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Intrahepatic cystic lesions in children with biliary atresia after Kasai procedure
YJPSU-59319; No of Pages 5 Journal of Pediatric Surgery xxx (xxxx) xxx
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Intrahepatic Cystic Lesions in Children with Biliary Atresia After Kasai Procedure☆ Jingying Jiang 1, Junfeng Wang 1, Xuexin Lu, Zhen Shen, Gong Chen, Yanlei Huang, Rui Dong ⁎, Shan Zheng ⁎ Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, Shanghai, China
a r t i c l e
i n f o
Article history: Received 9 August 2019 Accepted 24 August 2019 Available online xxxx Key words: Biliary atresia Intrahepatic cystic lesions Kasai procedure
a b s t r a c t Background: Intrahepatic cystic lesion (ICL) is a common complication for biliary atresia post-Kasai portoenterostomy. The purpose of this study was to review the cases in our hospital and assess the correlation between characteristics of ICL and clinical outcomes. Methods: We retrospectively analyzed 787 cases of biliary atresia from 2012 to 2016. Demographics, clinical details, and postoperative outcomes were reviewed. Results: A total of 76 patients were diagnosed with ICLs using ultrasound post-Kasai procedure, and the incidence was 9.7%. Preoperative characteristics showed no significant differences between ICL (+) and ICL (−) groups. Nearly 70% (53/76) of the patients with ICLs had a history of cholangitis. The 2-year native liver survival rate was 60.4% for those with a history of cholangitis and 87% for those without (P = 0.017). Further analysis showed that the 2-year native liver survival rate was 42.9% for those diagnosed within 3 months post-Kasai procedure, 54.2% for those diagnosed between 3 and 6 months, and 80.0% for those diagnosed beyond 6 months (P = 0.002), while no significance was observed for type (P = 0.094) or site (P = 0.406) of ICL. Conclusion: Patients with ICLs had a high incidence of cholangitis. The prognosis was closely related with the history of cholangitis and the onset time of ICLs. Level of evidence: Level II. © 2019 Elsevier Inc. All rights reserved.
Biliary atresia (BA) is a severe liver disease in neonates, characterized by fibroinflammatory destruction of extra- or intrahepatic bile ducts [1], and accounts for nearly one-third of all neonatal cholestasis and more than 90% of obstructive cholestasis [2]. If left undiagnosed and untreated, BA can rapidly progress into hepatobiliary cirrhosis, hepatic failure, or even death within 2–3 years after birth. Kasai portoenterostomy has been the consensual strategy for BA since 1959. It has been reported that some patients may suffer from intrahepatic cystic lesions (ICLs) after Kasai procedure, which can be regarded as a sign of poor prognosis. The incidence of ICLs ranges from 6% to 28% according to the previous literature. In Shimadera's study, the liver fibrosis
grade at the time of Kasai procedure may help to predict the development of postoperative ICLs [3]. Most of the previous reports have also concentrated on the correlation between the shape of cysts and the prognosis [4–6]. However, it still remains debatable. Therefore, we conducted this retrospective study to analyze the ultrasound images and clinical features of ICLs after Kasai procedure, to assess the prognosis based on the characteristics of the intrahepatic cysts.
☆ Financial support: This study received financial support from the Shanghai Key Disciplines (2017ZZ02022), The National Natural Science Foundation of China (81770519, 81771633 and 81873545), The Shanghai Hospital Development Center (SHDC12018X22), The Science Foundation of Shanghai Excellent Youth Scholars (2017YQ042), The Science Foundation of Shanghai (17411960600, 14411969800, 16411952200 and 18411969100), and The Children's National Medical Center (EK1125180104, EKYY20180204, EK112520180301 and EK112520180301). ⁎ Corresponding authors at: Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defects, 399 Wan Yuan Rd., Shanghai 201102, China. Tel.: +86 021 64931007; fax: +86 021 64931901. E-mail addresses: [email protected] (R. Dong), [email protected] (S. Zheng). 1 Jingying Jiang and Junfeng Wang contributed to the work equally and should be regarded as co-first authors.
1.1. Subjects
1. Materials and methods
Medical records were reviewed on 787 infants with BA, who underwent Kasai portoenterostomy in Department of Pediatric Surgery at Children's Hospital of Fudan University from January 2012 to December 2016. In this retrospective study, inclusion and exclusion criteria had been defined before any data extraction from the patients' medical records. The inclusion criteria of this study were that all BA patients were diagnosed using intraoperative cholangiography and histological exams of liver biopsies, and all underwent Kasai procedure. The exclusion criteria were severe systematic deformity, such as BA splenic
https://doi.org/10.1016/j.jpedsurg.2019.08.027 0022-3468/© 2019 Elsevier Inc. All rights reserved.
