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Am Surg. Author manuscript; available in PMC 2017 October 20. Published in final edited form as: Am Surg. 2014 September ; 80(9): 827–831.
Differentiating Biliary Atresia from Other Causes of Cholestatic Jaundice DANIEL K. ROBIE, M.D., SARAH R. OVERFELT, B.S., and LI XIE, S.C.M. Division of Pediatric Surgery, Nemours Children’s Clinic, Jacksonville, Florida
Abstract Author Manuscript Author Manuscript
Diagnosis of biliary atresia (BA) in infants presenting with cholestatic jaundice (CJ) requires exploratory surgery with cholangiography. However, the lack of a standardized approach to preoperative evaluation of infants with CJ can lead to a high number of negative surgical explorations. We reviewed our experience with CJ and BA to determine preoperative variables that might reliably identify BA. Infants explored for possible BA over a 5–year period were retrospectively reviewed. Preoperative clinical indices and liver biopsy results were reviewed. Statistical analysis was conducted by Student’s t test and Fisher’s exact test (P < 0.05). Twenty patients were identified, 10 with BA and 10 without (50% negative exploration rate). Nuclear cholescintigraphy (HIDA) excretion into the gastrointestinal tract was absent in all BA and in 8 of 10 without BA. Hepatomegaly was more common in the BA group (OR = 9.3, P = 0.07). BA had higher mean (± standard error) serum gamma-glutamyl transpeptidase levels (542 ± 130 vs 139 ± 25.8 U/L in nonBA, P = 0.03). There were insignificant differences in sex, type of feeding, TPN exposure and sepsis between the two groups. Although our small sample size limits conclusions, we suggest screening infants with CJ by measuring GGT levels, absence of hepatomegaly, presence of cholic stools and/or excretion on HIDA scan to undergo pecutaneous liver biopsy given the lower likelihood of BA necessary. The presence of cholestatic jaundice (CJ) at two weeks of age in an otherwise healthy infant warrants investigation to determine the underlying cause.1 Its etiology includes numerous causes under two broad groups, obstructive lesions and hepatocellular conditions. Diagnosis requires an extensive radiographic and laboratory investigation.2 After this workup, short of invasive diagnostic procedures, liver biopsy, and open cholangiography, the most common causes that remain are biliary atresia (BA) and neonatal hepatitis (NH).
Author Manuscript
Early diagnosis of BA is crucial because portojejunostomy before 45 to 60 days of life gives the infant the best chance for survival with the native liver.2 Given the priority of early treatment for BA, an expert committee of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition recommends a liver biopsy where the cause of CJ cannot be determined after noninvasive laboratory and imaging tests.1 The definitive diagnosis of BA requires surgical exploration and intraoperative cholangiography to verify
Address correspondence and reprint requests to Daniel K. Robie, M.D., Division of Pediatric Surgery, Nemours Children’s Clinic, 807 Children’s Way, Jacksonville, FL 32207. [email protected]. Presented at the Annual Scientific Meeting, Postgraduate Course Program, and Southeastern Pediatric Surgical Congress at the Southeastern Surgical Congress, Savannah, GA, February 22–25, 2014.
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the absence of a patent extrahepatic biliary system. If no open ducts are found, the surgeon proceeds with portojejunostomy with Roux-en-Y jejunojejunostomy, the Kasai procedure.2 In those who have patent bile ducts, surgery will be nontherapeutic and expose the infants to the risks of laparotomy and anesthesia. Thus, it is of interest to identify predictive pre-operative clinical indices and diagnostic tests that distinguish BA from NH and other causes of CJ. We reviewed our experience to refine a diagnostic approach that allows early in BA and minimizes non-therapeutic surgical exploration.
Methods
Author Manuscript
After obtaining Institutional Review Board approval, the electronic medical records for our practice locations were queried using standard diagnosis and procedure codes to capture all cases with CJ (Table 1) over a 5-year period from 2009 to 2013.3, 4 Record review identified all infants with BA and those with CJ who underwent an evaluation for BA with open or laparoscopic liver biopsy and cholangiography. Patients undergoing only percutaneous liver biopsy without open surgery were excluded.
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Clinical items reviewed included gender, gestational age, route of nutrition (enteral vs parenteral), history of sepsis, transfusions, liver size and firmness, and age in weeks at the time of surgery. Of specific interest was stool color (acholic vs yellow or green) and whether a green stool was passed within the week before surgery. Laboratory indices included serum levels of bilirubin (total and direct) and liver enzymes aspartate transaminase (AST), alanine transaminase, alkaline phosphatase, and gamma-glutamyl transpeptidase (GGT). Radiological reports provided findings on ultrasonography (US) and nuclear cholescintigraphy (hepatobiliary iminodiacetic acid [HIDA]). Pathology reports gave microscopic findings at liver biopsy, including proliferation of bile ducts, bile plugs, portal fibrosis, bridging fibrosis, multinucleated giant cell transformation, myeloid metaplasia, inflammatory infiltrate, and hepatocellular swelling. The results of open cholangiography were reviewed. Those in whom bile ducts were opacified did not have BA (non-BA) and no further surgical procedures were performed. The diagnosis of BA was made where there was no opacification of the biliary tree. Patients with BA then proceeded to an immediate Kasai procedure. Their records were reviewed for clearance of jaundice (serum bilirubin less than 2 mg/dL), occurrence of cholangitis, and need for transplant.
Author Manuscript
Two-sample unpaired t test was used to compare the continuous variables between the BA and non-BA patients. Fisher’s exact test analyzed differences in ratios of dichotomous variables. For both, P < 0.05 reached significance. Odds ratios with associated 95 per cent confidence intervals were calculated for categorical variables in univariate analyses. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for selected tests. A Kaplan-Meier curve was plotted to capture the survival with native liver.
