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.

Non-alcoholic fatty liver disease (NAFLD) is the number one chronic liver disease worldwide and is estimated to affect nearly 40% of obese youth and up to 10% of the general pediatric population without any obvious signs or symptoms. Although the early stages of NAFLD are reversible with diet and lifestyle modifications, detecting such stages is hindered by a lack of non-invasive methods of risk assessment and diagnosis. This absence of non-invasive means of diagnosis is directly related to the scarcity of long-term prospective studies of pediatric NAFLD in children and adolescents. In the majority of pediatric NAFLD cases, the mechanisms driving the origin and rapid progression of NAFLD remain unknown. The progression from NAFLD to non-alcoholic steatohepatitis (NASH) in youth is associated with unique histological features and possible immune processes and metabolic pathways that may reflect different mechanisms compared with adults. Recent data suggest that circulating microRNAs (miRNAs) are important new biomarkers underlying pathways of liver injury. Several factors may contribute to pediatric NAFLD development, including high-sugar diets, in utero exposures via epigenetic alterations, changes in the neonatal microbiome, and altered immune system development and mitochondrial function. This review focuses on the unique aspects of pediatric NAFLD and how nutritional exposures impact the immune system, mitochondria, and liver/gastrointestinal metabolic health. These factors highlight the need for answers to how NAFLD develops in children and for early stage-specific interventions.

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.

Background & Aims Steatotic liver responds with increased hepatocellular injury when exposed to an ischemic-reperfusion insult. Increasing evidence supports the role of immune cells as key mediators of this injury in a normal (lean) state, but data about their role in a steatotic liver are practically non-existent. The objective of the current study was to delineate contribution of specific phenotypes of T cells and adhesion molecules in exacerbated cell death in steatotic liver injury. Methods RNA sequencing was performed on isolated steatotic primary hepatocytes and T cell markers were assessed in hepatic lymphocytes after ischemia reperfusion injury (IRI) in high fat diet (HFD) fed mice. CD8−/− and CD4−/− mice along with CD8 and L-selectin antibody treated mice were fed on a HFD and hepatocellular injury was assessed by histology, propidium iodide injection and ALT after IRI. Results RNA sequencing demonstrated a strikingly differential gene profile in steatotic hepatocytes vs. lean hepatocytes. After injury, the HFD liver showed increased necrosis, infiltrating CD8+ cells, ALT and proinflammatory cytokines. Hepatic lymphocytes demonstrated increased CD8+/CD62L+(L-selectin) cells in HFD fed mice after IRI. CD8−/− mice and CD8 depleted C57BL/6 mice, demonstrated significant protection from injury, which was not seen in CD4−/− mice. L-selectin blockade also demonstrated significant hepatoprotection from IRI. L selectin ligand MECA-79 was increased in HFD fed mice undergoing IRI. Conclusion Blockade of CD8 and L-selectin but not CD4, ameliorated hepatocellular injury, confirming that CD8+ cells are critical drivers of injury in a steatotic liver. This represents a novel therapeutic target in steatotic liver injury, underlining the importance of development of therapies specific to a steatotic liver.

Background & Aims Most studies on autoimmune hepatitis (AIH) in children are in predominantly Caucasian cohorts. Paediatric AIH in African Americans (AA) is understudied, with a dearth of clinical predictors of outcome, often leading to serious complications and even mortality. The aim of the study was to define disease presentation, progression, response to therapy and outcomes in paediatric AIH in a well‐defined, large, single centre, demographically diverse population. Methods We conducted a review of patients with AIH who were followed at this tertiary liver transplant centre. Clinical and laboratory covariates were assessed with regard to disease presentation, progression and outcomes in AA vs Non‐AA children. Results African Americans patients constituted 42% of this cohort. At 1‐year follow‐up, AA children were receiving significantly higher doses of steroids compared to non‐AA. More AA presented with end‐stage liver disease (ESLD) with high immunoglobulin G and GGT:platelet ratio. After adjusting for other risk factor variables like gender, age at presentation and ESLD, AA children were at 4.5 times higher risk for significant outcome liver transplant/death within the first 12 months of presentation. Post‐transplant, recurrent AIH was seen in 50% of AA vs 8% in non‐AA. Conclusions African American patients with AIH are more likely to present with ESLD and have an increased early risk for transplantation with high likelihood of disease recurrence post‐transplantation. Studies are needed to delineate factors such as inherent biology, genetics and access to care. Early referral and tailored immunosuppressive regimens are required for AA patients with AIH.