A recent study (A Ricciuto et al. Clin Gastroenterol Hepatol 2018; 16: 1098-1105) provides more data regarding the lack of symptom correlation and inflammatory bowel disease (IBD) activity in children with primary sclerosing cholangitis (PSC).
In a prospective study of children with colonic IBD with and without PSC, the authors followed clinical features (eg. PUCAI), fecal calprotectin and endoscopy severity.
- Patients with PSC-IBD (n=37) in clinical remission had higher endoscopic scores and greater odd of active endoscopic disease than IBD-only controls (n=50) (odds ratio 5.9, with CI 1.6-21.5)
- Fecal calprotectin level <93 mcg/g were identified mucosal healing with 100% sensitivity and 92% specificity when compared with UC Endoscopic Index of Severity (UCEIS)
Overall, this study is in agreement with a prior adult study showing higher levels of active disease in those with PSC-IBD compared to those with IBD alone, despite clinical remission (Why does PSC increase the risk of colorectal cancer in UC?).
My take: Particularly in individuals with the combination of IBD-PSC, objective biomarkers (eg. Calprotectin) are needed to identify the accuracy of clinical remission; though, even in patients with IBD without PSC, objective biomarkers are needed as well due to the limitations of clinical symptom indices.
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Moraine Lake, Banff
M Yakoot et al. JPGN 2018; 67: 86-89. This prospective, open-label, unblinded study from Egypt indicated that 29 of 30 (96.7%) pediatric (12-17 yr) patients with HCV (genotype 4) attained an SVR12 with sofusbuvir/daclatasvir. No serious adverse effects were evident. The one patient who did not achieve SVR12 was lost to followup but had viral negativity after completing treatment.
Related blog post: New HCV Treatment Effective in Adolescents –Important Study Now Published Online
O El-Sherif, ZG Jiang et al. Gastroenterol 2018; 154: 2111-21. This study showed that a “BE3A Score” based on BMI <25, no Encephalopathy, no Ascites, Albumin >3.5 and ALT >60 IU/L could be used to discriminate the likelihood of reducing the Child-Pugh-Turcotte (CPT) score to class A in patients with hepatitis C virus-associated decompensated cirrhosis who received DAA therapy. This retrospective analysis was based on 4 trials of a sofusbuvir-therapy with 502 CPT class B and 120 CPT class C patients.
AH Ali et al. Hepatology 2018; 67: 2338-51. This study convincingly shows that surveillance for hepatobiliary cancers improves outcomes in patients with primary sclerosing cholangitis. Among their cohort of 830 patients (Mayo clinic), 79 developed malignancies. Of those under surveillance (n=40), the 5-year survival was 68% compared to 20% for those who had not been under surveillance. While the true cynic might ascribe some of the difference to ‘lead-time’ bias, this is unlikely to account for this difference at 5 years.
F Aberg et al. Hepatology 2018; 67: 2141-49. This Finish-population prospective study, over an 11 year follow-up, using a nationally-representative cohort (n=6771) showed that even moderate alcohol consumption worsened outcomes (eg hepatic decompensation, hepatocellular carcinoma) in patients with nonalcoholic fatty liver disease. In addition, the authors showed that diabetes the most significant predictor of poor outcome (HR 6.79). In a related commentary, pg 2072-73, the authors state that this article “put an end to the ongoing ddebate whether moderate alcohol drinking (less than 20 g of alcohol/day or 2 drinks per day) could be helpful.”
C Sikavi et al. Hepatology 2018; 67: 847-57. This systematic review highlights that the combination of hepatitis C virus (HCV) infection and HIV infection is no longer a difficult-to-treat population with the implementation of direct-acting antivirals (DAAs). There are similar sustained virologic responses (SVRs) among those with and those without HIV. In clinical trials, patients with combined HCV-HIV had SVRs of 93.5-98% with DAA treatment; “real-world cohorts” had SVRs of 90.9%-98%.
MS Middleton et al. Hepatology 2018; 67: 858-72. Using data from the prospective CyNCh trial (cysteamine for NAFLD), the authors examined MRIs for diagnostic accuracy among 169 enrolled children. In this group, 110 (65%) and 83 (49%) had MRI and liver biopsy at baseline. MRI-PDFF (proton density fat fraction) was able to classify grade 1 steatosis from grade 2-3 steatosis with area under receiving operator characteristic curve of 0.87. Thus, this study shows MRI-estimated PDFF has high diagnostic accuracy.
G Mieli-Vergani et al. JPGN 2018; 66: 345-60. Position paper for Pediatric Autoimmune Liver Disease (AIH, ASC, de novo AIH after liver transplantation). This is a very useful review. A couple of pointers from the authors:
- “Present experience with budesonide as the first-line treatment is limited and does not appear to offer clear clinical advantage over the standard treatment”[prednisone]
- Fecal calprotectin should be obtained to evaluate for IBD in patients with autoimmune liver disease, “even in asymptomatic children.”
JM Cotter et al. JPGN 2018; 66: 227-33. This retrospective study with 39 patients with primary sclerosing cholangitis (PSC) showed a lack of correlation between liver tests and fibrosis at presentation. Average age of PSC diagnosis was 11.2 years, 74% had inflammatory bowel disease and 51% had autoimmune hepatitis. Related blog post: Big Pediatric PSC Study (with 781 children)
A recent retrospective study (Clin Gastroenterol Hepatol 2018; 16: 68-74) compared adult patients who had ulcerative colitis (UC) with (n=23) and without primary sclerosing cholangitis (n=120) (PSC). All patients had pancolitis and were in clinical remission.
