Category Archives: Pediatric Gastroenterology Liver Disease

Landmark Study on Universal Screening for Biliary Atresia -It Works!

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S Harpavat et al. JAMA 2020; 323: 1141-50. Link:  Diagnostic Yield of Newborn Screening for Biliary Atresia Using Direct or Conjugated Bilirubin Measurements

This article provides details on how to improve the outcomes of children with biliary atresia by detecting cases at an earlier age.  The authors provide details on their 2-stage approach at near-universal screening of 124,385 infants in South Texas/Texas Medical Center from 2015-2018 and compare their results to a prior cohort.

Methods: The authors sought to have all infants have a fractionated bilirubin within the first 60 hours of life.  This information can easily be obtained due to preexisting policy of testing total bilirubin in this time-frame.  Those with any abnormal direct bilirubin or conjugated bilirubin had a 2nd stage screening at 2 weeks of life.  At stage 2, any infant with a direct bilirubin >1 mg/dL or higher than 1st stage were considered abnormal.  The stage 2 screening aligned with AAP-recommended 2 week check up. During the screening time-frame (2015-2018), 7 patients were identified with BA (one treated at outside institution), 7 more from nonstudy hospitals who had replicated protocol, and 6 referred due to clinical symptoms.

Key findings:

  • 7 infants with biliary atresia were detected with 100% sensitivity and 100% NPV. The PPV was 5.9% and specificity was 99.9%.  Due to the small number of infants identified, the confidence limits for sensitivity was 56%-100%.
  • During the first stage, 1354 infants (1.1%) had abnormal values. At stage 2, 119 had abnormal values (0.1% of initial cohort and 8.9% of those with 1st stage abnormalities).
  • Range of direct/conjugated bilirubins in those with eventual biliary atresia: Stage 1 —0.4-2.3,and Stage 2 —1.6-3.5
  • In the 2015-2018 time-frame, age at time of Kasai was lowered from 56 days to 36 days, P=.004.
    • The actual time between presentation to specialist to time of Kasai was unchanged ~12 days.
    • In the 2015-18 time-frame, 11 of 19 (58%) had Kasai at less than 30 days (optimal timing) compared to 3 of 24 in historical cohort.
  • Many (n=53) other cholestatic conditions were identified in the stage 2 cohort.  52.7% of abnormal stage 2 tests had no diagnosis determined.
    • Nine had cholestatic diseases: Alagille (n=4), A1AT (n=3), ABCB11 (n=1), Choledochal cyst (n=1).
    • Twelve were heterozygous for a liver disease.
    • Seventeen had conditions associated with neonatal cholestasis: Trisomy 21 (n=5), Trisomy 18 (n=3), portosystemic shunt (n=2), maternal lupus, omphalocele, and panhypopituitarism.
    • Eight had infections including CMV (n=3), and syphilis (n=3). Seven had excessive red blood cell turnover.
  • Many of those with abnormal stage 2 evaluations required minimal workup.  Additional fractionated bilirubin alone were needed for 28 (25%).
  • Premature infants were more likely to have abnormal screening.
  • Transplant-free survival at 1 year was greater in cohort during screening period: 94.7% vs. 70.8% with historical cohort (this did not reach statistical significance)

Discussion:

  • This 2-stage approach is much more promising than stool color cards.  These cards have shown some modest success in countries like Japan and Taiwan which have a national call center and standard 1-month checkups; however, even in these countries, age at time of Kasai were 60 days and 46 days respectively.
  • “The challenge specialists [and pediatricians] face was highlighted by an infant who had a true positive screening result in the study, but underwent the Kasai portoenterostomy at 75 days.”
  • The cost-effectiveness of this approach is unclear.

My take: The best chance for transplant-free survival in biliary atresia involves establishing an early diagnosis.  This study shows one way to accomplish this goal -nothing else has worked despite more than 30 years of trying.

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Online Aspen Webinar (Part 7) -Liver Organ Allocation

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Below I’ve included a few slides and some notes from recent Aspen Webinars; my notes may have errors of omission or transcription.

Key Points:

  • The new allocation policy tries to make liver organ allocation more equitable in terms of disease acuity at time of transplantation and access to allografts
  • The changes, based on some preliminary data, appear to improve the likelihood of children receiving needed organs. Dr. Bondoc specifically cited the work of Dr. John Bucuvalas in pointing out some of the systemic ways that the previous system disadvantaged children.
    • Infants are at the greatest risk on the wait list.  Yet, successful transplantation in children could be beneficial for many decades
    • PELD underestimates mortality risk
    • 25% of pediatric donors have historically gone to adults

 

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Online Aspen Webinar (Part 6) -NAFLD and NASH

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Aspen Online Webinar July  14-16, 2020

Below I’ve included some of my notes and slides.  There may be errors of omission or transcription.