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Results There were 19 infants explored for possible BA and one was explored for malrotation and was found to have BA during operation. Ten had BA and underwent an immediate Kasai portojejunostomy; 10 infants had patent bile ducts and thus did not have BA (non-BA; Table 2). The mean age at time of surgery was equivalent for the two groups (BA, 65 days, range 3 to 112 days; non-BA, 53 days, 29 to 90 days). Of the clinical and laboratory variables listed in the “Materials and Methods,” only GGT reached significance (mean ± standard error of the mean; BA, 542 ± 130 vs 139 ± 25.8 U/L in non-BA, P = 0.03). The remaining features on physical and laboratory examinations did not distinguish between the two groups. All BA patients had serum GGT above 300 U/L, giving a specificity of 100 per cent and a sensitivity of 67 per cent (Table 3).
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HIDA excretion into the gastrointestinal tract was absent in all nine patients with BA who underwent the study and in 8 of the 10 non-BA patients (Table 3). US was obtained in nine BA and 10 non-BA patients. The gallbladder was not seen in two BA and three non-BA patients. The common bile duct was reported as present in six BA and all 10 non-BA patients. Specific mention of the triangular cord sign on focused examination of the portal bifurcation was not made. Wedge liver biopsy specimens were obtained in 19 patients (nine BA, 10 non-BA) at surgery and provided pathological diagnoses and conditions associated with BA and CJ (Table 4). One non-BA patient was thought initially to have BA based on preoperative percutaneous liver biopsy had a normal cholangiogram and open liver biopsy showing neontatal giant cell hepatitis (NNGCH). Another non-BA patient with nonspecific pathologic findings was later found to have Alagille’s syndrome.
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Average postoperative follow-up of patients with BA after a Kasai procedure was 30.3 months (Fig. 1). Eight were jaundice-free with their native liver. Jaundice cleared in these patients an average of 54 days (7 of 8 within 90 days and one at 98 days) post-Kasai. Two patients whose jaundice cleared at 122 and 236 days have since undergone successful fiver transplant. There were no patients with BA with cystic BA or biliary atresia–splenic malformation syndrome and one with heterotaxy and a single spleen.
Discussion
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Our findings emphasize the importance of demonstration of biliary excretion on HIDA scan and biochemical evidence of hepatocellular inflammation with elevation of serum GGT in the workup of an infant with CJ and suspected of having BA. Appearance of HIDA in the duodenum excluded the diagnosis of BA (100% NPV). All cases of BA had elevated serum GGT above 300 U/L (100% PPV). Taken alone, neither was diagnostic; in our limited series, the two studies predicted the diagnosis that was confirmed on open cholangiography. Serial documentation of stool color—green in infancy—gives direct clinical evidence of bile excretion; in BA, the stool is acholic.2 Despite the importance of the finding, we noted few physicians examined and documented stool color and had to rely on nurses’ notes to establish the pigment of the stool. Because within 1 week of surgery, 50 per cent of the non-
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BA patients had a green stool, documentation of its color is essential and may obviate a HIDA scan. Lee and Chai,5 in a series of 146 infants with neonatal cholestasis of which 35 had BA, found stool color to be highly sensitive in BA (83%) but with less specificity (51%). BA is progressive and stool color may progress from green to acholic. Of the two patients with BA in our series with pigmented stools, one was very young and the other a premature infant, and so the diagnosis may have caught the disease early in its course. In their larger series, Lee and Chai5 observed two to have pigmented stools becoming acholic later in the course of disease. The universal screening program using stool color cards in Taiwan reflects its importance in the early diagnosis and treatment of BA.6, 7
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Others have noted the association of BA with elevated GGT.8–12 A study by Tang and associates noted a significant difference between patients with BA and those with neonatal hepatitis (mean level 353 vs 115, respectively, both expressed in U/L; P < 0.001) for a GGT level greater than 300, a sensitivity of 38 per cent and specificity of 98 per cent.11 They noted an GGT/ AST ratio greater than 2 to be highly predictive of BA (odds ratio, 8.0; P < 0.001). In our series, the ratio was not predictive of BA (83% of BA, 40% of non-BA). A meta-analysis by Rendon-Macias and colleagues10 found the optimal threshold for elevation of GGT levels to change with age: greater than 150 for ages less than four weeks; greater than 250, four to eight weeks; and greater than 300, greater than eight weeks.
