Category Archives: Pediatric Gastroenterology Liver Disease

NPR: Children Missing Out on Hepatitis C Treatment

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From NPR: Children Missing Out on Hepatitis C Treatment

An excerpt:

A study by the Philadelphia Department of Health points to what Wen and others in the medical profession see as a worrisome trend: Children with hepatitis C may be unaware of their diagnosis and the potential need for treatments down the road in order to prevent long-term liver damage.

Using city surveillance data, the study found that as many as 8 in 10 children at high risk for hepatitis C exposure in Philadelphia were never screened for the condition. More specifically, of the approximately 500 moms-to-be who were registered as having hepatitis C between 2011 and 2013, only 84 of their newborns, or about 16 percent, were tested for the virus by 20 months of age.

My take: As the article discusses, with the advent of better treatments, which will be available for children (?next 1-2 years), identifying Hepatitis C acquired prenatally is becoming important.

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Rising HCV mortality

Preventing Neonatal Hepatitis B Transmission with Tenofovir

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A recent study (CQ Pan et al. NEJM 2016; 374: 2324-34) showed that tenofovir administered to mothers starting at 30-32 weeks of gestation lowered the rate of perinatal hepatitis B virus (HBV) acquisition.This was a multi center, open-label, randomized parallel-group design trial.  The maternal tenofovir dose was 300 mg.

Key points:

  • 200 mothers with HBeAg and HBV DNA >200,000 IU/mL in this study
  • 68% achieved an HBV DNA level <200,000 IU/mL (compared with 2% of controls).  Above this threshold has been shown to be associated with increased HBV transmission.
  • 5 of 97 (5%) in the treatment group acquired HBV compared to 18 of 100 in the control group.  However, in the per-protocol analysis which excluded infants born to women who withdrew consent, were lost to follow-up, or discontinued therapy there were 0 cases of transmission (0 of 88).
  • There were no specific safety signals identified in this study.  In the discussion, the authors note that the Antiretroviral Pregnancy Registry which includes data from 4013 women who received tenofovir, the rate of birth defects with TDF was 2.4% compared to the general population rate of 2.7%.

My take: This study provides more evidence that antivirals can prevent perinatal HBV infection.

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Screen Shot 2016-06-19 at 10.56.30 PM

Intellectual Disability in Pediatric Liver Transplantation

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A recent study (A Wightman et al. JPGN 2016; 62: 808-12) describes the prevalence of intellectual disability in a retrospective cohort from 2008-2013. The importance and the discomfort of the topic is referenced in the introduction:

  • “A 2005 survey of pediatric liver transplant programs (n=12) found that 33% of centers reported that cognitive disability was “always or usually” considered in their decision. No pediatric centers, however, considered mild or moderate cognitive disability alone (IQ 35-70) to be a relative or absolute contraindication to transplantation.”
  • The 2005 AASLD guideline states that “children with mental retardation pose significant logistical and ethical challenges” but does not comment on whether this is a contraindication.

This retrospective study of children who underwent an isolated liver transplant from 2008-2013 (n=254).

Key findings:

  • 15% of all first pediatric liver transplantation recipients have intellectual disability
  • Graft function and patient survival were similar among those with and without intellectual disabilities.  Metabolic disease, as the indication for liver transplantation, was the etiology more commonly among children with intellectual disability.

This study had numerous limitations.  Due to these limitations (eg. selection bias, lack of a standardized mechanism of measuring intellectual disability), it is likely that intellectual disability occurs more commonly than in 15% of pediatric liver transplant recipients. In fact, a previous study showed 42% of recipients required special education and 29% had IQ <85 (Cognitive Outcomes after Liver Transplantation | gutsandgrowth).

Related neurocognitive recommendations from the 2014 AASLD Pediatric Liver Transplantation Guidelines:

  • 28. “Neurocognitive testing should be performed in children awaiting LT to identify areas warranting early intervention to minimize later cognitive diffi- culties (2-B).”
  • 75, 76, and 92. LT is contraindicated with Alper’s disease, multiorgan mitochondrial disease, and Niemann-Pick type C.
  • In nearly 40 pages of recommendations, this guideline offers very little guidance on this topic.
AASLD 2014 Pediatric Transplantation Guidelines

AASLD 2014 Pediatric Transplantation Guidelines

Solitary Hepatic Nodule and Alagille Syndrome

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A retrospective study (A Alhammad et al. JPGN 2016; 62: 226-32) of 55 children from 1999-2014 examined the frequency of a solitary hepatic nodule adjacent to the right portal vein as a potential diagnostic finding for Alagille syndrome.  Only 39 had appropriate imaging to examine.

Key findings:

  • In 12 (of 39) focal hepatic lesions were evident (11 were solitary).
  • The median diameter was 8.1 cm.
  • In those with pathology review, the cases were suggestive of a regenerative nodule.
  • In all but one case, the alpha-fetoprotein levels were normal.
  • 10 of these lesions were adjacent to the right portal vein.

One other point from the discussion:

  • ~21% of patients with Alagille require liver transplantation, primarily for unremitting cholestasis and pruritus

My take: Recognition of this entity will help avoid mistaking this lesion for hepatocellular carcinoma.

