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
Letters to the Editor reassessed with or without incorporation of PEHS and with or without removal of liver biopsy in a large study. In addition, there seems an error in the manuscript; the cut-off value may be ‘‘31.164’’, not ‘‘311.644’’ in Fig. 1C and D.
Conflict of interest The authors declared that they do not have anything to disclose 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 HA, et al. Design and validation of a diagnostic score for biliary atresia. J Hepatol 2014;61:116–123. [2] 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. [3] Kwatra N, Shalaby-Rana E, Narayanan S, Mohan P, Ghelani S, Majd M. Phenobarbital-enhanced hepatobiliary scintigraphy in the diagnosis of biliary atresia: two decades of experience at a tertiary center. Pediatr Radiol 2013;43:1365–1375.
[4] Liu SX, Huang ZH. The value of radionuclide hepatobiliary scintigraphy in combination with determination of bilirubin from duodenal drainage in differential diagnosis of infantile persistent jaundice. Front Med China 2010;4:342–345. [5] Lin WY, Lin CC, Changlai SP, Shen YY, Wang SJ. Comparison technetium of Tc-99m disofenin cholescintigraphy with ultrasonography in the differentiation of biliary atresia from other forms of neonatal jaundice. Pediatr Surg Int 1997;12:30–33. [6] Rockey DC, Caldwell SH, Goodman ZD, Nelson RC, Smith AD. Liver biopsy. Hepatology 2009;49:1017–1044.
⇑
Rui Dong Shan Zheng Department of Pediatric Surgery, Children’s Hospital of Fudan University, and Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China ⇑Corresponding author. Address: Department of Pediatric Surgery, Children’s Hospital of Fudan University, and Key Laboratory of Neonatal Disease, Ministry of Health, 399 Wan Yuan Road, Shanghai 201102, China. Tel.: +86 021 64931007; fax: +86 021 64931901. E-mail address: [email protected]
Reply to: ‘‘Scoring system in diagnosing biliary atresia’’ To the Editor: We appreciate the interest of Dong and Zheng in our recent study [1]. Although hepatobiliary scintigraphy (HBS) is one of the most sensitive methods for the diagnosis of biliary atresia (BA), it has a low specificity (70.4%) as reported in a meta-analysis of 81 studies [2]. Sun et al. [3] reported a 13.3% (66/498) false positive rate of HBS. They concluded that the excessive dependence on HBS may contribute to the misdiagnosis of BA. Although HBS, showing biliary excretion, excludes BA, non-excretion neither confirms the diagnosis of BA nor rules out the diagnosis of non-BA aetiologies [4]. Oral phenobarbital can enhance the diagnostic performance of HBS by re-examination one week later [5]; however, for the potential delay in diagnosis it is not routinely practiced [6]. Moreover, the reported BA score specificity (97.67%) [1] cannot be enhanced by HBS, which has a much lower specificity [2]. Liu and Huang [5] reported that if no bile was found in the duodenal tube test (DTT), the drainage tube would be kept for up to 72 h. In some cases, the duodenal fluid changed from white to yellow after several days or weeks. Therefore, persistent examination of the duodenal fluid is very important. This also prolongs the time of diagnosis and is not routinely performed. However, DTT may have a special importance in situations where other tests are not available [6]. An important concept of our BA score [1] is that it depends on parameters that are an integral part of the workup and are routinely performed for patients suffering neonatal cholestasis (NC) whether suspected to be BA or non-BA. Contrarily, HBS and DTT cannot be considered as such. Dong and Zheng were encouraged by the article of Liu and Huang [5] that reports a performance of combined HBS and 1442
DTT of 100% sensitivity and 100% specificity. We read the article with great interest but we found two major concerns. First, recruitment of patients was selective as patients with certain aetiologies were excluded from the study. This selectivity may render the calculated specificity inaccurately a representative one. Furthermore, it supports the concept that these procedures are needed for selected patients. Second, the method of calculating the combined performance is not clear. According to their results, 3 groups of patients can be discriminated: (1) Patients having HBS with no excretion and DTT with no bile; (26 patients with BA). (2) Patients having HBS with excretion and DTT with bile; (41 patients with non-BA). (3) Patients having HBS with no excretion and DTT with bile; (17 patients; 3 were BA and 14 were non-BA). These results can never, in any way, lead to a sensitivity and specificity of 100%. It seems that Liu and Huang [5] simply combined the sensitivity of one test (HBS) with the specificity of the other (DTT) which is unreasonable. Dong and Zheng, suggested that liver biopsy should be avoided whenever possible. We disagree with this concept as we believe that liver biopsy should be performed unless there is a contraindication or when parents refuse the procedure. For that, liver biopsy is considered as an integral part of the diagnostic workup of NC patients and is strongly encouraged according to ‘‘The Cholestasis Guideline Committee’’ of the NASPGN [7]. The aim of liver biopsy in NC is not only to evaluate the features of biliary outflow obstruction but is also an essential tool in revealing the aetiology of the liver disease, and in assessing the fibrosis stage which affects treatment policy. Such targets are irreplaceable by HBS and DTT. For that, liver biopsy is generally considered the ‘‘gold standard’’ compared to other diagnostic
Journal of Hepatology 2014 vol. 61 j 1438–1452
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
Letters to the Editor reassessed with or without incorporation of PEHS and with or without removal of liver biopsy in a large study. In addition, there seems an error in the manuscript; the cut-off value may be ‘‘31.164’’, not ‘‘311.644’’ in Fig. 1C and D.
