Amanda Ricciuto

The natural history of primary sclerosing cholangitis in 781 children: A multicenter, international collaboration

There are limited data on the natural history of primary sclerosing cholangitis (PSC) in children. We aimed to describe the disease characteristics and long‐term outcomes of pediatric PSC. We retrospectively collected all pediatric PSC cases from 36 participating institutions and conducted a survival analysis from the date of PSC diagnosis to dates of diagnosis of portal hypertensive or biliary complications, cholangiocarcinoma, liver transplantation, or death. We analyzed patients grouped by disease phenotype and laboratory studies at diagnosis to identify objective predictors of long‐term outcome. We identified 781 patients, median age 12 years, with 4,277 person‐years of follow‐up; 33% with autoimmune hepatitis, 76% with inflammatory bowel disease, and 13% with small duct PSC. Portal hypertensive and biliary complications developed in 38% and 25%, respectively, after 10 years of disease. Once these complications developed, median survival with native liver was 2.8 and 3.5 years, respectively. Cholangiocarcinoma occurred in 1%. Overall event‐free survival was 70% at 5 years and 53% at 10 years. Patient groups with the most elevated total bilirubin, gamma‐glutamyltransferase, and aspartate aminotransferase‐to‐platelet ratio index at diagnosis had the worst outcomes. In multivariate analysis PSC–inflammatory bowel disease and small duct phenotypes were associated with favorable prognosis (hazard ratios 0.6, 95% confidence interval 0.5‐0.9, and 0.7, 95% confidence interval 0.5‐0.96, respectively). Age, gender, and autoimmune hepatitis overlap did not impact long‐term outcome. Conclusion: PSC has a chronic, progressive course in children, and nearly half of patients develop an adverse liver outcome after 10 years of disease; elevations in bilirubin, gamma‐glutamyltransferase, and aspartate aminotransferase‐to‐platelet ratio index at diagnosis can identify patients at highest risk; small duct PSC and PSC–inflammatory bowel disease are more favorable disease phenotypes. (Hepatology 2017;66:518–527).

Symptoms Do not Correlate With Findings From Colonoscopy in Children With Inflammatory Bowel Disease and Primary Sclerosing Cholangitis

Background & Aims: Approximately 75% of children with primary sclerosing cholangitis (PSC) also have inflammatory bowel disease (IBD). IBD in patients with PSC (PSC‐IBD) often has a unique phenotype, including a mild clinical course, yet it is associated with an increased risk of colorectal cancer compared with colonic IBD without PSC. We investigated whether subclinical endoscopic and histologic inflammation could account for the increased risk of colorectal cancer in patients with PSC‐IBD, and whether these patients have increased fecal levels of calprotectin, a marker of inflammation. Methods: We performed a prospective study of children (age, <18 y) with colonic IBD with and without PSC who underwent colonoscopy from February 1, 2016, through March 31, 2017, at the Hospital for Sick Children in Toronto, Canada. We collected pediatric ulcerative colitis activity index (PUCAI) scores (to measure symptoms) and fecal levels of calprotectin from 37 children with PSC‐IBD and 50 children with only IBD (controls; UC or IBD‐unclassified). Colonoscopies were scored using the Mayo endoscopic subscore and the UC Endoscopic Index of Severity (UCEIS) scores, and histologic activity was graded. Among patients in clinical remission, endoscopic scores and the odds of active endoscopic disease (based on a UCEIS score ≥1) were compared between patients with and without PSC in univariate and multivariable analyses. Correlations between activity markers were compared between groups. The ability of fecal calprotectin to identify mucosal healing in patients with PSC‐IBD was assessed using receiver operating characteristic curve analyses. Analogous analyses were performed for histologic activity. Results: Patients with PSC‐IBD in clinical remission had higher endoscopic scores and greater odds of active endoscopic disease than controls (odds ratio, 5.9; 95% CI, 1.6–21.5). There was a higher degree of correlation between PUCAI and UCEIS scores in controls (r = 0.82) than in patients with PSC‐IBD (r = 0.51; P = .01). Fecal levels of calprotectin correlated with UCEIS in patients with PSC‐IBD (r = 0.84) and controls (r = 0.82; P = .80). Fecal levels of calprotectin identified mucosal healing in patients with PSC‐IBD with an area under the receiver operating characteristic curve of 0.94 (optimal cut‐point, 93 &mgr;g/g; 100% sensitivity and 92% specificity). Histologic activity scores and the odds of active histologic disease were also greater in patients in clinical remission with PSC‐IBD than controls. Conclusions: Children with PSC‐IBD in clinical remission, based on PUCAI scores, have a significantly higher risk of active endoscopic and histologic disease than children with colitis without PSC. Fecal levels of calprotectin correlate with endoscopic findings in pediatric patients with PSC‐IBD; levels below 93 &mgr;g/g are associated with mucosal healing.