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HeavenHellBillMurray

Changing Approach to Neonatal Acute Liver Failure

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A recent review (SA Taylor, PF Whittington. Liver Transplantation 2016; 22: 677-85) provides several important concepts for practitioners who may need to manage neonatal acute liver failure.

The most common etiologies (in parenthesis the approximate percentage of cases in their experience):

  • Gestational alloimmune liver disease (GALD) (60-90%)
  • Viral hepatitis (20-30%)-particularly HSV, followed by HHV-6, and rarely CMV
  • Hemophagocytic lymphohistiocytosis (HLH) (<10%)
  • Mitochondrial hepatopathy (<5%)
  • Rare causes include galactosemia, hereditary tyrosinemia type 1, and hereditary fructose intolerance. (<1%)  In addition, bile acid synthetic defect 5-beta-reductase deficiency can cause neonatal liver failure.

While INR ≥2.0 was used in the PALF studies as a primary defining feature of liver failure, since an INR of 2.0 can occur in the normal newborn, the authors recommend using an INR≥ 3.0 for neonatal liver failure.

Their Table 1 helps provide some important differences, Distinguishing features:

  • With GALD, ALT values are typically <100 due to underdeveloped hepatic parenchyma and ferritin is typically >800 and <7000.  IUGR is frequent (70-90%) as is hypoglycemia. Hepatosplenomegaly is uncommon.
  • With viral infections and HLH, ALT values are typically high, ferritin often very high, hepatosplenomegaly is common. IUGR is rare.
  • With mitochondrial disorders, ALT typically is between 100-500, ferritin levels are variable, and IUGR occurs in 20-30%.  A distinguishing feature is lactate: pyruvate ratio and ketone body ratios.
  • By thinking carefully about the reasons for liver failure in the neonatal period and not trying to examine for every possible liver disease, the use of these variables can expedite the evaluation and decrease the cost.  Genetic testing is not recommended due to the slow turnaround time, “and many diseases that are prominent causes of cholestatic disease …just do not cause NALF.”

With regard to treatment, the authors advocate use of IVIG if suspicion for GALD.  If workup (lip biopsy and/or MRI) confirms GALD then exchange transfusion and repeat IVIG is recommended.

My take: This reference should be helpful when managing a neonate with severe liver disease.

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Set from the Musical "Beautiful"

Set from the Musical “Beautiful”

Concise Review: Fatty Liver in Pediatrics

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A recent review (J Schwimmer. Hepatology 2016; 1718-25) provides a succinct up-to-date approach to the common problem of Nonalcoholic Fatty Liver Disease.

As this was a review, much of the material has been covered by this blog and previous publications.  The review discusses the upper limit of normal for alanine aminotransferase and its utility.  Liver imaging is discussed: “MRI is well suited for use in clinical research” whereas “ultrasound does not meet the standard clinical threshold required to be used to diagnose fatty liver…or used as an outcome measure.”

Dr. Schwimmer reviews a prospective study of 347 overweight or obese children with suspected NAFLD (blog review of this study: Screening for NAFLD).  He notes that 24% (n=61) of those who underwent liver biopsy ultimately had other diagnoses, especially autoimmune liver disease (n=11) and celiac disease (n=4). “The clinical challenge is to determine who needs how much of a workup. The greater potential for hepatotoxicity and the more advanced the disease is believed to be, the greater the need to be certain of the diagnosis and to properly grade and stage the disease.”  Currently, “no other diagnostic modality has shown sufficient accuracy to be appropriate for clinical use in the place of biopsy.”

He reviews associated health conditions with NAFLD including obesity, dyslipidemia, hypertension, cardiac dysfunction, and obstructive sleep apnea (~60% of NAFLD patients).

What about treatment? “There is not an available, proven, safe, and effective [pharmacologic] treatment for NAFLD in children…Current treatment is …focused on optimizing lifestyle, including nutrition, physical activity, and mental well-being.”

My take: Despite 20 years of clinical practice, the workup for NAFLD remains a vexing problem.  It is not practical to offer a liver biopsy to 10% of the pediatric population.  So determining who (besides those with more severe presentations) will benefit from an exhaustive workup remains unclear.  In the meanwhile, at a minimum, we need to keep looking for treatable liver conditions (eg. autoimmune hepatitis, celiac disease, Wilson’s disease, and viral hepatitis).

An article with a similar focus (Dr. Schwimmer is the corresponding author): J Pediatric 2016; 172: 9-13.  This report and Dr. Schwimmer’s review both tout the safety of liver biopsy.  Neither report presents much data on costs of either liver biopsies or MRI.

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Zoo Atlanta 2016

Zoo Atlanta 2016

 

What to Make of a Low Alkaline Phosphatase

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Every now and then I see a low alkaline phosphatase (ALP)–usually this is an inconsequential finding.  A recent study (V Saraff et al. J Pediatr 2016; 172: 181-6) provides insight into this problem.