Please cite this article as: J. Jiang, J. Wang, X. Lu, et al., Intrahepatic Cystic Lesions in Children with Biliary Atresia After Kasai Procedure, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2019.08.027
2
J. Jiang et al. / Journal of Pediatric Surgery xxx (xxxx) xxx
malformation syndrome, cystic lesions present on ultrasound before Kasai procedure. The diagnosis of ICLs was confirmed using ultrasound. For each patient, medical records were reviewed on their demographics, clinical manifestations, operation details, ultrasound findings, and postoperative outcomes. The follow-up information was collected from outpatient clinic records, telephone communication and questionnaires. This study was approved by the Ethics Committee of Children's Hospital of Fudan University (approval number: 2018-270), with a waiver of requirement for informed consent owing to the nature of this retrospective study. 1.2. Statistical analysis All data analyses were performed using SPSS 23.0 (IBM SPSS Statistics, IBM Corporation, New York, USA) and STATA14 (StataCorp, Texas, USA). Qualitative data were presented as n. Continuous data were presented as the mean ± standard deviation (SD), median and Q1, Q3. In univariate analysis, the differences between qualitative data were analyzed using Chi-squared test, while those between continuous data were analyzed using student-t test or Wilcoxon rank-sum test if failing Shapiro–Wilk W test for normal distribution. Logistic regression was applied for multivariate analysis. Kaplan–Meier survival analysis using log-rank test was performed to compare the 2-year native liver survival rate of each group based on the characteristics of ICLs. A p-value of less than 0.05 was considered statistically significant. 2. Results 2.1. Patient demographics From January 2012 to December 2016, 787 children with BA underwent the Kasai procedure and were routinely followed up, among whom 76 patients were diagnosed with ICLs by the ultrasound after the Kasai surgery, and they were assigned into ICL(+) group. The incidence of ICLs after Kasai procedures is 9.7%. The male-to-female ratio was 36:40, and their mean age at Kasai procedure was 67.11 ± 20.59 days in ICL(+) group, which were comparable to the ICL(−) group. The postoperative follow-up duration varied from 2 years to 6.25 years, and 9 patients were lost to follow-up within the first year (Table 1). 2.2. Preoperative characteristics of BA infants between the ICL (+) and ICL (−) groups To determine the independent variables associated with the development of ICLs after Kasai procedure, univariate analysis was performed in the preoperative clinical parameters, including gender, day of surgery, platelet count (PLT), direct bilirubin (DB), total bilirubin (TB), alanine transaminase (ALT), gamma-glutamyl transpeptidase (GGT), aspartate transaminase (AST), albumin (ALB), total bile acid (TBA) and DB/TB, DB decreasing rate within one month after Kasai, aspartate aminotransferase-to-platelet ratio index (APRi). None of these showed significant differences. Further multivariate analysis achieved the same result (Table 1). 2.3. Further analysis in the ICL (+) group 2.3.1. Characteristics of ICLs on ultrasound Nearly 70% (53/76) had a history of cholangitis. The postoperative ultrasound images and the characteristics of ICLs were further explored by analyzing the incidence of cholangitis and the site, type and diagnostic time of the cysts. We found that ICLs occurred more frequently in the left lobe of liver than that in the right lobe or both lobes (39: 23: 14). Based on the Watanabe's classification, 52 of them were referred as simple cysts, while 24 were referred as multiple complicated cysts. For the
diagnostic time, 7 cases were diagnosed within 3 months after the Kasai procedures, 24 between 3 and 6 months, and 45 after 6 months (Table 2). 2.3.2. Relationship between characteristics of ICLs and the native liver survival rate We further divided ICL (+) patients into several subgroups based on the occurrence of cholangitis, site, type and diagnostic time of the cysts, labeled as yes vs no, simple vs complicated, left vs right vs both, and b 3 months vs 3–6 months vs N 6 months. Kaplan–Meier survival analysis was performed to compare the 2-year native liver survival rate among all subgroups and we found that the occurrence of cholangitis and the diagnostic time of cysts had a significant effect on the outcome, that is, 60.4% for those with a history of cholangitis and 85% for those without (P = 0.017), 42.9% for b 3 months, 54.2% for 3–6 months, and 80.0% for N6 months (P = 0.002), while the site and type of cysts had no statistical effect on the outcome (P = 0.094, P = 0.406) (Table 2, Fig. 1). 