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Although the presence of hepatomegaly did not reach significance (80% BA, 30% non-BA; P = 0.07) and a palpably “hard” liver less so (50 vs 30%, respectively), Lee and Chai found liver span of greater than 4 cm (sensitivity 77%, specificity 51%) and a hard liver (80 and 65%, respectively) to be a useful assessment in BA.5 Gupta and associates8 reported that a liver edge that was firm and sharp (as opposed to soft and smooth) was one of five clinical features that predicted BA in 87 per cent of cases (82 of 120). US and HIDA are the core radiological tests in the evaluation of CJ. Infants with BA can have a distended gall bladder on US and an identifiable CBD on US, an observation in our series and noted by others. Other workers have described more specific US findings useful in identifying patients with BA.13–17 In nine patients with BA, Choi and colleagues13 described the “triangular cord” sign that was absent in another nine non-BA patients. Mittal and coworkers14 also found the sign to be specific (97%) but not sensitive (23%). Not finding a gallbladder was a specific finding for BA (100%) but also not sensitive (23%). Others suggest that when the gallbladder is seen in BA, it has a characteristically abnormal appearance (the “pseudo-gallbladder” or “gallbladder ghost triad”: atretic gallbladder less than 1.9 cm length, thin and indistinct wall, irregular or lobular contour).15, 17
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The high sensitivity and low specificity of HIDA scans in non-BA have been well documented.18–22 Specificity of nonexcretion of HIDA ranges from 3521 to 74 per cent.18 The 20 per cent specificity in our study may be particularly low but may be explained by our inclusion of only those patients who subsequently underwent surgical exploration. Other series include all infants with CJ including those that did not undergo surgery. Priming bile excretion with ursodeoxycholic acid before HIDA scan may improve excretion of nuclide and thus specificity to 89 from 54 per cent.19
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Pediatric gastroenterologists, through their professional organization, favor percutaneous liver biopsy before surgery where a clear diagnosis is absent.1 A recent study tested interpretation of core and wedge liver biopsies by pathologists experienced in pediatric liver disease reported 91 per cent accuracy in diagnosis of BA.23 The most common pathological findings were bile duct proliferation, portal fibrosis, and absence of sinusoidal fibrosis. Although preoperative biopsy is helpful in the diagnosis of BA, false-positive and falsenegative interpretations occur. Adding confusion to the interpretation of liver biopsy is the change from bile duct proliferation to its gradual disappearance as inflammation and fibrosis progress. Repeat biopsies may be necessary should jaundice fail to clear.24 Other items in the history do not appear to distinguish BA from non-BA patients, specifically events known to contribute to CJ in infancy. Prematurity, blood transfusions, sepsis, and parenteral nutrition were features of both BA and non-BA patients in our series.
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In conclusion, distinguishing CJ infants with BA from those without BA requires thoughtful and thorough evaluation in order to reduce the negative exploration rate. We believe that a step-wise approach similar to approaches advocated by others with prompt exploration of those predicted to have BA is most appropriate.20, 21, 25, 26 Our approach includes noting key clinical findings (stool color and liver size), measuring serum GGT levels and performing radiologic testing (US, HIDA) and possible percutaneous core liver biopsy individualized to each patient.
References
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1. Moyer V, Freese DK, Whitington PF, et al. Guideline for the evaluation of cholestatic jaundice in infants: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr. 2004; 39:115–28. [PubMed: 15269615] 2. Muraji T. Early detection of biliary atresia: past, present and future. Expert Rev Gastroenterol Hepatol. 2012; 6:583–9. [PubMed: 23061709] 3. American Medical Association. 2013 ICD-9-CM for Hospitals. Chicago, IL: American Medical Association; 2013. 4. American Medical Association. CPT. 2012 Professional Edition for Physicians. Chicago, IL: American Medical Association; 2012. 5. Lee WS, Chai PF. Clinical features differentiating biliary atresia from other causes of neonatal cholestasis. Ann Acad Med Singapore. 2010; 39:648–54. [PubMed: 20838708] 6. Lien TH, Chang MH, Wu JF, et al. Effects of the infant stool color card screening program on 5-year outcome of biliary atresia in Taiwan. Hepatology. 2011; 53:202–8. [PubMed: 21140377] 7. Hsiao CH, Chang MH, Chen HL, et al. Universal screening for biliary atresia using an infant stool color card in Taiwan. Hepatology. 2008; 47:1233–10. [PubMed: 18306391] 8. Gupta DK, Srinivas M, Bajpai M. AIIMS clinical score: a reliable aid to distinguish neonatal hepatitis from extra hepatic biliary atresia. Indian J Pediatr. 2001; 68:605–8. [PubMed: 11519282] 9. Sun S, Chen G, Zheng S, et al. Analysis of clinical parameters that contribute to the misdiagnosis of biliary atresia. J Ped Surg. 2013; 48:1490–4. 10. Rendon-Macias ME, Villasis-Keever A, Castraneda-Mucino G, et al. Improvement in accuracy of gamma-glutamyl transferase for differential diagnosis of biliary atresia by correlation with age. Turk J Pediatr. 2008; 50:253–9. [PubMed: 18773671] 11. Tang KS, Huang LT, Huang YH, et al. Gamma-glutamyl transferase in the diagnosis of biliary atresia. Acta Paediatr Tw. 2007; 48:196–200.