Conflict of interest The authors declared that they do not have anything to disclose 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 HA, et al. Design and validation of a diagnostic score for biliary atresia. J Hepatol 2014;61:116–123. [2] 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. [3] Kwatra N, Shalaby-Rana E, Narayanan S, Mohan P, Ghelani S, Majd M. Phenobarbital-enhanced hepatobiliary scintigraphy in the diagnosis of biliary atresia: two decades of experience at a tertiary center. Pediatr Radiol 2013;43:1365–1375.
[4] Liu SX, Huang ZH. The value of radionuclide hepatobiliary scintigraphy in combination with determination of bilirubin from duodenal drainage in differential diagnosis of infantile persistent jaundice. Front Med China 2010;4:342–345. [5] Lin WY, Lin CC, Changlai SP, Shen YY, Wang SJ. Comparison technetium of Tc-99m disofenin cholescintigraphy with ultrasonography in the differentiation of biliary atresia from other forms of neonatal jaundice. Pediatr Surg Int 1997;12:30–33. [6] Rockey DC, Caldwell SH, Goodman ZD, Nelson RC, Smith AD. Liver biopsy. Hepatology 2009;49:1017–1044.
⇑
Rui Dong Shan Zheng Department of Pediatric Surgery, Children’s Hospital of Fudan University, and Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China ⇑Corresponding author. Address: Department of Pediatric Surgery, Children’s Hospital of Fudan University, and Key Laboratory of Neonatal Disease, Ministry of Health, 399 Wan Yuan Road, Shanghai 201102, China. Tel.: +86 021 64931007; fax: +86 021 64931901. E-mail address: [email protected]
Reply to: ‘‘Scoring system in diagnosing biliary atresia’’ To the Editor: We appreciate the interest of Dong and Zheng in our recent study [1]. Although hepatobiliary scintigraphy (HBS) is one of the most sensitive methods for the diagnosis of biliary atresia (BA), it has a low specificity (70.4%) as reported in a meta-analysis of 81 studies [2]. Sun et al. [3] reported a 13.3% (66/498) false positive rate of HBS. They concluded that the excessive dependence on HBS may contribute to the misdiagnosis of BA. Although HBS, showing biliary excretion, excludes BA, non-excretion neither confirms the diagnosis of BA nor rules out the diagnosis of non-BA aetiologies [4]. Oral phenobarbital can enhance the diagnostic performance of HBS by re-examination one week later [5]; however, for the potential delay in diagnosis it is not routinely practiced [6]. Moreover, the reported BA score specificity (97.67%) [1] cannot be enhanced by HBS, which has a much lower specificity [2]. Liu and Huang [5] reported that if no bile was found in the duodenal tube test (DTT), the drainage tube would be kept for up to 72 h. In some cases, the duodenal fluid changed from white to yellow after several days or weeks. Therefore, persistent examination of the duodenal fluid is very important. This also prolongs the time of diagnosis and is not routinely performed. However, DTT may have a special importance in situations where other tests are not available [6]. An important concept of our BA score [1] is that it depends on parameters that are an integral part of the workup and are routinely performed for patients suffering neonatal cholestasis (NC) whether suspected to be BA or non-BA. Contrarily, HBS and DTT cannot be considered as such. Dong and Zheng were encouraged by the article of Liu and Huang [5] that reports a performance of combined HBS and 1442
DTT of 100% sensitivity and 100% specificity. We read the article with great interest but we found two major concerns. First, recruitment of patients was selective as patients with certain aetiologies were excluded from the study. This selectivity may render the calculated specificity inaccurately a representative one. Furthermore, it supports the concept that these procedures are needed for selected patients. Second, the method of calculating the combined performance is not clear. According to their results, 3 groups of patients can be discriminated: (1) Patients having HBS with no excretion and DTT with no bile; (26 patients with BA). (2) Patients having HBS with excretion and DTT with bile; (41 patients with non-BA). (3) Patients having HBS with no excretion and DTT with bile; (17 patients; 3 were BA and 14 were non-BA). These results can never, in any way, lead to a sensitivity and specificity of 100%. It seems that Liu and Huang [5] simply combined the sensitivity of one test (HBS) with the specificity of the other (DTT) which is unreasonable. Dong and Zheng, suggested that liver biopsy should be avoided whenever possible. We disagree with this concept as we believe that liver biopsy should be performed unless there is a contraindication or when parents refuse the procedure. For that, liver biopsy is considered as an integral part of the diagnostic workup of NC patients and is strongly encouraged according to ‘‘The Cholestasis Guideline Committee’’ of the NASPGN [7]. The aim of liver biopsy in NC is not only to evaluate the features of biliary outflow obstruction but is also an essential tool in revealing the aetiology of the liver disease, and in assessing the fibrosis stage which affects treatment policy. Such targets are irreplaceable by HBS and DTT. For that, liver biopsy is generally considered the ‘‘gold standard’’ compared to other diagnostic
Journal of Hepatology 2014 vol. 61 j 1438–1452