In a retrospective study spanning 8 years, the authors identified 1526 samples from 323,064 which had an ALP <100 U/L.  Most of these were transient.  Only 18 were identified as having persistently low ALP.  In this group, 13 were tracked down. In this group, among four who had ongoing low ALP, two had mutations in the ALPL gene.

The authors propose, in Figure 3, how to manage a low ALP.  In those with an accurate ALP (not a degraded blood sample) and who were not chronically ill, they suggest looking for symptoms of hypophosphatasia:

  • respiratory failure
  • vitamin B6 responsive seizures
  • elevated calcium, phosphate and/or nephrocalcinosis
  • failure to thrive/short stature
  • fractures/bone pain
  • craniosynostosis
  • chest deformity
  • delayed walking, waddling gait
  • premature loss of teeth/late dentition

In those with likely hypophosphatasia, confirm with a pyridoxal-5′-phosphate and urinary phosphoethanolamine. If these are normal, hypophosphatasia is unlikely.  If these are elevated, the next step per the authors would be checking knee, lateral/AP skull.  If these are suggestive, then undergoing genetic testing is recommended or seeing a bone specialist.

In those with those who do not have symptoms of hypophosphatasia, the authors recommend checking for other causes.  Workup could include zinc, magnesium, thyroid function, blood counts, renal/liver assays, parathyroid hormone, vitamins B12/C/D, celiac serology, and ceruloplasmin.

My take: In those with persistently low alkaline phosphatase, keep this reference handy.

Related blog post (for high alkaline phosphatase): We still see this

Gibbs Gardens

Gibbs Gardens

What I did not know …a few items

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  1. 6-Mercaptopurine (6-MP) often can be used when patients are intolerant of azathioprine. S Hubener et al. Clin Gastroenterol Hepatol 2016; 14: 445-53.  This retrospective study showed that 15 of 20 patients with autoimmune hepatitis and prior azathioprine intolerance responded to 6-MP.  This is somewhat unexpected as azathioprine is metabolized into 6-MP.  However, rather than 6-thiouracil, the “imidazol component of azathioprine, which is cleaved off…might trigger adverse reactions.”  Another artical on thiopurines (Aliment Pharmacol Ther 2016; 43: 863-883) (thanks to Ben God for this reference) provides a thorough review of the pharmacogenetics and pharmocokinetics of these medications.  While this review reinforces the recommendation to check TPMT before treatment, it notes that only a small proportion of thiopurine toxicity is related to deficient TPMT activity.
  2. There is no formal validated or consensus definitions of mild, moderate, or severe IBD. L Peyrin-Biroulet et al. Clin Gastroenterol Hepatol 2016; 14: 348-54.  While the Lemann index measures the cumulative structural bowel disease, the authors propose criteria which involves three areas of severity: impact of the disease on the patient (eg. clinical symptoms), inflammatory burden (eg. biomarkers, mucosal disease, disease extent), and disease course (eg. structural disease, intestinal resection, perianal disease, extraintestinal manifestations)
  3. Fundic gland polyps (often associated with proton pump inhibitor therapy) are not premalignant lesions. There is an “inverse correlation between the FGPs and gastric neoplasia.” S Varghese et al. Gastroenterol Hepatol; 2016; 12: 153-4.
  4. Parents of newborns do not know how to use car seats.  BD Hoffman et al (J Pediatr 2016; 171: 48-54) showed that 95% of car seats were misused (291 families).  Serious misuse was present in 91%.

 

Related blog posts: Lemann index: Short Takes on IBD Articles | gutsandgrowth

Gibbs Gardens has >20 million daffodils

Gibbs Gardens has >20 million daffodils

Know Hepatitis B Campaign

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The CDC has launched a campaign to improve identification of Hepatitis B, particularly among Asian Americans.  Here’s the link: Know Hepatitis B Campaign

There are plenty of resources on this site.

Key fact:

“While Asian Americans make up about 5% of the total U.S. population, they account for half of the 2.2 million Americans living with chronic hepatitis B. In fact, one in 12 Asian Americans has hepatitis B.”

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What Happened to Skepticism re: Lipid Emulsion Position Paper

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A recent position paper (from ESPGHAN) (I Hojsak et al. JPGN 2016; 62: 776-92) made me wonder how different people can look at the same data and come to opposite conclusions.

In short, this article systemically reviews intravenous lipid emulsions and the risk of hepatotoxicity.  The review on the data is quite helpful.  The authors conclude that short-term use of the various emulsions currently in use do not result in a significant difference in neonates, infants and children.

The authors acknowledge that the data for long-term use of these emulsions is limited. They state that “there is evidence indicating that just tailoring and adjusting PN in children on long-term PN could improve liver disease, meaning that the focus should not only be on the type of ILE.”

“Although the quality of data are lacking there is some evidence that the use of multicomponent fish oil-containing ILE may contribute to a decrease” in liver toxicity.

What I don’t understand: The authors recommend: “it appears prudent to use multicomponent FO [fish oil]-containing ILE (GR C)” and literally the next sentence: “The present evidence base is inadequate to determine the optimal strategy for intravenous lipid supply.”

My take: I think we need to gather the data before having official position paper  recommendations.

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