What’s Hot? NAFLD and NASH Stavra Xanthakos

  • Fatty liver disease burden of NAFLD and NASH is increasing.  This increases the rate of cirrhosis, liver cancer and liver transplantation; the latter is being needed at younger ages
  • Explained that “Lean” (normal BMI) NAFLD is common
  • Diabetes is strongest risk factor for severe fatty liver disease (NASH or fibrosis). PNPLA3 is genetic risk factor for NAFLD risk.
  • Discussed treatment, particularly diet  and bariatric surgery.  Stated that some emerging treatments look promising.
  • In those with suspected NAFLD, Dr. Xanthokos recommends liver biopsy, if lifestyle therapy is ineffective, under specific circumstances: prior to bariatric surgery, in some cases to determine severity, and prior to instituting therapy (eg Vitamin E)

              

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Online Aspen Webinar (Part 5) -Biliary Atresia Diagnosis and Screening

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Online Webinar –Annual Aspen Conference  —July 14, 2000

Below I’ve included a few slides and some notes; my notes may have errors of omission or transcription.

Biliary Atresia -Prompt Diagnosis and Screening Ronald Sokol

Key Points:

  • We have NOT improved age of diagnosis in biliary atresia in the past 30 years
  • Uniform screening of fractionated bilirubin has been effective in Texas:  Diagnostic Yield of Newborn Screening for Biliary Atresia Using Direct or Conjugated Bilirubin Measurements S Harpavat et al. JAMA 2020; 323: 1141-50
  • Pale stools are usually NOT due to biliary atresia but should prompt investigation (eg. fractionated bilirubin)
  • MMP-7 may improve diagnostic approach; unclear if MMP-7 performs well in all populations (eg. prematurity)
  • Outcome key factors: age at diagnosis (goal less than 30-45 days) and surgeon/center

 

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Online Aspen Webinar (Part 4) -How to Treat Hepatitis C in Children

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Below I’ve included a few slides and some notes; my notes may have errors of omission or transcription.

How I Treat Children with Hepatitis C  William Balistreri

Key points:

  • The recommendations for pediatric hepatitis C infection have been rapidly-changing due to a large number of recent studies/new direct-acting antivirals.  There are many new treatment options (see HCVguidelines.org); currently available treatment regimens noted below
  • All children >3 years of age with HCV should be treated –high cure rates (91-100% SVR) and this leads to long-term improvements in health outcomes
  • Test for Hepatitis B before instituting DAA therapy
  • Universal screening has been recommended for all adults >18 years.  This omits the pediatric age group; however, if all pregnant women are screened, the majority of pediatric HCV infections could be identified

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Online Aspen Webinar (Part 3) -Primary Sclerosing Cholangitis

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Below I’ve included a few slides and some notes; my notes may have errors of omission or transcription.

Primary Sclerosing Cholangitis: Beyond Anecdotal Medicine  Jim Squires

Key points:

  • MMP-7 is emerging as better biomarker than alk phos or GGT
  • Patients with PSC-IBD often have PUCAI scores which underestimates severity of IBD activity. Even PSC-IBD patients in “clinical remission” often have disease activity.
  • PSC-IBD phenotype includes pancolitis (often with rectal sparing and backwash ileitis
  • Long-term prognosis is associated with level of GGT values
  • Prognosis: ~70% have event-free survival at 5 years
  • Adult prognosis models are inadequate due to frequent differences between disease in children and disease in adults.  Adults also have more comorbidities: obestiy, smoking, alcohol and medications
  • SCOPE index is a useful prognostic model for children (scores of 3 or less indicate very low risk of disease progression over next 5 years)
  • Actigall is current first line treatment in children based on biochemical improvement (no long term proof of efficacy); vancomycin has only anecdotal evidence of effectiveness

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Online Aspen Webinar (Part 2) -Abnormal Liver Enzymes in a Tween

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What Do Abnormal Liver Enzymes Mean in a Tween William Balistreri

Below I’ve included a few slides and some notes; my notes may have errors of omission or transcription.

Key Points:

  • Provided updated normal reference data for ALT/AST along with patterns of abnormalities
  • Reviewed step-wise workup for teenagers with elevated ALT/AST, particularly fatty liver disease and drug-induced liver disease
  • Increasingly frequent cause of fatty liver disease: psychotropic medications
  • Discussed role/indications of liver biopsy. Liver biopsy is NOT practical option for all children with fatty liver disease and elevated liver enzymes
  • However, ALT values tend to underestimate severity of liver disease

 

 

Online Aspen Webinar (Part 1)

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Online Webinar –Annual Aspen Conference  —July 14, 2000

Below I’ve included a few slides and some notes; my notes may have errors of omission or transcription.

