after the 1st, 2nd and 3rd LP). The mean PN needs decreased in the non-transplant patients from 75% prior to 1st LP to 50% and to 44% after the 2nd STEP. In 3 patients who had 3rd STEP the PN decreased from 68% to 31%. Of the 24 patients, one is lost to follow up, 7 were considered candidates for a liver- small bowel transplant; 2 declined to be listed (one is now off PN and the 2nd have decreased the PN needs by 35%). Five were listed, 3 were transplanted, one weaned off PN without transplant and one was unlisted, his PN decreased from 100% to 33%. Three patients died (single ventricle, genetic syndrome and post-transplant). Of the remaining 18; 8 (44.4%) weaned off their PN and 10 have decreased their PN needs from a median of 100% to 26%. Laboratory parameters and growth significantly improved. Overall survivability is 87.5% and among those who were not transplanted is 90.5%. Children with USBS can improve their liver functions and nutritional parameters with the ability to decrease or wean off their PN with careful medical/surgical approach. Intestinal lengthening procedures help them to improve their enteral nutrition. The IRP has enabled these patients to approach school age and have normal growth. Although 87.5% of the cohort has IFALD, 96 % of them resolved their cholestasis. Survivability rate is excellent.

Objective We report the outcomes of short bowel syndrome (SBS) parenteral nutrition (PN) dependent patients with IFALD enrolled in our intestinal rehabilitation program (IRP). Methods Over a 10 year period, 124 SBS PN-dependent patients were enrolled, 78 (63%) of them had IFALD, defined as conjugated bilirubin (CB) of >=2mg/dL at enrollment and/or abnormal liver biopsy (stage 2-4 fibrosis). Outcomes included death, transplant, time to be weaned off PN, time to achieve normal CB levels. Independent variables included gender, gestational age, diagnosis, and intestinal length. Platelets, albumin, CB were obtained at the start and end of the study. Results Seventy-eight patients (51 males) had IFALD; of these, at the time of enrollment in IRP, 11 (14%) had normalized CB but had abnormal liver biopsies at CNHS and 66 (85%) had elevated CB. One patient acquired elevated CB, related to severe comorbidities. Median CB was 7.3 mg/dl (2-32 mg/dL). Thirty-three patients (42%) had liver biopsies, of which 32 (97%) had fibrosis, including 17 (52%) with bridging fibrosis or cirrhosis. Fifty-five patients (70.5%) were premature (GA <36 weeks). Median intestinal length was 44 cm (28/78 patients (36 %) had <35 cm). Median age at enrollment was 3.7 months and median daily caloric requirement by PN was 100%. Of the 67 patients with elevated CB, 66 (98.5%) normalized their bilirubin with medical treatment over an average of 11.6 weeks (st.dev. 9.1), using soy bean intralipid emulsion. Fifty seven (85%) reversed their cholestasis while still receiving PN, 2 patients were transplanted (they had 4 and 10 cm of remaining bowel), 2 patients died (cardiac anomalies and Down Syndrome). Four patients moved to another state after normalizing their CB, decreasing their PN from 100 to 56%. Of the 70 remaining patients 57 were weaned off PN (81.4%) over a median time of 5 months. A subset of 8 (10%) patients with initial platelet count of < 100 x 103/mcl (mean 59) was identified. In this subgroup, mean CB was 18.4mg/dL, and mean aspartate aminotransferase (AST) to platelet ratio index (APRI) was 19.4. Yet, all but one of this group achieved normalization of CB within an average of 15.6 weeks (st.dev =12), and a significant improvement of platelet count at the end of follow-up (p-value < 0.001). Overall survival was 97.4%. Due to low mortality in our cohort, logistic regression controlling for independent variables did not find association between initial bilirubin levels and mortality. Conclusion We demonstrate superior outcomes among children with IFALD. In spite of high acuity (e.g. significant proportion of extreme short gut patients, initial high dependence on PN), we were able to quickly reduce their PN needs and improve IFALD without relying on fish oil base lipid. As one of the larger and well established IRP in the US, we demonstrate high survival rates of our patients without the need for liver/intestinal transplant. Early referral to IRP is recommended.

Adverse clinical events in primary sclerosing cholangitis (PSC) happen too slowly to capture during clinical trials. Surrogate endpoints are needed, but no such validated endpoints exist for children with PSC. We evaluated the association between gamma glutamyltransferase (GGT) reduction and long-term outcomes in pediatric PSC patients. We evaluated GGT normalization (< 50 IU/L) at 1 year among a multicenter cohort of children with PSC who did or did not receive treatment with ursodeoxycholic acid (UDCA). We compared rates of event-free survival (no portal hypertensive or biliary complications, cholangiocarcinoma, liver transplantation, or liver-related death) at 5 years. Of the 287 children, mean age of 11.4 years old, UDCA was used in 81% at a mean dose of 17 mg/kg/day. Treated and untreated groups had similar GGT at diagnosis (314 versus 300, P = not significant [NS]). The mean GGT was reduced at 1 year in both groups, with lower values seen in treated (versus untreated) patients (99 versus 175, P = 0.002), but 5-year event-free survival was similar (74% versus 77%, P = NS). In patients with GGT normalization (versus no normalization) by 1 year, regardless of UDCA treatment status, 5-year event-free survival was better (91% versus 67%, P < 0.001). Similarly, larger reduction in GGT over 1 year (> 75% versus < 25% reduction) was also associated with improved outcome (5-year event-free survival 88% versus 61%, P = 0.005). Conclusion: A GGT < 50 and/or GGT reduction of > 75% by 1 year after PSC diagnosis predicts favorable 5-year outcomes in children. GGT has promise as a potential surrogate endpoint in future clinical trials for pediatric PSC.