3. Discussion Since postoperative intrahepatic cystic lesions in BA was first reported in 1960 [7], an increasing number of studies have considered the occurrence of ICLs as a common complication but also a predictor of a poor prognosis in BA. Watanabe's morphological classification proposed in 2007 is well accepted now, and ICLs are generally divided into two types: solitary simple cystic lesions or multiple continuous oval or beaded lesions [6]. Tainaka et al. reported that solitary cysts might be a bile lake associated with poor prognosis, and continuous beaded cysts might be dilated bile ducts, which may be reversed [5]. However, Goda et al. found that the rate of poor prognosis in round type and multiple-bead type was 27% and 83% respectively, which is opposite to the study by Tainaka et al. [4]. Thus we retrospectively reviewed our cases, trying to explore the correlation between the various characteristics of cysts and the outcome of BA patients. Our retrospective analysis demonstrated the incidence of ICLs was 9.7%, which is within the range of 6–28% reported by previous studies. However, our number can be relatively in the lower limit of the incidence range, which may be because of our large samples and loss of patients who had given up further treatment within the first year after surgery. Preoperative characteristic comparison showed no significant differences between the ICL + and ICL − groups using both univariate and multivariate logistic regression analysis, which are similar to the results of Shimadera et al. [3]. However, the liver fibrosis level at the time of Kasai procedure was not available in our patients. For the outcome, we found that the overall 2-year native liver survival rate of the ICL (+) group was 68.45%, which was comparable to our previous studies reporting the outcome of the whole population with BA during 2004–2010 [8,9], indicating the occurrence of ICL itself may not be an independent factor. Further analysis showed that the outcome of BA with ICLs after Kasai procedure mainly correlates with the occurrence of cholangitis and the diagnostic time which could be interpreted as the onset time of cysts. The 2-year native liver survival rate is 60.4% for those with a history of cholangitis and 87% for those without, and 42.9% for b 3 months, 54.2% for 3–6 months, and 80.0% for N6 months, while there is no obvious relevance in type or site as reported previously. For the results obtained above, some of which are inconsistent with previous studies including the correlation between the prognosis and type of cysts. Given the largest samples ever reported, our results should be reliable. Furthermore, most of the previous studies adopted the current native liver survival rate as the outcome, while we think it may not be reasonable because the follow-up period is not the same for each patient, or actually is extremely different ranging from several months to several years. Therefore, a unified 2-year native liver survival rate was
Please cite this article as: J. Jiang, J. Wang, X. Lu, et al., Intrahepatic Cystic Lesions in Children with Biliary Atresia After Kasai Procedure, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2019.08.027
J. Jiang et al. / Journal of Pediatric Surgery xxx (xxxx) xxx
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Table 1 Comparison of demographics and preoperative clinical data between ICL+ and ICL− groups.
Gender, n Male Female Age, days Mean±SD Median Q1, Q3 GGT, IU/L Mean±SD Median Q1, Q3 TB, umol/L Mean±SD Median Q1, Q3 DB, umol/L Mean±SD Median Q1, Q3 DB/TB Mean±SD Median Q1, Q3 TBA, umol/L Mean±SD Median Q1, Q3 ALT, IU/L Mean±SD Median Q1, Q3 AST, IU/L Mean±SD Median Q1, Q3 ALB, g/L Mean±SD Median Q1, Q3 PLT, *10^9/L Mean±SD Median Q1, Q3 APRi Mean±SD Median Q1, Q3
ICL+ (n=76)
ICL- (n=711)
Pa
Pb
36 40
335
0.360
0.567
67.11±20.59 65.5 49, 84
67.51±26.16 63 52, 77
0.9640
0.744
831.57±653.69 608.5 365, 1201
756.55 ±571.05 623.5 302, 1088
0.4723
0.240
151.11±32.94 147.6 129.15, 163.35
163.32 ±59.85 154.8 128.1, 182.8
0.1000
0.448
105.91±25.17 102.55 90, 120.9
113.73 ±35.94 107.4 88.45, 129.9
0.1441
0.488
0.70±0.07 0.68 0.65, 0.71
0.70 ±0.08 0.69 0.66, 0.75
0.7479
0.778
142.34±65.25 128.6 95.7, 169.1
137.52 ±77.64 128.7 100.2, 160
0.7047
0.174
92.18±57.85 79.5 50, 110
105.60 ±88.49 85 54, 134
0.3339
0.869
143.86±68.1 127 96, 187
173.01 ±118.5 139 95, 209
0.1366
0.823
38.92±3.3 39.2 36.3, 41.4
38.72±4.19 38.9 36.7, 41.2
0.8639
0.619
316.44±109.41 312 240, 378
311.69 ±124.76 293 22, 386
0.4784
0.520
1.30±0.84 1.08 0.73, 1.64
1.73 ±1.77 1.2 0.74, 2.045
0.1290
0.315
376
Age: day of surgery, DB: direct bilirubin, TB: total bilirubin, GGT: gamma-glutamyl transpeptidase, AST: aspartate transaminase, ALT: alanine transaminase, platelet count (PLT), APRi: aspartate aminotransferase-to-platelet ratio index (APRi), TBA: total bile acid, ALB: albumin. Pa: P value between ICL+ and ICL- groups using Chi-squared test or Wilcoxon rank-sum test. Pb: P value between ICL+ and ICL- groups using multivariate logistic regression.
applied to analyze the outcome of our patients. We found that the incidence of ICLs does not lead to a poor prognosis, but actually the characteristics of the cysts make the crucial effect, especially for the history of cholangitis and the onset time of the cysts.