Can We Skip Liver Biopsies in Infants with Cholestasis? Jim Squires

Key points:

  • Data suggest that cholestasis in infants needs to be defined as direct bilirubin/conjugated bilirubin >0.3 (if TB <5) or 10% if TB >5.
  • Identifying cholestasis is challenging as cholestasis occurs in ~1 in 2500 whereas jaundice occurs in 15% of all infants
  • Genetic testing (eg. Cholestasis Panel, or exome) needs to be moved up earlier in diagnostic algorithm, after ultrasound completed and after A1AT & biliary atresia considered

Related blog posts:

Not part of webinar:

More School Advice for Organ Transplant Recipients, Plus Another Benefit of the Influenza Vaccine

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Link to PDF (from Pediatric Infectious Disease Society:

FAQs Regarding Return to School for Children after Solid Organ Transplant in the United States During the COVID-19 Pandemic

Some excerpts:

Are pediatric SOT recipients at higher risk for getting COVID-19 compared with other children?
Children of any age can get COVID-19, but they seem to have milder disease than adults. Pediatric SOT recipients do not seem to get COVID-19 more often than other children.

If infected with COVID-19, are pediatric SOT recipients at higher risk for developing severe disease or complications?

Based on experience with other viruses, and from reports of COVID-19 in adult SOT patients, there are a few things that may increase the risk of severe COVID-19. These include:
1) Having undergone transplantation in the last 3-6 months
2) Receiving high doses of immunosuppression (such as for treatment of rejection)
3) Having other medical problems such as diabetes, obesity, or certain lung conditions (refer to CDC website under Helpful Resources for more details)
It is not known if the above factors also put children with SOT at risk. In fact, of all the reports among pediatric SOT recipients with COVID-19 published so far, the majority have had mild symptoms and recovered.

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Renal Disease Associated With Fatty Liver Disease & Dexamethasone-COVID-19 Data

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Looking for and managing hypertension has been an important component of care in children and adults with nonalcoholic fatty liver disease (NAFLD)/metabolic syndrome.  In addition, hypertension is frequently associated with renal impairment.

As such, it is perhaps not surprising that in both adults and children, there is a high rate of renal impairment.   The data in children is much more sparse than in adults.  A recent retrospective pediatric cohort study (T Yodoshi et al. J Pediatr 2020; 222: 127-33) adds more information to this problem.

More background information:

  • Chronic kidney disease is highly prevalent in adults with NAFLD: 20-55% (J Hepatol 2020; 72: 785-801; Am J Kidney Dis 2014; 64: 638-52)
  • NAFLD is currently the leading indication for concurrent liver and kidney transplantation
  • In adults, the severity of NAFLD histology is associated with renal impairment
  • The first stage of renal impairment is glomerular hyperfiltration. This is hypothesized to be a precursor of intraglomerular hypertension which leads to albuminuria and glomerular filtration rate (GFR) decline/progressive renal dysfunction
  • Early intervention in high risk patients with angiotensin receptor inhibitors may prevent or delay progressive renal disease

Key findings in 179 patients with biopsy-confirmed NAFLD:

  • 82% non-Hispanic, median age 14 yrs
  • 36 (20%) had glomerular hyperfiltration and 26 (15%) had low GFR (w/in 3 months of liver biopsy) based on Schwartz equation
  • Hyperfiltration was independently associated with higher NAFLD activity score (aOR 2.96)

Discussion:

  • Mechanism: The authors speculate that “it is possible that they [renal and liver disease] are both the end result of the same ‘hit.’ The renin-angiotensin system may play a key role….Notably, there is an ongoing…clinical trial investigating an ATI receptor blocker, losartan, for the treatment of NAFLD in children.” Other potential contributors include fructose and insulin resistance.
  • Limitations: This single center biopsy-confirmed population may not be representative of most children with NAFLD.  Also, as this was a retrospective study, more precise measures of renal function were not available.

My take: This study confirms a high rate of renal dysfunction (35%) in children with NAFLD. As such:

  • Children with NAFLD need to have their blood pressure monitored
  • Clinicians should have a low threshold for nephrology referral if suspected renal impairment.

NEJM Recovery Collaborative Group: July 17, 2020
DOI: 10.1056/NEJMoa2021436: Full Link: Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report

Form NEJM Journal blog:

In the open-label RECOVERY trial, some 2100 U.K. patients hospitalized with COVID-19 were randomized to usual care plus oral or intravenous dexamethasone (6 mg once daily for up to 10 days), and 4300 were randomized to usual care alone.

Among patients on invasive mechanical support at the time of randomization, the mortality rate within 28 days was significantly lower with dexamethasone than with usual care alone (29% vs. 41%). A benefit was also seen among those on oxygen without invasive ventilation (23% vs. 26%). However, among patients not receiving respiratory support, mortality rates did not differ significantly between treatment groups.