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Abstract

We thank Sciveres et al for the interest in our work and for the opportunity to respond to the issues raised. We described in a prospective study the use of large scale parallel genetic testing, exploiting the diagnostic potential of next generation sequencing (NGS) in neonatal and infantile cholestasis. The major and earliest crossroad was the stool color assessment. Sciveres et al commented on the use of liver biopsy and intraoperative cholangiogram to diagnose biliary atresia in patients with acholic stools. They claim that “the clinical finding of a hard hepatomegaly, strongly suggestive of biliary atresia, and a fasting sonography, in good hands, may reveal a combination of signs suggestive of biliary atresia, potentially avoiding the need of liver biopsy.” We respectfully disagree with this comment. The discussion on the best tests to diagnose biliary atresia has been on-going, and many centers have tried developing noninvasive diagnostic tool. Often this attitude is biased by the local unavailability of liver pathology expertise. In many centers (including ours), reviewing all pediatric liver histology samples with an expert pathologist, liver biopsy remains the most accurate tool to rule in biliary atresia, with direct cholangiography to confirm the diagnosis.1Yang J.G. Ma D.Q. Peng Y. Song L. Li C.L. Comparison of different diagnostic methods for differentiating biliary atresia from idiopathic neonatal hepatitis.Clin Imaging. 2009; 33: 439-446Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar,2Fawaz R. Baumann U. Ekong U. Fischler B. Hadzic N. Mack C.L. et al.Guideline for the evaluation of cholestatic jaundice in infants: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition.J Pediatr Gastroenterol Nutr. 2017; 64: 154-168Crossref PubMed Scopus (246) Google Scholar The same authors a few years back wrote a letter on a noninvasive scoring system adopted to diagnose biliary atresia, stating that in their experience the diagnostic accuracy of that approach was low.3Sciveres M. Milazzo M.P. Maggiore G. A scoring system for biliary atresia: is this the right one?.J Hepatol. 2015; 62: 985-986Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar The general approach in our specific setting is oriented at avoiding a missed diagnosis of biliary atresia. In our series, only 9% of the children who ultimately underwent explorative surgery did not have biliary atresia, which seems acceptable if we consider that a noninvasive prediction model published resulted in 19% false positive and 11% false negative for the diagnosis of biliary atresia.4Shneider B.L. Moore J. Kerkar N. Magee J.C. Ye W. Karpen S.J. et al.Initial assessment of the infant with neonatal cholestasis-Is this biliary atresia?.PLoS One. 2017; 12: e0176275Crossref PubMed Scopus (31) Google Scholar In our study, without a thorough approach, those infants (9%) would have missed the chance to undergo surgical correction. No case of biliary atresia was missed, thus, indicating that stool pigmentation alone has a high negative predictive value. On the other hand, NGS identified a genetic liver disorder in more than one-half of children without biliary atresia with pale stools. In the era of precision medicine, and in view of future trials on severe liver diseases of infancy, making a clear diagnosis is mandatory. We agree with Sciveres et al that a biochemical and microbiological work-up, as well as radiology investigations for Alagille syndrome (AGS), should ideally be performed earlier than liver biopsy. Nonetheless, in our real life experience, the patients were often referred late. As reported in the Methods section and in reference to Table II, we identified first-tier and second-tier tests to be performed before and after genetic testing, but we also specified that clinicians were free to perform relevant tests according to suspicion of a specific etiology or according to the availability of newborn screening. These tests, in the presence of pale stools, often were performed in parallel to liver biopsy. We did perform echocardiogram and spine radiography in all patients with suspected AGS, and all patients were referred to a clinical geneticist. In fact, out of 11 patients with AGS in our cohort, 7 were diagnosed through genetic testing, whereas the remaining 4 underwent invasive procedures because of stool depigmentation, in the presence of an incomplete phenotype, increasingly recognized in this disease. In conclusion, we still consider liver biopsy to be the best tool to rule in the diagnosis of biliary atresia. If coupled to clinical and biochemical pointers, NGS is able to rapidly and efficiently diagnose monogenic disorders causing neonatal/infantile cholestasis, provided extrahepatic causes have been primarily excluded. Diagnostic protocol of neonatal and infantile cholestasis: can it be improved?The Journal of PediatricsVol. 216PreviewNicastro et al proposes a diagnostic protocol for neonatal/infantile cholestasis, implemented by next-generation sequencing gene panels (NGSGP).1 This protocol targeted infants with “low-γGT cholestasis”2 and normal stools, identifying 8 monogenic liver disorders in 12 patients. 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