- Patients with UC-PSC had more subclinical endoscopic activity (odds ratio (OR) 4.21) and histologic activity (OR 5.13) in the right colon compared with patients without PSC
It is known that the presence of PSC is a risk factor for colorectal cancer (CRC). A previous meta-analysis (RM Soetiknno et al. Gastrointest Endosc 2002; 56: 48-54) described a OR of CRC of 4.09.
My take: This study shows that UC patients with PSC who are in clinical remission have a greater degree of endoscopic and histologic inflammation in the proximal colon compared to patients without PSC. This increased inflammation is a likely factor in the increased risk for CRC.
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This blog entry has abbreviated/summarized this presentation. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well.
Improvement in GGT Predicts Event-free Survival in Primary Sclerosing Cholangitis Regardless of Ursodeoxycholic Acic Treatment.
Mark Deneau et al. (Grand Watkins Prize).
- PSC is difficult to study due to its rarity and due to its slow progression; thus surrogate biomarkers are needed.
- Alkaline phosphatase is not a good biomarker in children
- GGT level at one year after diagnosis was predictive of prognosis
- Ursodeoxycholic acid does not appear to be effective
Optimizing Nutrition in Intestinal Failure
Justine Turner, University of Alberta
- Human milk is an ideal “formula” for infants, including those with intestinal failure
- Oral feedings are important
- Combination of bolus feeds and continuous feeds is reasonable
- SMOFlipid allows higher lipid dose administration without hepatoxicity; this may improve cognitive outcomes
- Amino acid based formulas have higher osmolality which can contribute to diarrhea
Patients with >50% of small bowel and >50% of colon were most likely to achieve enteral autonomy (GIFT registry)
This blog entry has abbreviated/summarized these presentations. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well.
William Balistreri Prize: Katja Kovaic et al. Neurostimulation for functional abdominal pain disorders in children –a randomized, double-blind, sham-controlled trial. This study enrolled 104 patients. Lancet Gastroenterol Hepatol 2017; 2: 727-37.
Fellow Research Award: Symptoms Underestimate Endoscopic Activity in PSC-IBD. Amanda Ricciuto et al. Hospital for Sick Children.
- In patients with IBD-PSC, clinical remission based on clinical symptoms is not reliable indicator of histologic remission.
- Patients with PSC-IBD are more likely to have active endoscopic disease even when in “clinical remission”
- Calprotectin levels (not PUCAIs) are helpful in confirming clinical remission. A calprotectin <93 mcg/g was optimal level in determining clinical remission
- Better control of disease could improve clinical outcomes (eg. colon cancer, liver progression)
Keynote Address: Organoids: Current and future promise for changing treatment of gastrointestinal and liver disorders. James Wells Cincinnati Children’s Hospital Medical Center.
This was a terrific lecture.
- Example of use of pluripotent stem cell usage: Diabetes. Phase 1 study has been started.
- Organoids are in essence miniature versions of organs in a dish and with complex combination of cell types.
- Organoids allow easier testing on these tissues for treatment and diagnosis of diseases
- Organoids will allow for personalized testing of medications. Some patients will respond differently. This technology could be used to grow a specific organoid for a specific person and determine response on the organoid before giving to the patient.
- Can engraft organoids into mice which can provide blood supply and allow larger organoids.
- Clinical projects for organoids: Hirschsprung’s, H pylori, Clostridium difficile, Short bowel syndrome, Fatty liver disease
In July, this blog reviewed a recent big study of primary sclerosing cholangitis (PSC) in adults with more than 7000 patients. A recent study in the pediatric age group enrolled 781 children from 36 institutions: MR Deneau et al. Hepatology 2017; 66: 518-27 (Congratulations to Nitika Gupta and Miriam Vos -in-town colleagues and contributing authors to this study.)
This retrospective study’s key findings:
- Median age 12 years at diagnosis; 39% were female
- Autoimmune hepatitis (overlap) was present in 33%
- Small-duct PSC was present in 13%
- Inflammatory bowel disease (IBD) was present in 76%
- PSC-IBD and Small-duct PSC (normal cholangiograms) had more favorable prognosis with hazard ratio of 0.6 of developing complications
- Portal hypertensive and biliary complications were noted in 38% and 25% respectively. After developing these complications, the median survival with native liver was 2.8 years and 3.5 years respectively
- Survival with native liver was noted in 70% at 5 years and 53% at 10 years
- Elevations in bilirubin, GGT, and AST-to-platelet count ratio were associated with highest risk of progressive disease.
- Cholangiocarcinoma (CCA) developed in 1% (median, 6 years after diagnosis)
The discussion notes that while pediatric PSC is a progressive disease, complications were slower to develop compared with adult-onset PSC. 10-year survival with native liver is typically lower in adults ~60% (vs 70% in this study). “Up to one third of adults with PSC may have esophageal varices within a year of diagnosis” compared with only 13% in this cohort. Dominant strictures are more common in adults, occurring in the majority within 5 years whereas this occurred in 16% of this cohort.
With regard to CCA, the authors note that current recommendations suggest starting to screen for CCA in patients over age 18 years with ultrasound and CA 19-9 at 6-12 month intervals. These studies “could reasonably be extended to PSC patients aged 15 and above and [for those requiring dilatation] of biliary strictures.”
My take: This large pediatric PSC study provides more clarity on the outcomes of patient’s with PSC and the associated conditions.
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