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12. Yamagiwa I, Iwafuchi M, Obata K, et al. Pre-operative time course changes in liver function tests in biliary atresia: its usefulness in the discrimination of biliary atresia in early infancy. Acta Paediatr Jpn. 1996; 38:506–12. [PubMed: 8942012] 13. Choi SO, Park WH, Woo SK. Triangular cord sign: a sonographic finding applicable in the diagnosis of biliary atresia. J Pediatr Surg. 1996; 31:363–6. [PubMed: 8708904] 14. Mittal V, Saxena AK, Sokhi KS, et al. Role of abdominal sonography in the preoperative diagnosis of extrahepatic biliary atresia in infants younger than 90 days. Jm J Roentgen. 2011; 196:W438– 15. 15. Aziz S, Wild Y, Rosenthal P, et al. Pseudo-gallbladder sign in biliary atresia—an imaging pitfall. Pediatr Radiol. 2011; 41:620–6. [PubMed: 21409545] 16. Sun Y, Zheng S, Qian Q. Ultrasonographic evaluation in the differential diagnosis of biliary atresia and infantile hepatitis syndrome. Pediatr Surg Int. 2011; 27:675–9. [PubMed: 21207229] 17. Tan-Kendrick AP, Phua KB, Ooi BC, et al. Biliary atresia: making the diagnosis by the gallbladder ghost triad. Pediatr Radiol. 2003; 33:311–5. [PubMed: 12695863] 18. Gilmour SM, Hershkop M, Reifen R, et al. Outcome of hepatobiliary scanning in neonatal hepatitis syndrome. J Nucl Med. 1997; 38:1279–82. [PubMed: 9255166] 19. Poddar U, Bhattacharya A, Thapa BR, et al. Ursodeoxycholic acid-augmented hepatobiliary scintigraphy in the evaluation of neonatal jaundice. J Nucl Med. 2004; 45:1488–92. [PubMed: 15347715] 20. Arora NK, Kohli R, Gupta DK, et al. Hepatic technetium-99m-mebrofenin iminodiacetate scans and serum GGT levels interpreted in series to differentiate between extrahepatic biliary atresia and neonatal hepatitis. Acta Paediatr. 2001; 90:975–81. [PubMed: 11683209] 21. Park WH, Choi SO, Lee HJ, et al. A new diagnostic approach to biliary atresia with emphasis on the ultrasonographic triangular cord sign: comparison of ultrasonography, hepatobiliary scintigraphy, and liver needle biopsy in the evaluation of infantile cholestasis. J Ped Surg. 1997; 11:1555–9. 22. Lai MW, Chang MH, Hsu SC, et al. Differential diagnosis of extrahepatic biliary atresia from neonatal hepatitis: a prospective study. J Pediatr Gastroenterol Nutr. 1994; 18:121–7. [PubMed: 8014758] 23. Russo P, Magee JC, Boitnott J, et al. Design and validation of the biliary atresia research consortium histologic assessment system for cholestasis in infancy. Clin Gastroenterol Hepatol. 2011; 9:357–62. [PubMed: 21238606] 24. Yeh MM. Pathologic diagnosis of biliary atresia on liver biopsy: is tissue the issue? J Gastroenterol Hepatol. 2009; 24:936–8. [PubMed: 19638075] 25. Roquete MLV, Ferreira AR, Fagundes EDT, et al. Accuracy of echogenic periportal enlargement image in ultrasonographic exams and histopathology in differential diagnosis of biliary atresia. J Pediatr. 2008; 84:331–6. 26. Hartley JL, Davenport M, Kelly DA. Biliary atresia. Lancet. 2009; 374:1704–13. [PubMed: 19914515]
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Author Manuscript Author Manuscript Fig. 1.
Kaplan-Meier plot of jaundice-free survival with native liver (solid line) in days. Ninety-five per cent confidence interval shown (dashed lines).
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Table 1
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ICD-9-CM and CPT Codes Used to Identify Cases for Review ICD-9-CM Codes
Diagnosis
573.8
Other specified disorders of liver
573.9
Unspecified disorder of liver
576.8
Other specified disorders of biliary tract Adhesions of bile duct [any] Atrophy of bile duct [any] Cyst of bile duct [any] Hypertrophy of bile duct [any] Stasis of bile duct [any] Ulcer of bile duct [any] Excludes
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Congenital choledochal cyst (751.69) 751.61
Biliary atresia Congenital: Absence of bile duct (common) or passage Hypoplasia of bile duct (common) or passage Obstruction of bile duct (common) or passage Stricture of bile duct (common) or passage
774.6
Unspecified fetal and neonatal jaundice Icterus neonatorum Neonatal hyperbilirubinemia (transient) Physiologic jaundice NOS in newborn
CPT
Procedure
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47700
Exploration for congenital atresia of bile ducts, without repair, with or without liver biopsy, with or without cholangiography
47701
Portoenterostomy (e.g., Kasai procedure)
47100
Biopsy of liver, wedge
47605
Cholecystectomy; with cholangiography
ICD-9-CM, International Classification of Diseases, 9th Revision, Clinical Modification; CPT, Current Procedural Terminology; NOS, not otherwise specified.
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Table 2
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Comparison of Selected Indices of Patients with and without Biliaiy Atresia
Sex (maleifemale) Hepatomegaly Pigmented stools GGT (U/L; mean ± SEM) History of sepsis
P Value
Biliary Atresia (n = 10)
Nonbiliary Atresia (n = 10)
5:5
9:1
0.14
8
3
0.07
2
5
0.35
542 ± 130 (n = 6)
139 ± 25.8 (n = 5)
0.028
2
4
0.63
Feedings (formula vs breast)
8:2
4:6
0.17
Parenteral nutrition (> 7 days)
0
3
0.210
GGT, serum gamma-glutamyl transpeptidase level; SEM, standard error of mean.
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Table 3
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Sensitivity, Specificity, and Positive and Negative Predictive Values in Distinguishing between Patients with and without Biliary Atresia
GGT > 300 U/L HIDA nonexcretion
Sensitivity
Specificity
PPV
NPV
67%
100%
100%
71%
100%
20%
56%
100%
PPV, positive predictive value; NPV, negative predictive value; GGT, serum gamma-glutamyl transpeptidase level; HIDA, nuclear cholescintigraphy with hepatobiliary iminodiacetic acid.
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Table 4
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Pathologic Diagnoses on Liver Biopsy in Patients with and without Biliary Atresia with Cholestatic Jaundice* Pathologic Finding
Biliary Atresia (n = 9)
Nonbiliary Atresia (n = 10)
Proliferating bile ducts
8
7
Bridging fibrosis
8
5
Neonatal giant cell hepatitis
0
4
Parenteral nutrition-associated liver disease
0
3
Other
0
2
Nonspecific
1
1
*
Totals are more than total number of patients because patients had more than one pathologic finding. Total number of patients with biliary atresia is 10; one did not have a liver biopsy.
