- Email: [email protected]
Reply to: “A diagnostic score for biliary atresia”
Letters to the Editor
A diagnostic score for biliary atresia To the Editor: We read with great interest the paper by El-Guindi et al. [1], evaluating a new diagnostic score for biliary atresia (BA). BA is a destructive inflammatory obliterative cholangiopathy of unknown origin that affects intra- and extrahepatic bile ducts. Success of surgical correction, in form of a Kasai portoenterostomy amongst other factors, depends on early diagnosis and timely intervention. Presently, there are no non-invasive diagnostic methods that can clearly identify infants with BA from other causes of neonatal cholestasis (NC). The current paradigm to exclude BA in any cholestatic infant hence requires evidence to prove patency of the extrahepatic bile duct [2–5]. To date, many research groups have tried to improve the differential diagnosis [6] but none has yet reached sensitivity and specificity as high as in the present study. We are convinced that elements of the proposed scoring may help in the pre-selection of infants to undergo imaging of the extrahepatic bile duct. However we are concerned that the study cohort of patients investigated might be skewed, thus limiting the diagnostic power of this score. (1) Entry criteria did not describe if there were children with drug- or total parenteral nutrition-associated cholestasis or premature infants in the study population. (2) There was no information whether there were children with the syndromic form of BA, with biliary stones, dilatation of bile ducts or choledochal cysts in the study cohort. (3) Important and common causes of NC, such as alpha-1 antitrypsin deficiency, cystic fibrosis, bile acid synthetic disorders, tyrosinemia type 1, galactosemia and hypopituitarism were not identified. (4) Normal or low values of gamma-glutamyl transpeptidase (GGT) in a child with NC imply a defect of bile excretion at the canalicular level. So it was not surprising that in the group of non-BA patients the level of GGT was lower than in the BA group. There was no information about the type of the progressive familial intrahepatic cholestasis (PFIC I or II) and whether the multi-drug resistance protein 3 (MDR3) was examined. A variety of diseases can exactly mimic all separate features of BA and only systematic evaluation of the entire spectrum will lead to a reliable diagnosis. Only innovative tools, such as next
generation sequencing, may possibly change this and contribute to a differential diagnosis in the future. Easy diagnosis of BA has been on the agenda for decades. But, despite all efforts, as long as we still do not understand the aetiology and triggering factors of BA we remain at risk of missing the correct diagnosis for a child with NC just based on non-invasive diagnostics.
Conflict of interest The authors declared that they do not have anything to disclosure regarding funding or conflict of interest with respect to this manuscript. References [1] El-Guindi MA, Sira MM, Sira AM, Salem TA, El-Abd OL, Konsowa AS, et al. Design and validation of a diagnostic score for biliary atresia. J Hepatol 2014;61:116–123. [2] Petersen C, Meier PN, Schneider A, Turowski C, Pfister ED, Manns MP, et al. Endoscopic retrograde cholangiopancreaticography prior to explorative laparotomy avoids unnecessary surgery in patients suspected for biliary atresia. J Hepatol 2009;51:1055–1060. [3] Shteyer E, Wengrower D, Benuri-Silbinger I, Gozal D, Wilschanski M, Goldin E. Endoscopic retrograde cholangiopancreatography in neonatal cholestasis. J Pediatr Gastroenterol Nutr 2012;55:142–145. [4] Kianifar HR, Tehranian S, Shojaei P, Adinehpoor Z, Sadeghi R, Kakhki VR, et al. Accuracy of hepatobiliary scintigraphy for differentiation of neonatal hepatitis from biliary atresia: systematic review and meta-analysis of the literature. Pediatr Radiol 2013;43:905–919. [5] Lee MJ, Kim MJ, Yoon CS, Chung YE, Han SJ, Koh H. Gadopentetate dimeglumine-enhanced MR cholangiopancreatography in infants with cholestasis. Pediatric Radiol 2011;41:488–494. [6] Sun S, Chen G, Zheng S, Xiao X, Xu M, Yu H, et al. Analysis of clinical parameters that contribute to the misdiagnosis of biliary atresia. J Pediatr Surg 2013;48:1490–1494.
