A recent study (A Chandrakumar et al. J Pediatr 2019; 215: 144-51) followed 190 children with inflammatory bowel disease from 2011 to 2018 in a longitudinal population-based cohort in Manitoba and examined the development of primary sclerosing cholangitis (PSC). The diagnosis of PSC was made on discretion of the treating physician; thus, only a subset of patients underwent extensive evaluations for PSC.
- 9 developed PSC-UC (9/95) and overall 11 developed PSC-IBD (11/190)
- Among children with PSC-UC, 8 had high GGT (>50) at baseline and only 1 had a normal GGT at baseline.
- All UC patients who developed PSC were diagnosed withing 6 months of their UC diagnosis.
- At baseline, 22 patients with UC had an elevated GGT and 73 had a normal GGT. Thus, about one-third of patients with an elevated GGT developed PSC (possibly more as all patients were not subjected to extensive testing)
My view: This study reinforces two concepts: 1) GGT is valuable as a screening test 2) PSC (often asymptomatic) is fairly common in UC and needs to be considered especially in the first year of diagnosis. What this study does not do is help us figure out what should be done about children with asymptomatic PSC as there are no proven therapies.
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A recent clinical practice update (CL Bowlus et al. Clin Gastroenterol Hepatol 2019; 17: 2416-22) makes several recommendations on surveillance for hepatobiliary cancers in patients with primary sclerosing cholangitis (PSC).
Full Text Link: AGA Clinical Practice Update on Surveillance for Hepatobiliary Cancers in Patients With Primary Sclerosing Cholangitis: Expert Review
I will highlight the most important recommendation for pediatric hepatologists:
- Best practice advice 6: Surveillance for cholangiocarcinoma should not be performed in PSC patients with small-duct PSCs or those younger than age 20.
In the text, the authors note that “in pediatric PSC patients, cholangiocarcinoma is very rare, with only 8 of 781 (1%) …developing cholangiocarcinoma” (MR Deneau et al. Hepatology 2017; 66: 518-27)
Here are the other recommendations:
- Best practice advice 1 Surveillance for cholangiocarcinoma and gallbladder cancer should be considered in all adult patients with PSC regardless of disease stage, especially in the first year after diagnosis and in patients with ulcerative colitis and those diagnosed at an older age.
- Best practice advice 2 Surveillance for cholangiocarcinoma and gallbladder cancer should include imaging by ultrasound, computed tomography, or magnetic resonance imaging, with or without serum carbohydrate antigen 19-9, every 6 to 12 months
- Best practice advice 3 Endoscopic retrograde cholangiopancreatography with brush cytology should not be used routinely for surveillance of cholangiocarcinomas in PSC.
- Best practice advice 4 Cholangiocarcinomas should be investigated by endoscopic retrograde cholangiopancreatography with brush cytology with or without fluorescence in situ hybridization analysis and/or cholangioscopy in PSC patients with worsening clinical symptoms, worsening cholestasis, or a dominant stricture.
- Best practice advice 5 Fine-needle aspiration of perihilar biliary strictures should be used with caution in PSC patients considered to be liver transplant candidates because of concerns for tumor seeding if the lesion is a cholangiocarcinoma.
- Best practice advice 7 The decision to perform a cholecystectomy in PSC patients with a gallbladder polyp should be based on the size and growth of the polyp, as well as the clinical status of the patient, with the knowledge of the increased risk of gallbladder cancer in polyps greater than 8 mm.
- Best practice advice 8 Surveillance for hepatocellular carcinoma in PSC patients with cirrhosis should include ultrasound, computed tomography, or magnetic resonance imaging, with or without α-fetoprotein every 6 months.
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From The Onion
Link to full NASPGHAN 2019 Abstracts.