Author Manuscript Author Manuscript Author Manuscript Am Surg. Author manuscript; available in PMC 2017 October 20.
Am Surg. Author manuscript; available in PMC 2017 October 20. Published in final edited form as: Am Surg. 2014 September ; 80(9): 827–831.
Differentiating Biliary Atresia from Other Causes of Cholestatic Jaundice DANIEL K. ROBIE, M.D., SARAH R. OVERFELT, B.S., and LI XIE, S.C.M. Division of Pediatric Surgery, Nemours Children’s Clinic, Jacksonville, Florida
Abstract Author Manuscript Author Manuscript
Diagnosis of biliary atresia (BA) in infants presenting with cholestatic jaundice (CJ) requires exploratory surgery with cholangiography. However, the lack of a standardized approach to preoperative evaluation of infants with CJ can lead to a high number of negative surgical explorations. We reviewed our experience with CJ and BA to determine preoperative variables that might reliably identify BA. Infants explored for possible BA over a 5–year period were retrospectively reviewed. Preoperative clinical indices and liver biopsy results were reviewed. Statistical analysis was conducted by Student’s t test and Fisher’s exact test (P < 0.05). Twenty patients were identified, 10 with BA and 10 without (50% negative exploration rate). Nuclear cholescintigraphy (HIDA) excretion into the gastrointestinal tract was absent in all BA and in 8 of 10 without BA. Hepatomegaly was more common in the BA group (OR = 9.3, P = 0.07). BA had higher mean (± standard error) serum gamma-glutamyl transpeptidase levels (542 ± 130 vs 139 ± 25.8 U/L in nonBA, P = 0.03). There were insignificant differences in sex, type of feeding, TPN exposure and sepsis between the two groups. Although our small sample size limits conclusions, we suggest screening infants with CJ by measuring GGT levels, absence of hepatomegaly, presence of cholic stools and/or excretion on HIDA scan to undergo pecutaneous liver biopsy given the lower likelihood of BA necessary. The presence of cholestatic jaundice (CJ) at two weeks of age in an otherwise healthy infant warrants investigation to determine the underlying cause.1 Its etiology includes numerous causes under two broad groups, obstructive lesions and hepatocellular conditions. Diagnosis requires an extensive radiographic and laboratory investigation.2 After this workup, short of invasive diagnostic procedures, liver biopsy, and open cholangiography, the most common causes that remain are biliary atresia (BA) and neonatal hepatitis (NH).
Author Manuscript
Early diagnosis of BA is crucial because portojejunostomy before 45 to 60 days of life gives the infant the best chance for survival with the native liver.2 Given the priority of early treatment for BA, an expert committee of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition recommends a liver biopsy where the cause of CJ cannot be determined after noninvasive laboratory and imaging tests.1 The definitive diagnosis of BA requires surgical exploration and intraoperative cholangiography to verify
Address correspondence and reprint requests to Daniel K. Robie, M.D., Division of Pediatric Surgery, Nemours Children’s Clinic, 807 Children’s Way, Jacksonville, FL 32207. [email protected]. Presented at the Annual Scientific Meeting, Postgraduate Course Program, and Southeastern Pediatric Surgical Congress at the Southeastern Surgical Congress, Savannah, GA, February 22–25, 2014.
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the absence of a patent extrahepatic biliary system. If no open ducts are found, the surgeon proceeds with portojejunostomy with Roux-en-Y jejunojejunostomy, the Kasai procedure.2 In those who have patent bile ducts, surgery will be nontherapeutic and expose the infants to the risks of laparotomy and anesthesia. Thus, it is of interest to identify predictive pre-operative clinical indices and diagnostic tests that distinguish BA from NH and other causes of CJ. We reviewed our experience to refine a diagnostic approach that allows early in BA and minimizes non-therapeutic surgical exploration.
Methods
Author Manuscript
After obtaining Institutional Review Board approval, the electronic medical records for our practice locations were queried using standard diagnosis and procedure codes to capture all cases with CJ (Table 1) over a 5-year period from 2009 to 2013.3, 4 Record review identified all infants with BA and those with CJ who underwent an evaluation for BA with open or laparoscopic liver biopsy and cholangiography. Patients undergoing only percutaneous liver biopsy without open surgery were excluded.
Author Manuscript
Clinical items reviewed included gender, gestational age, route of nutrition (enteral vs parenteral), history of sepsis, transfusions, liver size and firmness, and age in weeks at the time of surgery. Of specific interest was stool color (acholic vs yellow or green) and whether a green stool was passed within the week before surgery. Laboratory indices included serum levels of bilirubin (total and direct) and liver enzymes aspartate transaminase (AST), alanine transaminase, alkaline phosphatase, and gamma-glutamyl transpeptidase (GGT). Radiological reports provided findings on ultrasonography (US) and nuclear cholescintigraphy (hepatobiliary iminodiacetic acid [HIDA]). Pathology reports gave microscopic findings at liver biopsy, including proliferation of bile ducts, bile plugs, portal fibrosis, bridging fibrosis, multinucleated giant cell transformation, myeloid metaplasia, inflammatory infiltrate, and hepatocellular swelling. The results of open cholangiography were reviewed. Those in whom bile ducts were opacified did not have BA (non-BA) and no further surgical procedures were performed. The diagnosis of BA was made where there was no opacification of the biliary tree. Patients with BA then proceeded to an immediate Kasai procedure. Their records were reviewed for clearance of jaundice (serum bilirubin less than 2 mg/dL), occurrence of cholangitis, and need for transplant.