⇑
Eva-Doreen Pfister Claus Petersen Joachim Kübler Ulrich Baumann Pediatric Gastroenterology and Hepatology, Pediatric Surgery, Hannover Medical School, Hannover, Germany ⇑Corresponding author. E-mail address: Pfi[email protected]
Reply to: ‘‘A diagnostic score for biliary atresia’’ To the Editor: We appreciate the interest of Pfister et al. in our recent study [1] and would like to comment on the issues raised in their letter. 1440
Although the concerns that were raised by Pfister et al. are interesting, none is related to the applicability of the BA score as the recruitment in our study was consecutive for all cases
Journal of Hepatology 2014 vol. 61 j 1438–1452
JOURNAL OF HEPATOLOGY with neonatal cholestasis except for those with contraindications to liver biopsy. For that reason, we did not go through such recruitment details in our article. None of the patients was preterm and diagnoses were as described in the article. Causes like alpha-1 antitrypsin, cystic fibrosis and hypopituitarism were not proven in our study population. In the validation group, diagnoses like galactosemia, tyrosinemia, cytomegalovirus induced hepatitis, biliary paucity and progressive familial intrahepatic cholestasis (PFIC) were confirmed by completing the workup after being allocated earlier by the score as non-BA. The PFIC patients, diagnosed in our study, were of type 3 with high gammaglutamyl transpeptidase (GGT) levels and negative hepatic immunostaining for multidrug resistance protein 3 and none were type PFIC1 or 2. In accordance with our recent reports [2–4], earlier studies [5–8] also reported that GGT levels differ significantly and can be used in discriminating BA from non-BA cases. So, we agree with Pfister et al. that such difference should not be surprising.
Conflict of interest The authors declare that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. References
[2] El-Guindi MA, Sira MM, Konsowa HA, El-Abd OL, Salem TA. Value of hepatic subcapsular flow by color Doppler ultrasonography in the diagnosis of biliary atresia. J Gastroenterol Hepatol 2013;28:867–872. [3] Ghoneim EM, Sira MM, Abd Elaziz AM, Khalil FO, Sultan MM, Mahmoud AB. Diagnostic value of hepatic intercellular adhesion molecule-1 expression in Egyptian infants with biliary atresia and other forms of neonatal cholestasis. Hepatol Res 2011;41:763–775. [4] Sira MM, El-Guindi MA, Saber MA, Ehsan NA, Rizk MS. Differential hepatic expression of CD56 can discriminate biliary atresia from other neonatal cholestatic disorders. Eur J Gastroenterol Hepatol 2012;24:1227–1233. [5] Liu CS, Chin TW, Wei CF. Value of gamma-glutamyl transpeptidase for early diagnosis of biliary atresia. Zhonghua Yi Xue Za Zhi 1998;61:716–720. [6] Sinatra FR. The role of gamma-glutamyl transpeptidase in the preoperative diagnosis of biliary atresia. J Pediatr Gastroenterol Nutr 1985;4:167–168. [7] Vajaradul C, Vanprapar N, Chuenmeechow T, Ongajyooth S. Use of serum gamma glutamyl transpeptidase to differentiate between extrahepatic biliary atresia and neonatal hepatitis. J Med Assoc Thai 1989;72:395–399. [8] Wright K, Christie DL. Use of gamma-glutamyl transpeptidase in the diagnosis of biliary atresia. Am J Dis Child 1981;135:134–136.
Mohamed Abdel-Salam El-Guindi ⇑ Mostafa Mohamed Sira Ahmad Mohamed Sira Tahany Abdel-Hameed Salem Department of Pediatric Hepatology, National Liver Institute, Menofiya University, Shebin El-koom, Menofiya, Egypt ⇑Corresponding author. Address: Department of Pediatric Hepatology, National Liver Institute, Menofiya University, 32511 Shebin El-koom, Menofiya, Egypt. Tel.: +20 48 222 2740; fax: +20 48 223 4586. E-mail address: [email protected]
[1] El-Guindi MA, Sira MM, Sira AM, Salem TA, El-Abd OL, Konsowa HA, et al. Design and validation of a diagnostic score for biliary atresia. J Hepatol 2014; 61:116–123.
