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Journal of Pediatric Gastroenterology & Nutrition:
doi: 10.1097/MPG.0b013e31826abe97
Invited Commentaries

Heavy Breathing: A Step to Noninvasive Assessment of Hepatic Fibrosis and Function in Infants and Children

Narkewicz, Michael R.

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Department of Pediatrics, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Pediatric Liver Center, Children's Hospital Colorado, Aurora, CO.

Address correspondence and reprint requests to Michael R. Narkewicz, MD, Children's Hospital Colorado B290, 13123 East 16th Ave, Aurora, CO 80045 (e-mail:

Received 9 July, 2012

Accepted 19 July, 2012

The author reports no conflicts of interest.

See “Continuous13C-Methacetin Breath Test Differentiates Biliary Atresia From Other Causes of Neonatal Cholestasis” by Shteyer on page 60.

The search for noninvasive markers of hepatic fibrosis and function has a long and generally disappointing history. Recently, assessment of fibrosis with serum biomarkers, transient elastography, and advanced imaging with magnetic resonance imaging have shown potential in adults with chronic liver disease, primarily chronic hepatitis C (1,2). There are limited data for children and even less data for infants with liver disease. A major issue in pediatrics is that many of the diseases of infants and children have biliary fibrosis (biliary atresia, cystic fibrosis) and the results of adult studies do not readily translate to children. Assessment of hepatocyte function has been less successful.

Breath tests have been around for >2 decades. In general, they involve ingestion of a substance with a strategic stable label and measurement of the exhaled concentration of the labeled metabolite. Collection has generally required patient cooperation and the results were often delayed by many days. The most commonly used stable isotope breath test in pediatrics is probably the 13C-urease breath test for Helicobacter pylori(3). Recently, molecular correlation spectroscopy has become available. This technology allows continuous sampling of CO2 and determination of the ratio of 13CO2 to 12CO2. The ability to continuously sample exhaled breath and provide real-time results presents the potential to extend breath testing to infants and children.

In this issue of JPGN, Shteyer et al (4) present their pilot data on the use of the 13C-methacetin breath test using continuous in-line molecular correlation spectroscopy in 15 infants with cholestasis. These are the first data on the use of this technology in infants with liver disease. In their study, they used 13C-methacetin, a compound primarily metabolized by CYP1A2. They show that there are significant differences between the 8 infants with biliary atresia and 7 infants with other causes of neonatal cholestasis in the amount of 13CO2 recovered (percent dose recovered) and the time to the peak concentration of the 13CO2 recovered. They conclude that the 13C-methacetin breath test may help differentiate biliary atresia from other causes of neonatal cholestasis.

Some caution is needed in the interpretation of their findings. The 2 groups of infants had a dramatic difference in the degree of hepatic fibrosis. All of the patients with biliary atresia had significant fibrosis (grade 4–5), whereas the patients with neonatal cholestasis had virtually no fibrosis (grade 0–1). In the present study, hepatic fibrosis would likely have had the same specificity (100%) for biliary atresia. This is not unexpected given that the neonatal cholestasis group had infants with diseases that generally do not lead to early infantile hepatic fibrosis (neonatal cholestasis, cytomegalovirus hepatitis, HIV hepatitis, Alagille syndrome, Down syndrome with intrahepatic bile duct paucity, and progressive familial intrahepatic cholestasis type 2).

Thus, it may be that the 13C-methacetin breath test is a tool for the assessment of hepatic fibrosis or hepatic blood flow. For methacetin to be acted upon by CYP1A2, the compound must reach the hepatocyte. Changes in portal blood flow caused by portal hypertension or redistribution of lobular blood flow because of fibrosis or inflammation could clearly affect this process. Decreases in hepatocyte mass by ongoing acute or chronic injury could play a role. Alterations in CYP1A2 activity by inducers or inhibitors could confound interpretation.

Nevertheless, stable isotope tracing of hepatic metabolism using continuous breath sampling is a potentially valuable tool to assess hepatic fibrosis and function. I suspect that this approach will be most valuable in the longitudinal assessment of hepatic fibrosis and function in chronic pediatric liver diseases such as chronic viral hepatitis (B and C), cystic fibrosis liver disease, Alagille syndrome, and long-term liver transplant recipients. There is also a potential role in the assessment of rapidly changing hepatic function in acute liver failure.

There is still more to learn:

Are there age-related differences in the metabolism of methacetin? Is the dose used in the present study the best dose? Is 4 to 5 hours of fasting necessary and can the compound be delivered in a smaller volume?

We are entering a new era of noninvasive early assessment of hepatic fibrosis and function. Maybe we should all have our patients take a deep breath, exhale, and measure 13CO2.

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1. Castera L. Noninvasive methods to assess liver disease in patients with hepatitis B or C. Gastroenterology 2012; 142:1293–1302.

2. Schmeltzer PA, Talwalkar JA. Noninvasive tools to assess hepatic fibrosis: ready for prime time? Gastroenterol Clin North Am 2011; 40:507–521.

3. Guarner J, Kalach N, Elitsur Y, et al. Helicobacter pylori diagnostic tests in children: review of the literature from 1999 to 2009. Eur J Pediatr 2010; 169:15–25.

4. Shteyer E, Lalazar G, Hemed N, et al. Continuous 13C-methacetin breath test differentiates biliary atresia from other causes of neonatal cholestasis. J Pediatr Gastroenterol Nutr 2013;56:60–5.

Copyright 2013 by ESPGHAN and NASPGHAN


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