One of our limitations in this study was that a lot of our patients developed ICLs more than 6 months or even more than a year after Kasai procedure, so the period between the onset of cyst and the outcome applied may be very short, which may not be suitable for
Table 2 Summary of patients with ICLs.
Cholangitis Site of cysts
Type of cysts Diagnostic time of cysts
yes no left lobe right lobe both lobes simple multiple complicated within 3 months 3–6 months beyond 6 months
n
2-year native liver survival rate
P
53 23 39 14 23 52 24 7 24 45
60.4% 87% 71.8% 64.3% 65.2% 73.6% 56.5% 42.9% 54.2% 80%
0.017 0.406
0.094 0.002
ICLs: intrahepatic cystic lesions.
Please cite this article as: J. Jiang, J. Wang, X. Lu, et al., Intrahepatic Cystic Lesions in Children with Biliary Atresia After Kasai Procedure, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2019.08.027
4
J. Jiang et al. / Journal of Pediatric Surgery xxx (xxxx) xxx
Fig. 1. Native liver survival analysis based on characteristics of cysts: (A) Native liver survival rate between those with and without a history of cholangitis. (B) Native liver survival rate based on the diagnostic time of cysts. (C) Native liver survival rate based on the site of the cysts. (D) Native liver survival rate based on the type of the cysts.
postoperative 2-year native liver survival rate analysis. Besides, we did not evaluate the histological features of all patients, so we could not draw the conclusion whether there is any difference of fibrosis level at the time of Kasai procedure between the ICL (+) and ICL (−) groups. Furthermore, we failed to obtain all the outcomes of the ICL (−) group, so we compared the outcome with our previous studies, but the conclusion may not be valid enough owing to the different experience of surgeons or postoperative treatment strategy. However, we are trying to obtain the histological and outcome information to make further analysis in the aspect of ICLs among BA patients. And these patients are still under follow-up, and more evidence will be provided on the correlation between characteristics of ICLs and long term outcome of BA. In conclusion, we found that the postoperative occurrence of cholangitis and the onset time of ICLs have much to do with the outcome of BA patients, which indicates that ICL monitoring within 6 months after Kasai procedures is very important, and it also directs the interventions taken for those patients. Percutaneous transhepatic cholangiodrainage (PTCD) has been reported to treat solitary cysts, and those with recurrent cholangitis should be treated with prophylactic antibiotics [6,10,11]. According to our results, those who develop ICLs beyond 6 months after surgery have a relatively better outcome; thus, the onset time should be taken into consideration for the treatment strategy, and further research should be conducted to help understand the mechanism of ICLs.
Declaration of competing interest All authors declare that they have no conflict of interest. Acknowledgements This study received financial support from Shanghai Key Disciplines (no. 2017ZZ02022), National Natural Science Foundation of China (no. 81770519, no. 81771633 and no. 81873545), Shanghai Hospital Development Center (no. SHDC12018X22), The Science Foundation of Shanghai Excellent Youth Scholars (no. 2017YQ042), The Science Foundation of Shanghai (no. 17411960600, no. 14411969800, no. 16411952200 and no. 18411969100), and Children's National Medical Center (no. EK1125180104, no. EKYY20180204, no. EK112520180301 and no. EK112520180301). References [1] Mack CL. What causes biliary atresia? Unique aspects of the neonatal immune system provide clues to disease pathogenesis. Cell Mol Gastroenterol Hepatol. 2015;1 (3):267–74. [2] Hartley JL, Davenport M, Kelly DA. Biliary atresia. Lancet (London, England). 2009; 374(9702):1704–13. [3] Shimadera S, Iwai N, Deguchi E, et al. Predicting factors on the occurrence of cystic dilatation of intrahepatic biliary system in biliary atresia. Pediatr Surg Int. 2010;26 (6):611–4.
Please cite this article as: J. Jiang, J. Wang, X. Lu, et al., Intrahepatic Cystic Lesions in Children with Biliary Atresia After Kasai Procedure, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2019.08.027
J. Jiang et al. / Journal of Pediatric Surgery xxx (xxxx) xxx [4] Goda T, Kubota A, Kawahara H, et al. The clinical significance of intrahepatic cystic lesions in postoperative patients with biliary atresia. Pediatr Surg Int. 2012;28(9):865–8. [5] Tainaka T, Kaneko K, Seo T, et al. Intrahepatic cystic lesions after hepatic portoenterostomy for biliary atresia with bile lake and dilated bile ducts. J Pediatr Gastroenterol Nutr. 2007;44(1):104–7. [6] Watanabe M, Hori T, Kaneko M, et al. Intrahepatic biliary cysts in children with biliary atresia who have had a Kasai operation. J Pediatr Surg. 2007;42(7):1185–9. [7] Cameron R, Bunton GL. Congenital biliary atresia. Br Med J. 1960;2(5208):1253–7. [8] Dong R, Song Z, Chen G, Zheng S, Xiao XM. Improved outcome of biliary atresia with postoperative high-dose steroid. Gastroenterology research and practice 2013;2013: 902431.