Author Manuscript
Two-sample unpaired t test was used to compare the continuous variables between the BA and non-BA patients. Fisher’s exact test analyzed differences in ratios of dichotomous variables. For both, P < 0.05 reached significance. Odds ratios with associated 95 per cent confidence intervals were calculated for categorical variables in univariate analyses. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for selected tests. A Kaplan-Meier curve was plotted to capture the survival with native liver.
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Results There were 19 infants explored for possible BA and one was explored for malrotation and was found to have BA during operation. Ten had BA and underwent an immediate Kasai portojejunostomy; 10 infants had patent bile ducts and thus did not have BA (non-BA; Table 2). The mean age at time of surgery was equivalent for the two groups (BA, 65 days, range 3 to 112 days; non-BA, 53 days, 29 to 90 days). Of the clinical and laboratory variables listed in the “Materials and Methods,” only GGT reached significance (mean ± standard error of the mean; BA, 542 ± 130 vs 139 ± 25.8 U/L in non-BA, P = 0.03). The remaining features on physical and laboratory examinations did not distinguish between the two groups. All BA patients had serum GGT above 300 U/L, giving a specificity of 100 per cent and a sensitivity of 67 per cent (Table 3).
Author Manuscript
HIDA excretion into the gastrointestinal tract was absent in all nine patients with BA who underwent the study and in 8 of the 10 non-BA patients (Table 3). US was obtained in nine BA and 10 non-BA patients. The gallbladder was not seen in two BA and three non-BA patients. The common bile duct was reported as present in six BA and all 10 non-BA patients. Specific mention of the triangular cord sign on focused examination of the portal bifurcation was not made. Wedge liver biopsy specimens were obtained in 19 patients (nine BA, 10 non-BA) at surgery and provided pathological diagnoses and conditions associated with BA and CJ (Table 4). One non-BA patient was thought initially to have BA based on preoperative percutaneous liver biopsy had a normal cholangiogram and open liver biopsy showing neontatal giant cell hepatitis (NNGCH). Another non-BA patient with nonspecific pathologic findings was later found to have Alagille’s syndrome.
Author Manuscript
Average postoperative follow-up of patients with BA after a Kasai procedure was 30.3 months (Fig. 1). Eight were jaundice-free with their native liver. Jaundice cleared in these patients an average of 54 days (7 of 8 within 90 days and one at 98 days) post-Kasai. Two patients whose jaundice cleared at 122 and 236 days have since undergone successful fiver transplant. There were no patients with BA with cystic BA or biliary atresia–splenic malformation syndrome and one with heterotaxy and a single spleen.
Discussion
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Our findings emphasize the importance of demonstration of biliary excretion on HIDA scan and biochemical evidence of hepatocellular inflammation with elevation of serum GGT in the workup of an infant with CJ and suspected of having BA. Appearance of HIDA in the duodenum excluded the diagnosis of BA (100% NPV). All cases of BA had elevated serum GGT above 300 U/L (100% PPV). Taken alone, neither was diagnostic; in our limited series, the two studies predicted the diagnosis that was confirmed on open cholangiography. Serial documentation of stool color—green in infancy—gives direct clinical evidence of bile excretion; in BA, the stool is acholic.2 Despite the importance of the finding, we noted few physicians examined and documented stool color and had to rely on nurses’ notes to establish the pigment of the stool. Because within 1 week of surgery, 50 per cent of the non-
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BA patients had a green stool, documentation of its color is essential and may obviate a HIDA scan. Lee and Chai,5 in a series of 146 infants with neonatal cholestasis of which 35 had BA, found stool color to be highly sensitive in BA (83%) but with less specificity (51%). BA is progressive and stool color may progress from green to acholic. Of the two patients with BA in our series with pigmented stools, one was very young and the other a premature infant, and so the diagnosis may have caught the disease early in its course. In their larger series, Lee and Chai5 observed two to have pigmented stools becoming acholic later in the course of disease. The universal screening program using stool color cards in Taiwan reflects its importance in the early diagnosis and treatment of BA.6, 7
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Others have noted the association of BA with elevated GGT.8–12 A study by Tang and associates noted a significant difference between patients with BA and those with neonatal hepatitis (mean level 353 vs 115, respectively, both expressed in U/L; P < 0.001) for a GGT level greater than 300, a sensitivity of 38 per cent and specificity of 98 per cent.11 They noted an GGT/ AST ratio greater than 2 to be highly predictive of BA (odds ratio, 8.0; P < 0.001). In our series, the ratio was not predictive of BA (83% of BA, 40% of non-BA). A meta-analysis by Rendon-Macias and colleagues10 found the optimal threshold for elevation of GGT levels to change with age: greater than 150 for ages less than four weeks; greater than 250, four to eight weeks; and greater than 300, greater than eight weeks.