Clinical Outcomes With Therapeutic Drug Monitoring in Inflammatory Bowel Disease: A Systematic Review With Meta-Analysis

Background and Aims We undertook a systematic review and meta-analysis examining the effectiveness of therapeutic drug monitoring [TDM] to improve clinical outcomes in inflammatory bowel disease patients treated with anti-tumour necrosis factor alpha [anti-TNF] drugs. Methods We searched MEDLINE, Epub Ahead of Print, EMBASE and Cochrane up to October 2017 for randomized trials [RCTs] and cohort studies comparing proactive or reactive TDM to each other or empiric care. Outcomes included clinical remission [primary], clinical relapse, endoscopic remission, anti-TNF response durability, cost and adverse events [secondary]. Pooled odds ratios and mean differences were calculated. Results The search identified nine studies [three RCTs, six observational], focused on infliximab maintenance therapy in adults. Neither proactive nor reactive TDM was associated with superior clinical remission rates compared to empiric dose optimization. However, evidence of a cost benefit, particularly for reactive TDM vs empiric care, was identified. In several studies, TDM, particularly proactive TDM, was associated with favourable outcomes related to durability of anti-TNF response, such as lower drug discontinuation rates compared to empiric care and reactive TDM, and lower relapse rates compared to empiric care. No consistent benefit was found for endoscopic or surgical outcomes. Conclusions The existing limited evidence does not support an association between any TDM strategy and superior clinical remission rates but does support a cost savings benefit [particularly for reactive TDM] and suggests a potential benefit for anti-TNF durability [particularly proactive TDM]. Additional, longer-term studies are needed, particularly to further investigate proactive TDM, and to generate data on other anti-TNF agents, the induction period and paediatric populations.

Gamma Glutamyltransferase Reduction Is Associated With Favorable Outcomes in Pediatric Primary Sclerosing Cholangitis

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.

The IBD and PSC Phenotypes of PSC-IBD

Purpose of reviewTo review the characteristics of IBD and PSC that occur in association, as well as their reciprocal influences on disease evolution, in adult and pediatric populations.Recent findingsIBD co-existing with PSC is genetically and clinically distinct from IBD alone. It is frequently characterized by pancolitis, rectal sparing, and possibly backwash ileitis, as well as a threefold increased risk of colorectal dysplasia. Adults and children with colitis and PSC appear to be at increased risk of active endoscopic and histologic disease in the absence of symptoms compared to individuals without PSC. PSC occurring with Crohn’s disease has been observed to be less severe than PSC co-existing with ulcerative colitis, independent of its association with small duct disease. Recent studies suggest that colectomy is associated with a decreased risk of recurrent PSC after liver transplantation, challenging the traditional teaching that PSC and IBD evolve independently.SummaryWhile much about the gut-liver axis in PSC-IBD remains poorly understood, the IBD associated with PSC has a unique phenotype, of which subclinical inflammation is an important component. Additional research is needed to characterize further the potentially protective role of colectomy against recurrent PSC post-liver transplantation and to investigate the influence of IBD control and/or colectomy on PSC progression.

An Unexpected Cause of Upper Gastrointestinal Bleeding in a Child.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 An Unexpected Cause of Upper Gastrointestinal Bleeding in a Child 56 57 58 59 60 Amanda Ricciuto,* Catharine M. Walsh,*,‡,§,k and Peter C. Church* *Division of Paediatric Gastroenterology, Hepatology and Nutrition, Department of Paediatrics, Learning Institute, kResearch Institute, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 e present an 11-year-old boy who was trans78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 Wferred to our institution after an upper gastrointestinal bleed. He initially presented to a community hospital after several episodes of hematemesis and melena, preceded by 2 days of epigastric pain. The child was previously well, except for pharyngitis treated with antibiotics a few weeks prior. There was no history of nonsteroidal anti-inflammatory use. On presentation, he was in shock, with a lactate level of 10 mmol/L, a white blood cell count of 40 10/L, a hemoglobin level of 170 g/L, and a glucose level of 23 mmol/L. He was fluid-resuscitated, started on antibiotics, and transferred to our tertiary center. On arrival, he continued to report abdominal pain and nausea. Vital signs were stable and the physical examination showed only abdominal tenderness, primarily epigastric, without peritoneal signs. The hemoglobin level decreased to 105 g/L over 24 hours before stabilizing. The lactate level, glucose level, and white blood cell count normalized over 3 to 4 days. Other notable laboratory findings included hypoalbuminemia (23 g/L), and increased urea level (8.7 mmol/L), amylase level (167 U/L), lipase level (121 U/L), C-reactive protein level (76 mg/L), and erythrocyte sedimentation rate (16 mm/h). Liver enzyme levels, bilirubin level, and coagulation factors were normal. Stool was negative for gastrointestinal pathogens. An abdominal ultrasound showed mild wall