Here are some abstracts that I found interesting at this year’s NASPGHAN meeting:
- Off-label use of topiramate may be helpful in stabilizing weight and improving NAFLD
- Socioeconomic barriers are frequent in NAFLD patients (the 2nd poster did not appear to show a control population):
Primary Sclerosing Cholangitis -Use of Vedolizumab for PSC did not appear to help
- EoE is four times more likely in this cohort with inflammatory bowel disease
- 2nd poster describes very early-onset EoE
Inflammatory Bowel Disease:
- Use of infliximab in VEO IBD. Used in 46/122 (38% of patients) and 50% had persistent use 3 years later
Enteral nutrition –poster from our group describing good tolerance of plant-based formula (with Ana Ramirez).
Celiac disease. This poster indicates low yield of additional serology for celiac disease besides TTG IgA and serum IgA. This includes testing in young patients (< 2 years) with celiac disease.
A large retrospective study (M Deneau, M Perito, A Ricciuto, N Gupta et al. J Pediatr 2019; 209: 92-6) examined the outcomes/response of ursodeoxycholic acid (UDCA) for pediatric primary sclerosing cholangitis (PSC).
- “Within 10 years of diagnosis, 30% of children with PSC will require liver transplantation and 50% of children will develop complications, including biliary strictures and hypertension.”
- Because UDCA has not been shown to improve survival (& may worsen outcomes), it is not recommended in adults by the AASLD.
- In pediatrics, UDCA remains the most common treatment, used in more that 80% on long-term treatment
- 263 patients at 46 centers
- Median age 12.1 years
- UDCA median dose: 15 mg/kg/day
- Normalization of GGT (<50 IU/L) occurred in 46% of patients in the first year after diagnosis
- Patients with normalization was less likely among patients with Crohn’s disease and those with laboratory profiles indicative of more advanced hepatobiliary fibrosis (eg. lower platelet count, lower albumin, hyperbilirubinemia)
- The 5-year survival with native liver was 99% in those who achieved normalization vs 77% in those who did not
- Even in those without normalization, improvement in GGT was associated with better outcomes. “Those who had a reduction in GGT of >75% had nearly the same long-term survival as those with GGT<50 IU/L at 1 year.”
- It has previously been shown that nearly “one-third of children who are UDCA-naive have spontaneous GGT normalization by 1 year.” Thus, the number to treat with UDCA to have one additional case of GGT normalization is four.
- In a previous study, one-third of patients with GGT normalization on UDCA therapy for 1 year, maintained GGT <29 after withdrawal of UDCA for 12 weeks.
The authors note that “patients who do not achieve normalization could reasonably stop UDCA as they are likely not receiving clinical benefit.”
My take: This study shows that patients who have improvement/normalization of GGT with UDCA therapy have improved outcomes. The retrospective design of the study limits conclusions about whether UDCA therapy actually improves long-term outcomes, particularly since UDCA at higher doses has been associated with detrimental affects in adults with PSC.
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Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist. This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.
A recent study (O Olen et al. Gastroenterol 2019; 156: 614-22) was summarized quite succinctly by NEJM journal watch:
Using the Swedish National Patient Registry data, investigators identified 9442 incident cases of IBD diagnosed in patients under age 18 years from 1964 through 2014. Based on 139,000 person-years of follow-up, results were as follows:
- There were 259 deaths among people with IBD (133 were from cancer and 54 from digestive disease).
- The all-cause mortality rate in these patients was 2.1/1000 person-years, compared with 0.7 in matched reference individuals from the general population.
- The average age at death was 61.7 compared with 63.9 years in the reference group.
- The hazard ratio for death was 3.2 and was higher in those with ulcerative colitis (HR, 4.0), especially if they had concomitant primary sclerosing cholangitis (HR, 12.2), a first-degree relative with ulcerative colitis (HR, 8.3), or a history of surgery (HR, 4.6).
- Mortality risks were similar when limited to the period after the introduction of biologics (2002–2014).
My take: This study found that having IBD diagnosed in childhood increased the risk of mortality (~1 extra death for every 700 patients followed for 1 year) especially in patients with concomitant PSC and in patients with severe ulcerative colitis. The study did not see an effect of the newest therapies but was underpowered to directly assess this effect.
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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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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.”