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[9] Song Z, Dong R, Shen Z, et al. Surgical outcome and etiologic heterogeneity of infants with biliary atresia who received Kasai operation less than 60 days after birth: a retrospective study. Medicine. 2017;96(26):e7267. [10] Kawarasaki H, Itoh M, Mizuta K, et al. Further observations on cystic dilatation of the intrahepatic biliary system in biliary atresia after hepatic portoenterostomy: report on 10 cases. Tohoku J Exp Med. 1997;181(1):175–83. [11] Nakama T, Kitamura T, Matsui A, et al. Ultrasonographic findings and management of intrahepatic biliary tract abnormalities after portoenterostomy. J Pediatr Surg. 1991;26(1):32–6.
Please cite this article as: J. Jiang, J. Wang, X. Lu, et al., Intrahepatic Cystic Lesions in Children with Biliary Atresia After Kasai Procedure, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2019.08.027
Contents lists available at ScienceDirect
Journal of Pediatric Surgery journal homepage: www.elsevier.com/locate/jpedsurg
Intrahepatic Cystic Lesions in Children with Biliary Atresia After Kasai Procedure☆ Jingying Jiang 1, Junfeng Wang 1, Xuexin Lu, Zhen Shen, Gong Chen, Yanlei Huang, Rui Dong ⁎, Shan Zheng ⁎ Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, Shanghai, China
a r t i c l e
i n f o
Article history: Received 9 August 2019 Accepted 24 August 2019 Available online xxxx Key words: Biliary atresia Intrahepatic cystic lesions Kasai procedure
a b s t r a c t Background: Intrahepatic cystic lesion (ICL) is a common complication for biliary atresia post-Kasai portoenterostomy. The purpose of this study was to review the cases in our hospital and assess the correlation between characteristics of ICL and clinical outcomes. Methods: We retrospectively analyzed 787 cases of biliary atresia from 2012 to 2016. Demographics, clinical details, and postoperative outcomes were reviewed. Results: A total of 76 patients were diagnosed with ICLs using ultrasound post-Kasai procedure, and the incidence was 9.7%. Preoperative characteristics showed no significant differences between ICL (+) and ICL (−) groups. Nearly 70% (53/76) of the patients with ICLs had a history of cholangitis. The 2-year native liver survival rate was 60.4% for those with a history of cholangitis and 87% for those without (P = 0.017). Further analysis showed that the 2-year native liver survival rate was 42.9% for those diagnosed within 3 months post-Kasai procedure, 54.2% for those diagnosed between 3 and 6 months, and 80.0% for those diagnosed beyond 6 months (P = 0.002), while no significance was observed for type (P = 0.094) or site (P = 0.406) of ICL. Conclusion: Patients with ICLs had a high incidence of cholangitis. The prognosis was closely related with the history of cholangitis and the onset time of ICLs. Level of evidence: Level II. © 2019 Elsevier Inc. All rights reserved.
Biliary atresia (BA) is a severe liver disease in neonates, characterized by fibroinflammatory destruction of extra- or intrahepatic bile ducts [1], and accounts for nearly one-third of all neonatal cholestasis and more than 90% of obstructive cholestasis [2]. If left undiagnosed and untreated, BA can rapidly progress into hepatobiliary cirrhosis, hepatic failure, or even death within 2–3 years after birth. Kasai portoenterostomy has been the consensual strategy for BA since 1959. It has been reported that some patients may suffer from intrahepatic cystic lesions (ICLs) after Kasai procedure, which can be regarded as a sign of poor prognosis. The incidence of ICLs ranges from 6% to 28% according to the previous literature. In Shimadera's study, the liver fibrosis
grade at the time of Kasai procedure may help to predict the development of postoperative ICLs [3]. Most of the previous reports have also concentrated on the correlation between the shape of cysts and the prognosis [4–6]. However, it still remains debatable. Therefore, we conducted this retrospective study to analyze the ultrasound images and clinical features of ICLs after Kasai procedure, to assess the prognosis based on the characteristics of the intrahepatic cysts.
☆ Financial support: This study received financial support from the Shanghai Key Disciplines (2017ZZ02022), The National Natural Science Foundation of China (81770519, 81771633 and 81873545), The Shanghai Hospital Development Center (SHDC12018X22), The Science Foundation of Shanghai Excellent Youth Scholars (2017YQ042), The Science Foundation of Shanghai (17411960600, 14411969800, 16411952200 and 18411969100), and The Children's National Medical Center (EK1125180104, EKYY20180204, EK112520180301 and EK112520180301). ⁎ Corresponding authors at: Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defects, 399 Wan Yuan Rd., Shanghai 201102, China. Tel.: +86 021 64931007; fax: +86 021 64931901. E-mail addresses: [email protected] (R. Dong), [email protected] (S. Zheng). 1 Jingying Jiang and Junfeng Wang contributed to the work equally and should be regarded as co-first authors.