Scoring system in diagnosing biliary atresia To the Editor: We read with great interest the article by El-Guindi et al. [1] who propose a diagnostic scoring system for biliary atresia (BA), including clinical, laboratory, ultrasonographic, and histopathological parameters. They conclude that the scoring system could discriminate BA from other causes of neonatal cholestasis with a sensitivity, specificity and accuracy of 100%, 97.67%, and 98.83%, respectively, in the validation set. Thus, unnecessary intraoperative cholangiography can be avoided in non-BA patients. Although we appreciate their impressive findings, we would raise a few issues. First, it is known that hepatobiliary scintigraphy is an important diagnostic modality for neonatal cholestasis and phenobarbital-enhanced hepatobiliary scintigraphy (PEHS) is considered to be the most sensitive, non-invasive diagnostic method for BA [2,3]. Two decades of experience at one tertiary centre demonstrated that PEHS was 100% sensitive, 93.0% specific, and 94.6% accurate in diagnosing BA [3]. Experience at another centre demonstrated that 99mTc-EHIDA hepatobiliary scintigraphy in combination with duodenal fluid examination had both a sensitivity and specificity of 100% [4]. Thus, hepatobiliary scintigraphy is a
non-invasive, safe, and accurate method for differential diagnosis of BA and other causes of neonatal cholestasis [3,5]. Unfortunately, the present study did not incorporate hepatobiliary scintigraphy in obtaining a diagnostic score for BA. Thus, the lack of this important imaging parameter might be responsible for the false positivity in one of the patients who was wrongly diagnosed with BA by the scoring system. Second, although liver biopsy appears to be an important diagnostic steps in the evaluation of BA, which may be safely performed in small infants, it is undeniably an invasive procedure associated with several adverse events and complications, such as pain, bleeding, and even death [6]. Moreover, liver biopsy is limited by sampling errors and observer variability, with possibility of omissions and false-positive or false-negative results. Thus, liver biopsy should be avoided whenever possible, and hepatobiliary scintigraphy, especially PEHS, may take the place of liver biopsy in the diagnosis of BA [3,5]. Finally, the sample size was relatively small in the present study, and thus, validation of the scoring system in a large cohort of patients is essential before the scoring system can be used in clinical practice. We recommend that the scoring system be
Journal of Hepatology 2014 vol. 61 j 1438–1452
1441
A diagnostic score for biliary atresia To the Editor: We read with great interest the paper by El-Guindi et al. [1], evaluating a new diagnostic score for biliary atresia (BA). BA is a destructive inflammatory obliterative cholangiopathy of unknown origin that affects intra- and extrahepatic bile ducts. Success of surgical correction, in form of a Kasai portoenterostomy amongst other factors, depends on early diagnosis and timely intervention. Presently, there are no non-invasive diagnostic methods that can clearly identify infants with BA from other causes of neonatal cholestasis (NC). The current paradigm to exclude BA in any cholestatic infant hence requires evidence to prove patency of the extrahepatic bile duct [2–5]. To date, many research groups have tried to improve the differential diagnosis [6] but none has yet reached sensitivity and specificity as high as in the present study. We are convinced that elements of the proposed scoring may help in the pre-selection of infants to undergo imaging of the extrahepatic bile duct. However we are concerned that the study cohort of patients investigated might be skewed, thus limiting the diagnostic power of this score. (1) Entry criteria did not describe if there were children with drug- or total parenteral nutrition-associated cholestasis or premature infants in the study population. (2) There was no information whether there were children with the syndromic form of BA, with biliary stones, dilatation of bile ducts or choledochal cysts in the study cohort. (3) Important and common causes of NC, such as alpha-1 antitrypsin deficiency, cystic fibrosis, bile acid synthetic disorders, tyrosinemia type 1, galactosemia and hypopituitarism were not identified. (4) Normal or low values of gamma-glutamyl transpeptidase (GGT) in a child with NC imply a defect of bile excretion at the canalicular level. So it was not surprising that in the group of non-BA patients the level of GGT was lower than in the BA group. There was no information about the type of the progressive familial intrahepatic cholestasis (PFIC I or II) and whether the multi-drug resistance protein 3 (MDR3) was examined. A variety of diseases can exactly mimic all separate features of BA and only systematic evaluation of the entire spectrum will lead to a reliable diagnosis. Only innovative tools, such as next
generation sequencing, may possibly change this and contribute to a differential diagnosis in the future. Easy diagnosis of BA has been on the agenda for decades. But, despite all efforts, as long as we still do not understand the aetiology and triggering factors of BA we remain at risk of missing the correct diagnosis for a child with NC just based on non-invasive diagnostics.