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Although the presence of hepatomegaly did not reach significance (80% BA, 30% non-BA; P = 0.07) and a palpably “hard” liver less so (50 vs 30%, respectively), Lee and Chai found liver span of greater than 4 cm (sensitivity 77%, specificity 51%) and a hard liver (80 and 65%, respectively) to be a useful assessment in BA.5 Gupta and associates8 reported that a liver edge that was firm and sharp (as opposed to soft and smooth) was one of five clinical features that predicted BA in 87 per cent of cases (82 of 120). US and HIDA are the core radiological tests in the evaluation of CJ. Infants with BA can have a distended gall bladder on US and an identifiable CBD on US, an observation in our series and noted by others. Other workers have described more specific US findings useful in identifying patients with BA.13–17 In nine patients with BA, Choi and colleagues13 described the “triangular cord” sign that was absent in another nine non-BA patients. Mittal and coworkers14 also found the sign to be specific (97%) but not sensitive (23%). Not finding a gallbladder was a specific finding for BA (100%) but also not sensitive (23%). Others suggest that when the gallbladder is seen in BA, it has a characteristically abnormal appearance (the “pseudo-gallbladder” or “gallbladder ghost triad”: atretic gallbladder less than 1.9 cm length, thin and indistinct wall, irregular or lobular contour).15, 17
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The high sensitivity and low specificity of HIDA scans in non-BA have been well documented.18–22 Specificity of nonexcretion of HIDA ranges from 3521 to 74 per cent.18 The 20 per cent specificity in our study may be particularly low but may be explained by our inclusion of only those patients who subsequently underwent surgical exploration. Other series include all infants with CJ including those that did not undergo surgery. Priming bile excretion with ursodeoxycholic acid before HIDA scan may improve excretion of nuclide and thus specificity to 89 from 54 per cent.19
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Pediatric gastroenterologists, through their professional organization, favor percutaneous liver biopsy before surgery where a clear diagnosis is absent.1 A recent study tested interpretation of core and wedge liver biopsies by pathologists experienced in pediatric liver disease reported 91 per cent accuracy in diagnosis of BA.23 The most common pathological findings were bile duct proliferation, portal fibrosis, and absence of sinusoidal fibrosis. Although preoperative biopsy is helpful in the diagnosis of BA, false-positive and falsenegative interpretations occur. Adding confusion to the interpretation of liver biopsy is the change from bile duct proliferation to its gradual disappearance as inflammation and fibrosis progress. Repeat biopsies may be necessary should jaundice fail to clear.24 Other items in the history do not appear to distinguish BA from non-BA patients, specifically events known to contribute to CJ in infancy. Prematurity, blood transfusions, sepsis, and parenteral nutrition were features of both BA and non-BA patients in our series.
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In conclusion, distinguishing CJ infants with BA from those without BA requires thoughtful and thorough evaluation in order to reduce the negative exploration rate. We believe that a step-wise approach similar to approaches advocated by others with prompt exploration of those predicted to have BA is most appropriate.20, 21, 25, 26 Our approach includes noting key clinical findings (stool color and liver size), measuring serum GGT levels and performing radiologic testing (US, HIDA) and possible percutaneous core liver biopsy individualized to each patient.
References
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1. Moyer V, Freese DK, Whitington PF, et al. Guideline for the evaluation of cholestatic jaundice in infants: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr. 2004; 39:115–28. [PubMed: 15269615] 2. Muraji T. Early detection of biliary atresia: past, present and future. Expert Rev Gastroenterol Hepatol. 2012; 6:583–9. [PubMed: 23061709] 3. American Medical Association. 2013 ICD-9-CM for Hospitals. Chicago, IL: American Medical Association; 2013. 4. American Medical Association. CPT. 2012 Professional Edition for Physicians. Chicago, IL: American Medical Association; 2012. 5. Lee WS, Chai PF. Clinical features differentiating biliary atresia from other causes of neonatal cholestasis. Ann Acad Med Singapore. 2010; 39:648–54. [PubMed: 20838708] 6. Lien TH, Chang MH, Wu JF, et al. Effects of the infant stool color card screening program on 5-year outcome of biliary atresia in Taiwan. Hepatology. 2011; 53:202–8. [PubMed: 21140377] 7. Hsiao CH, Chang MH, Chen HL, et al. Universal screening for biliary atresia using an infant stool color card in Taiwan. Hepatology. 2008; 47:1233–10. [PubMed: 18306391] 8. Gupta DK, Srinivas M, Bajpai M. AIIMS clinical score: a reliable aid to distinguish neonatal hepatitis from extra hepatic biliary atresia. Indian J Pediatr. 2001; 68:605–8. [PubMed: 11519282] 9. Sun S, Chen G, Zheng S, et al. Analysis of clinical parameters that contribute to the misdiagnosis of biliary atresia. J Ped Surg. 2013; 48:1490–4. 10. Rendon-Macias ME, Villasis-Keever A, Castraneda-Mucino G, et al. Improvement in accuracy of gamma-glutamyl transferase for differential diagnosis of biliary atresia by correlation with age. Turk J Pediatr. 2008; 50:253–9. [PubMed: 18773671] 11. Tang KS, Huang LT, Huang YH, et al. Gamma-glutamyl transferase in the diagnosis of biliary atresia. Acta Paediatr Tw. 2007; 48:196–200.