1.1. Subjects
1. Materials and methods
Medical records were reviewed on 787 infants with BA, who underwent Kasai portoenterostomy in Department of Pediatric Surgery at Children's Hospital of Fudan University from January 2012 to December 2016. In this retrospective study, inclusion and exclusion criteria had been defined before any data extraction from the patients' medical records. The inclusion criteria of this study were that all BA patients were diagnosed using intraoperative cholangiography and histological exams of liver biopsies, and all underwent Kasai procedure. The exclusion criteria were severe systematic deformity, such as BA splenic
https://doi.org/10.1016/j.jpedsurg.2019.08.027 0022-3468/© 2019 Elsevier Inc. All rights reserved.
Please cite this article as: J. Jiang, J. Wang, X. Lu, et al., Intrahepatic Cystic Lesions in Children with Biliary Atresia After Kasai Procedure, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2019.08.027
2
J. Jiang et al. / Journal of Pediatric Surgery xxx (xxxx) xxx
malformation syndrome, cystic lesions present on ultrasound before Kasai procedure. The diagnosis of ICLs was confirmed using ultrasound. For each patient, medical records were reviewed on their demographics, clinical manifestations, operation details, ultrasound findings, and postoperative outcomes. The follow-up information was collected from outpatient clinic records, telephone communication and questionnaires. This study was approved by the Ethics Committee of Children's Hospital of Fudan University (approval number: 2018-270), with a waiver of requirement for informed consent owing to the nature of this retrospective study. 1.2. Statistical analysis All data analyses were performed using SPSS 23.0 (IBM SPSS Statistics, IBM Corporation, New York, USA) and STATA14 (StataCorp, Texas, USA). Qualitative data were presented as n. Continuous data were presented as the mean ± standard deviation (SD), median and Q1, Q3. In univariate analysis, the differences between qualitative data were analyzed using Chi-squared test, while those between continuous data were analyzed using student-t test or Wilcoxon rank-sum test if failing Shapiro–Wilk W test for normal distribution. Logistic regression was applied for multivariate analysis. Kaplan–Meier survival analysis using log-rank test was performed to compare the 2-year native liver survival rate of each group based on the characteristics of ICLs. A p-value of less than 0.05 was considered statistically significant. 2. Results 2.1. Patient demographics From January 2012 to December 2016, 787 children with BA underwent the Kasai procedure and were routinely followed up, among whom 76 patients were diagnosed with ICLs by the ultrasound after the Kasai surgery, and they were assigned into ICL(+) group. The incidence of ICLs after Kasai procedures is 9.7%. The male-to-female ratio was 36:40, and their mean age at Kasai procedure was 67.11 ± 20.59 days in ICL(+) group, which were comparable to the ICL(−) group. The postoperative follow-up duration varied from 2 years to 6.25 years, and 9 patients were lost to follow-up within the first year (Table 1). 2.2. Preoperative characteristics of BA infants between the ICL (+) and ICL (−) groups To determine the independent variables associated with the development of ICLs after Kasai procedure, univariate analysis was performed in the preoperative clinical parameters, including gender, day of surgery, platelet count (PLT), direct bilirubin (DB), total bilirubin (TB), alanine transaminase (ALT), gamma-glutamyl transpeptidase (GGT), aspartate transaminase (AST), albumin (ALB), total bile acid (TBA) and DB/TB, DB decreasing rate within one month after Kasai, aspartate aminotransferase-to-platelet ratio index (APRi). None of these showed significant differences. Further multivariate analysis achieved the same result (Table 1). 2.3. Further analysis in the ICL (+) group 2.3.1. Characteristics of ICLs on ultrasound Nearly 70% (53/76) had a history of cholangitis. The postoperative ultrasound images and the characteristics of ICLs were further explored by analyzing the incidence of cholangitis and the site, type and diagnostic time of the cysts. We found that ICLs occurred more frequently in the left lobe of liver than that in the right lobe or both lobes (39: 23: 14). Based on the Watanabe's classification, 52 of them were referred as simple cysts, while 24 were referred as multiple complicated cysts. For the
diagnostic time, 7 cases were diagnosed within 3 months after the Kasai procedures, 24 between 3 and 6 months, and 45 after 6 months (Table 2). 2.3.2. Relationship between characteristics of ICLs and the native liver survival rate We further divided ICL (+) patients into several subgroups based on the occurrence of cholangitis, site, type and diagnostic time of the cysts, labeled as yes vs no, simple vs complicated, left vs right vs both, and b 3 months vs 3–6 months vs N 6 months. Kaplan–Meier survival analysis was performed to compare the 2-year native liver survival rate among all subgroups and we found that the occurrence of cholangitis and the diagnostic time of cysts had a significant effect on the outcome, that is, 60.4% for those with a history of cholangitis and 85% for those without (P = 0.017), 42.9% for b 3 months, 54.2% for 3–6 months, and 80.0% for N6 months (P = 0.002), while the site and type of cysts had no statistical effect on the outcome (P = 0.094, P = 0.406) (Table 2, Fig. 1). 