Conflict of interest The authors declared that they do not have anything to disclosure regarding funding or conflict of interest with respect to this manuscript. References [1] El-Guindi MA, Sira MM, Sira AM, Salem TA, El-Abd OL, Konsowa AS, et al. Design and validation of a diagnostic score for biliary atresia. J Hepatol 2014;61:116–123. [2] Petersen C, Meier PN, Schneider A, Turowski C, Pfister ED, Manns MP, et al. Endoscopic retrograde cholangiopancreaticography prior to explorative laparotomy avoids unnecessary surgery in patients suspected for biliary atresia. J Hepatol 2009;51:1055–1060. [3] Shteyer E, Wengrower D, Benuri-Silbinger I, Gozal D, Wilschanski M, Goldin E. Endoscopic retrograde cholangiopancreatography in neonatal cholestasis. J Pediatr Gastroenterol Nutr 2012;55:142–145. [4] Kianifar HR, Tehranian S, Shojaei P, Adinehpoor Z, Sadeghi R, Kakhki VR, et al. Accuracy of hepatobiliary scintigraphy for differentiation of neonatal hepatitis from biliary atresia: systematic review and meta-analysis of the literature. Pediatr Radiol 2013;43:905–919. [5] Lee MJ, Kim MJ, Yoon CS, Chung YE, Han SJ, Koh H. Gadopentetate dimeglumine-enhanced MR cholangiopancreatography in infants with cholestasis. Pediatric Radiol 2011;41:488–494. [6] Sun S, Chen G, Zheng S, Xiao X, Xu M, Yu H, et al. Analysis of clinical parameters that contribute to the misdiagnosis of biliary atresia. J Pediatr Surg 2013;48:1490–1494.
⇑
Eva-Doreen Pfister Claus Petersen Joachim Kübler Ulrich Baumann Pediatric Gastroenterology and Hepatology, Pediatric Surgery, Hannover Medical School, Hannover, Germany ⇑Corresponding author. E-mail address: Pfi[email protected]
Reply to: ‘‘A diagnostic score for biliary atresia’’ To the Editor: We appreciate the interest of Pfister et al. in our recent study [1] and would like to comment on the issues raised in their letter. 1440
Although the concerns that were raised by Pfister et al. are interesting, none is related to the applicability of the BA score as the recruitment in our study was consecutive for all cases
Journal of Hepatology 2014 vol. 61 j 1438–1452
JOURNAL OF HEPATOLOGY with neonatal cholestasis except for those with contraindications to liver biopsy. For that reason, we did not go through such recruitment details in our article. None of the patients was preterm and diagnoses were as described in the article. Causes like alpha-1 antitrypsin, cystic fibrosis and hypopituitarism were not proven in our study population. In the validation group, diagnoses like galactosemia, tyrosinemia, cytomegalovirus induced hepatitis, biliary paucity and progressive familial intrahepatic cholestasis (PFIC) were confirmed by completing the workup after being allocated earlier by the score as non-BA. The PFIC patients, diagnosed in our study, were of type 3 with high gammaglutamyl transpeptidase (GGT) levels and negative hepatic immunostaining for multidrug resistance protein 3 and none were type PFIC1 or 2. In accordance with our recent reports [2–4], earlier studies [5–8] also reported that GGT levels differ significantly and can be used in discriminating BA from non-BA cases. So, we agree with Pfister et al. that such difference should not be surprising.