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12. Yamagiwa I, Iwafuchi M, Obata K, et al. Pre-operative time course changes in liver function tests in biliary atresia: its usefulness in the discrimination of biliary atresia in early infancy. Acta Paediatr Jpn. 1996; 38:506–12. [PubMed: 8942012] 13. Choi SO, Park WH, Woo SK. Triangular cord sign: a sonographic finding applicable in the diagnosis of biliary atresia. J Pediatr Surg. 1996; 31:363–6. [PubMed: 8708904] 14. Mittal V, Saxena AK, Sokhi KS, et al. Role of abdominal sonography in the preoperative diagnosis of extrahepatic biliary atresia in infants younger than 90 days. Jm J Roentgen. 2011; 196:W438– 15. 15. Aziz S, Wild Y, Rosenthal P, et al. Pseudo-gallbladder sign in biliary atresia—an imaging pitfall. Pediatr Radiol. 2011; 41:620–6. [PubMed: 21409545] 16. Sun Y, Zheng S, Qian Q. Ultrasonographic evaluation in the differential diagnosis of biliary atresia and infantile hepatitis syndrome. Pediatr Surg Int. 2011; 27:675–9. [PubMed: 21207229] 17. Tan-Kendrick AP, Phua KB, Ooi BC, et al. Biliary atresia: making the diagnosis by the gallbladder ghost triad. Pediatr Radiol. 2003; 33:311–5. [PubMed: 12695863] 18. Gilmour SM, Hershkop M, Reifen R, et al. Outcome of hepatobiliary scanning in neonatal hepatitis syndrome. J Nucl Med. 1997; 38:1279–82. [PubMed: 9255166] 19. Poddar U, Bhattacharya A, Thapa BR, et al. Ursodeoxycholic acid-augmented hepatobiliary scintigraphy in the evaluation of neonatal jaundice. J Nucl Med. 2004; 45:1488–92. [PubMed: 15347715] 20. Arora NK, Kohli R, Gupta DK, et al. Hepatic technetium-99m-mebrofenin iminodiacetate scans and serum GGT levels interpreted in series to differentiate between extrahepatic biliary atresia and neonatal hepatitis. Acta Paediatr. 2001; 90:975–81. [PubMed: 11683209] 21. Park WH, Choi SO, Lee HJ, et al. A new diagnostic approach to biliary atresia with emphasis on the ultrasonographic triangular cord sign: comparison of ultrasonography, hepatobiliary scintigraphy, and liver needle biopsy in the evaluation of infantile cholestasis. J Ped Surg. 1997; 11:1555–9. 22. Lai MW, Chang MH, Hsu SC, et al. Differential diagnosis of extrahepatic biliary atresia from neonatal hepatitis: a prospective study. J Pediatr Gastroenterol Nutr. 1994; 18:121–7. [PubMed: 8014758] 23. Russo P, Magee JC, Boitnott J, et al. Design and validation of the biliary atresia research consortium histologic assessment system for cholestasis in infancy. Clin Gastroenterol Hepatol. 2011; 9:357–62. [PubMed: 21238606] 24. Yeh MM. Pathologic diagnosis of biliary atresia on liver biopsy: is tissue the issue? J Gastroenterol Hepatol. 2009; 24:936–8. [PubMed: 19638075] 25. Roquete MLV, Ferreira AR, Fagundes EDT, et al. Accuracy of echogenic periportal enlargement image in ultrasonographic exams and histopathology in differential diagnosis of biliary atresia. J Pediatr. 2008; 84:331–6. 26. Hartley JL, Davenport M, Kelly DA. Biliary atresia. Lancet. 2009; 374:1704–13. [PubMed: 19914515]
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Kaplan-Meier plot of jaundice-free survival with native liver (solid line) in days. Ninety-five per cent confidence interval shown (dashed lines).
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Table 1
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ICD-9-CM and CPT Codes Used to Identify Cases for Review ICD-9-CM Codes
Diagnosis
573.8
Other specified disorders of liver
573.9
Unspecified disorder of liver
576.8
Other specified disorders of biliary tract Adhesions of bile duct [any] Atrophy of bile duct [any] Cyst of bile duct [any] Hypertrophy of bile duct [any] Stasis of bile duct [any] Ulcer of bile duct [any] Excludes
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Congenital choledochal cyst (751.69) 751.61
Biliary atresia Congenital: Absence of bile duct (common) or passage Hypoplasia of bile duct (common) or passage Obstruction of bile duct (common) or passage Stricture of bile duct (common) or passage
774.6
Unspecified fetal and neonatal jaundice Icterus neonatorum Neonatal hyperbilirubinemia (transient) Physiologic jaundice NOS in newborn
CPT
Procedure
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47700
Exploration for congenital atresia of bile ducts, without repair, with or without liver biopsy, with or without cholangiography
47701
Portoenterostomy (e.g., Kasai procedure)
47100
Biopsy of liver, wedge
47605
Cholecystectomy; with cholangiography
ICD-9-CM, International Classification of Diseases, 9th Revision, Clinical Modification; CPT, Current Procedural Terminology; NOS, not otherwise specified.
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Table 2
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Comparison of Selected Indices of Patients with and without Biliaiy Atresia
Sex (maleifemale) Hepatomegaly Pigmented stools GGT (U/L; mean ± SEM) History of sepsis
P Value
Biliary Atresia (n = 10)
Nonbiliary Atresia (n = 10)
5:5
9:1
0.14
8
3
0.07
2
5
0.35
542 ± 130 (n = 6)
139 ± 25.8 (n = 5)
0.028
2
4
0.63
Feedings (formula vs breast)
8:2
4:6
0.17
Parenteral nutrition (> 7 days)
0
3
0.210
GGT, serum gamma-glutamyl transpeptidase level; SEM, standard error of mean.
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Table 3
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Sensitivity, Specificity, and Positive and Negative Predictive Values in Distinguishing between Patients with and without Biliary Atresia
GGT > 300 U/L HIDA nonexcretion
Sensitivity
Specificity
PPV
NPV
67%
100%
100%
71%
100%
20%
56%
100%
PPV, positive predictive value; NPV, negative predictive value; GGT, serum gamma-glutamyl transpeptidase level; HIDA, nuclear cholescintigraphy with hepatobiliary iminodiacetic acid.
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Table 4
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Pathologic Diagnoses on Liver Biopsy in Patients with and without Biliary Atresia with Cholestatic Jaundice* Pathologic Finding
Biliary Atresia (n = 9)
Nonbiliary Atresia (n = 10)
Proliferating bile ducts
8
7
Bridging fibrosis
8
5
Neonatal giant cell hepatitis
0
4
Parenteral nutrition-associated liver disease
0
3
Other
0
2
Nonspecific
1
1
*
Totals are more than total number of patients because patients had more than one pathologic finding. Total number of patients with biliary atresia is 10; one did not have a liver biopsy.
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