3. Discussion Since postoperative intrahepatic cystic lesions in BA was first reported in 1960 [7], an increasing number of studies have considered the occurrence of ICLs as a common complication but also a predictor of a poor prognosis in BA. Watanabe's morphological classification proposed in 2007 is well accepted now, and ICLs are generally divided into two types: solitary simple cystic lesions or multiple continuous oval or beaded lesions [6]. Tainaka et al. reported that solitary cysts might be a bile lake associated with poor prognosis, and continuous beaded cysts might be dilated bile ducts, which may be reversed [5]. However, Goda et al. found that the rate of poor prognosis in round type and multiple-bead type was 27% and 83% respectively, which is opposite to the study by Tainaka et al. [4]. Thus we retrospectively reviewed our cases, trying to explore the correlation between the various characteristics of cysts and the outcome of BA patients. Our retrospective analysis demonstrated the incidence of ICLs was 9.7%, which is within the range of 6–28% reported by previous studies. However, our number can be relatively in the lower limit of the incidence range, which may be because of our large samples and loss of patients who had given up further treatment within the first year after surgery. Preoperative characteristic comparison showed no significant differences between the ICL + and ICL − groups using both univariate and multivariate logistic regression analysis, which are similar to the results of Shimadera et al. [3]. However, the liver fibrosis level at the time of Kasai procedure was not available in our patients. For the outcome, we found that the overall 2-year native liver survival rate of the ICL (+) group was 68.45%, which was comparable to our previous studies reporting the outcome of the whole population with BA during 2004–2010 [8,9], indicating the occurrence of ICL itself may not be an independent factor. Further analysis showed that the outcome of BA with ICLs after Kasai procedure mainly correlates with the occurrence of cholangitis and the diagnostic time which could be interpreted as the onset time of cysts. The 2-year native liver survival rate is 60.4% for those with a history of cholangitis and 87% for those without, and 42.9% for b 3 months, 54.2% for 3–6 months, and 80.0% for N6 months, while there is no obvious relevance in type or site as reported previously. For the results obtained above, some of which are inconsistent with previous studies including the correlation between the prognosis and type of cysts. Given the largest samples ever reported, our results should be reliable. Furthermore, most of the previous studies adopted the current native liver survival rate as the outcome, while we think it may not be reasonable because the follow-up period is not the same for each patient, or actually is extremely different ranging from several months to several years. Therefore, a unified 2-year native liver survival rate was
Please cite this article as: J. Jiang, J. Wang, X. Lu, et al., Intrahepatic Cystic Lesions in Children with Biliary Atresia After Kasai Procedure, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2019.08.027
J. Jiang et al. / Journal of Pediatric Surgery xxx (xxxx) xxx
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Table 1 Comparison of demographics and preoperative clinical data between ICL+ and ICL− groups.
Gender, n Male Female Age, days Mean±SD Median Q1, Q3 GGT, IU/L Mean±SD Median Q1, Q3 TB, umol/L Mean±SD Median Q1, Q3 DB, umol/L Mean±SD Median Q1, Q3 DB/TB Mean±SD Median Q1, Q3 TBA, umol/L Mean±SD Median Q1, Q3 ALT, IU/L Mean±SD Median Q1, Q3 AST, IU/L Mean±SD Median Q1, Q3 ALB, g/L Mean±SD Median Q1, Q3 PLT, *10^9/L Mean±SD Median Q1, Q3 APRi Mean±SD Median Q1, Q3
ICL+ (n=76)
ICL- (n=711)
Pa
Pb
36 40
335
0.360
0.567
67.11±20.59 65.5 49, 84
67.51±26.16 63 52, 77
0.9640
0.744
831.57±653.69 608.5 365, 1201
756.55 ±571.05 623.5 302, 1088
0.4723
0.240
151.11±32.94 147.6 129.15, 163.35
163.32 ±59.85 154.8 128.1, 182.8
0.1000
0.448
105.91±25.17 102.55 90, 120.9
113.73 ±35.94 107.4 88.45, 129.9
0.1441
0.488
0.70±0.07 0.68 0.65, 0.71
0.70 ±0.08 0.69 0.66, 0.75
0.7479
0.778
142.34±65.25 128.6 95.7, 169.1
137.52 ±77.64 128.7 100.2, 160
0.7047
0.174
92.18±57.85 79.5 50, 110
105.60 ±88.49 85 54, 134
0.3339
0.869
143.86±68.1 127 96, 187
173.01 ±118.5 139 95, 209
0.1366
0.823
38.92±3.3 39.2 36.3, 41.4
38.72±4.19 38.9 36.7, 41.2
0.8639
0.619
316.44±109.41 312 240, 378
311.69 ±124.76 293 22, 386
0.4784
0.520
1.30±0.84 1.08 0.73, 1.64
1.73 ±1.77 1.2 0.74, 2.045
0.1290
0.315
376
Age: day of surgery, DB: direct bilirubin, TB: total bilirubin, GGT: gamma-glutamyl transpeptidase, AST: aspartate transaminase, ALT: alanine transaminase, platelet count (PLT), APRi: aspartate aminotransferase-to-platelet ratio index (APRi), TBA: total bile acid, ALB: albumin. Pa: P value between ICL+ and ICL- groups using Chi-squared test or Wilcoxon rank-sum test. Pb: P value between ICL+ and ICL- groups using multivariate logistic regression.