Conflict of interest The authors declare that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. References
[2] El-Guindi MA, Sira MM, Konsowa HA, El-Abd OL, Salem TA. Value of hepatic subcapsular flow by color Doppler ultrasonography in the diagnosis of biliary atresia. J Gastroenterol Hepatol 2013;28:867–872. [3] Ghoneim EM, Sira MM, Abd Elaziz AM, Khalil FO, Sultan MM, Mahmoud AB. Diagnostic value of hepatic intercellular adhesion molecule-1 expression in Egyptian infants with biliary atresia and other forms of neonatal cholestasis. Hepatol Res 2011;41:763–775. [4] Sira MM, El-Guindi MA, Saber MA, Ehsan NA, Rizk MS. Differential hepatic expression of CD56 can discriminate biliary atresia from other neonatal cholestatic disorders. Eur J Gastroenterol Hepatol 2012;24:1227–1233. [5] Liu CS, Chin TW, Wei CF. Value of gamma-glutamyl transpeptidase for early diagnosis of biliary atresia. Zhonghua Yi Xue Za Zhi 1998;61:716–720. [6] Sinatra FR. The role of gamma-glutamyl transpeptidase in the preoperative diagnosis of biliary atresia. J Pediatr Gastroenterol Nutr 1985;4:167–168. [7] Vajaradul C, Vanprapar N, Chuenmeechow T, Ongajyooth S. Use of serum gamma glutamyl transpeptidase to differentiate between extrahepatic biliary atresia and neonatal hepatitis. J Med Assoc Thai 1989;72:395–399. [8] Wright K, Christie DL. Use of gamma-glutamyl transpeptidase in the diagnosis of biliary atresia. Am J Dis Child 1981;135:134–136.
Mohamed Abdel-Salam El-Guindi ⇑ Mostafa Mohamed Sira Ahmad Mohamed Sira Tahany Abdel-Hameed Salem Department of Pediatric Hepatology, National Liver Institute, Menofiya University, Shebin El-koom, Menofiya, Egypt ⇑Corresponding author. Address: Department of Pediatric Hepatology, National Liver Institute, Menofiya University, 32511 Shebin El-koom, Menofiya, Egypt. Tel.: +20 48 222 2740; fax: +20 48 223 4586. E-mail address: [email protected]
[1] El-Guindi MA, Sira MM, Sira AM, Salem TA, El-Abd OL, Konsowa HA, et al. Design and validation of a diagnostic score for biliary atresia. J Hepatol 2014; 61:116–123.
Scoring system in diagnosing biliary atresia To the Editor: We read with great interest the article by El-Guindi et al. [1] who propose a diagnostic scoring system for biliary atresia (BA), including clinical, laboratory, ultrasonographic, and histopathological parameters. They conclude that the scoring system could discriminate BA from other causes of neonatal cholestasis with a sensitivity, specificity and accuracy of 100%, 97.67%, and 98.83%, respectively, in the validation set. Thus, unnecessary intraoperative cholangiography can be avoided in non-BA patients. Although we appreciate their impressive findings, we would raise a few issues. First, it is known that hepatobiliary scintigraphy is an important diagnostic modality for neonatal cholestasis and phenobarbital-enhanced hepatobiliary scintigraphy (PEHS) is considered to be the most sensitive, non-invasive diagnostic method for BA [2,3]. Two decades of experience at one tertiary centre demonstrated that PEHS was 100% sensitive, 93.0% specific, and 94.6% accurate in diagnosing BA [3]. Experience at another centre demonstrated that 99mTc-EHIDA hepatobiliary scintigraphy in combination with duodenal fluid examination had both a sensitivity and specificity of 100% [4]. Thus, hepatobiliary scintigraphy is a
non-invasive, safe, and accurate method for differential diagnosis of BA and other causes of neonatal cholestasis [3,5]. Unfortunately, the present study did not incorporate hepatobiliary scintigraphy in obtaining a diagnostic score for BA. Thus, the lack of this important imaging parameter might be responsible for the false positivity in one of the patients who was wrongly diagnosed with BA by the scoring system. Second, although liver biopsy appears to be an important diagnostic steps in the evaluation of BA, which may be safely performed in small infants, it is undeniably an invasive procedure associated with several adverse events and complications, such as pain, bleeding, and even death [6]. Moreover, liver biopsy is limited by sampling errors and observer variability, with possibility of omissions and false-positive or false-negative results. Thus, liver biopsy should be avoided whenever possible, and hepatobiliary scintigraphy, especially PEHS, may take the place of liver biopsy in the diagnosis of BA [3,5]. Finally, the sample size was relatively small in the present study, and thus, validation of the scoring system in a large cohort of patients is essential before the scoring system can be used in clinical practice. We recommend that the scoring system be
Journal of Hepatology 2014 vol. 61 j 1438–1452
1441