applied to analyze the outcome of our patients. We found that the incidence of ICLs does not lead to a poor prognosis, but actually the characteristics of the cysts make the crucial effect, especially for the history of cholangitis and the onset time of the cysts.
One of our limitations in this study was that a lot of our patients developed ICLs more than 6 months or even more than a year after Kasai procedure, so the period between the onset of cyst and the outcome applied may be very short, which may not be suitable for
Table 2 Summary of patients with ICLs.
Cholangitis Site of cysts
Type of cysts Diagnostic time of cysts
yes no left lobe right lobe both lobes simple multiple complicated within 3 months 3–6 months beyond 6 months
n
2-year native liver survival rate
P
53 23 39 14 23 52 24 7 24 45
60.4% 87% 71.8% 64.3% 65.2% 73.6% 56.5% 42.9% 54.2% 80%
0.017 0.406
0.094 0.002
ICLs: intrahepatic cystic lesions.
Please cite this article as: J. Jiang, J. Wang, X. Lu, et al., Intrahepatic Cystic Lesions in Children with Biliary Atresia After Kasai Procedure, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2019.08.027
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J. Jiang et al. / Journal of Pediatric Surgery xxx (xxxx) xxx
Fig. 1. Native liver survival analysis based on characteristics of cysts: (A) Native liver survival rate between those with and without a history of cholangitis. (B) Native liver survival rate based on the diagnostic time of cysts. (C) Native liver survival rate based on the site of the cysts. (D) Native liver survival rate based on the type of the cysts.
postoperative 2-year native liver survival rate analysis. Besides, we did not evaluate the histological features of all patients, so we could not draw the conclusion whether there is any difference of fibrosis level at the time of Kasai procedure between the ICL (+) and ICL (−) groups. Furthermore, we failed to obtain all the outcomes of the ICL (−) group, so we compared the outcome with our previous studies, but the conclusion may not be valid enough owing to the different experience of surgeons or postoperative treatment strategy. However, we are trying to obtain the histological and outcome information to make further analysis in the aspect of ICLs among BA patients. And these patients are still under follow-up, and more evidence will be provided on the correlation between characteristics of ICLs and long term outcome of BA. In conclusion, we found that the postoperative occurrence of cholangitis and the onset time of ICLs have much to do with the outcome of BA patients, which indicates that ICL monitoring within 6 months after Kasai procedures is very important, and it also directs the interventions taken for those patients. Percutaneous transhepatic cholangiodrainage (PTCD) has been reported to treat solitary cysts, and those with recurrent cholangitis should be treated with prophylactic antibiotics [6,10,11]. According to our results, those who develop ICLs beyond 6 months after surgery have a relatively better outcome; thus, the onset time should be taken into consideration for the treatment strategy, and further research should be conducted to help understand the mechanism of ICLs.
Declaration of competing interest All authors declare that they have no conflict of interest. Acknowledgements This study received financial support from Shanghai Key Disciplines (no. 2017ZZ02022), National Natural Science Foundation of China (no. 81770519, no. 81771633 and no. 81873545), Shanghai Hospital Development Center (no. SHDC12018X22), The Science Foundation of Shanghai Excellent Youth Scholars (no. 2017YQ042), The Science Foundation of Shanghai (no. 17411960600, no. 14411969800, no. 16411952200 and no. 18411969100), and Children's National Medical Center (no. EK1125180104, no. EKYY20180204, no. EK112520180301 and no. EK112520180301). References [1] Mack CL. What causes biliary atresia? Unique aspects of the neonatal immune system provide clues to disease pathogenesis. Cell Mol Gastroenterol Hepatol. 2015;1 (3):267–74. [2] Hartley JL, Davenport M, Kelly DA. Biliary atresia. Lancet (London, England). 2009; 374(9702):1704–13. [3] Shimadera S, Iwai N, Deguchi E, et al. Predicting factors on the occurrence of cystic dilatation of intrahepatic biliary system in biliary atresia. Pediatr Surg Int. 2010;26 (6):611–4.
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Please cite this article as: J. Jiang, J. Wang, X. Lu, et al., Intrahepatic Cystic Lesions in Children with Biliary Atresia After Kasai Procedure, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2019.08.027