Biliary Atresia. Greg Tiao, MD. 3 rd Annual Pediatric Surgery Update Course GlobalCastMD

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1 Biliary Atresia Greg Tiao, MD GlobalCastMD 3 rd Annual Pediatric Surgery Update Course 2015

2 Case Pediatrician calls you about a 60 day old full term male who is otherwise healthy but is noted to have persistent jaundice. Image courtesy of

3 Case Physical exam reveals a jaundiced male who is otherwise well. Sclera are icteric, hepatomegaly present. Stool is acholic Laboratory Analysis Dbili 5.8 Tbili 8.3 Alk phos 527 AST 295 ALT 169 GGT 1062 WBC 19.7 HGB 8.6 Abdominal x-ray: normal.

4 Differential Diagnosis for Cholestasis in an Infant Anatomic Biliary Atresia Choledochal Cysts Inspissated Bile Syndrome Non anatomic Biliary Hypoplasia - Alagille s Inborn errors of bile acid synthesis - PFIC Intrahepatic Cholestasis PFIC Metabolic disorders Alpha 1 anti-trypsin, cystic fibrosis Infection Sepsis, CMV, Rubella Idiopathic neonatal hepatitis

5 Question How would you further assess this patient? What studies would you perform to establish a diagnosis of biliary atresia?

6 Diagnostic Evaluation Biochemical analysis Fractionated bilirubin and liver enzyme analysis including GGT Other laboratory studies Alpha1 antitrypsin level and phenotype TSH If GGT low, serum bile acids Jaundice Chip Imaging Ultrasound HIDA scan Percutaneous liver biopsy Intraoperative cholangiogram and biopsy

7 Diagnostic Imaging in Cholestatic Infant US: primary modality No sedation, no radiation, good visualization Distal CBD often limited by bowel gas Assess for biliary atresia Exclude other causes of obstructive jaundice Look for associated anomalies (e.g. situs inversus) US Myth #1: Absence of the GB confirms BA Truth: GB may not be seen in: Severe neonatal hepatitis (10%) with low bile production Congenital absence (without BA) or ectopic GB

8 Diagnostic Imaging in Cholestatic Infant US Myth #2: Presence/visualization of the GB excludes BA Truth: GB is usually seen in BA with newer transducers Expect to see and closely evaluate the GB US Myth #3: Ultrasound does not specifically differentiate between biliary atresia and neonatal hepatitis Truth: Recent radiology studies show high specificity of ultrasound signs for biliary atresia

9 Biliary Atresia Ultrasound Triangular Cord Sign Triangular or tubular density cranial to the portal vein bifurcation The fibrotic remnant of the obliterated cord/ extrahepatic bile ducts Sensitivity = 80% Specificity = 98% PPV/NPV = 94% Well-defined triangular echogenic cord in 6-week-old infant (transverse scan). Lee et al, Radiology, 2003 Tan Kendrick et al, Pediatr Radiol, 2000

10 Diagnostic Imaging in Cholestatic Infant HIDA scan Pre-treat with phenobarbital 2.5 mg/kg for 3-5 days Normal Scintigraphy: Immediate liver uptake Hepatobiliary tree, CDB, GB visualized by 30 min. Then small bowel activity. If non-visualization of any structures, delayed images up to 24 hrs. Normal hepatobiliary scan frontal images obtained every five minutes.

11 Abnormal Scintigraphy Immediate increased liver uptake Rapid clearance of the cardiac blood pool No GB or bowel uptake Sensitivity =91.7 %, Specificity = 76.9 %, Accuracy = 81.6% Biliary Atresia Kwatra et al, Pediatr Radiol, 2013

12 Evaluation of Cholestatic Infant Do you routinely obtain a liver biopsy? A) Yes B) No

13 Evaluation of Cholestatic Infant How would you perform a liver biopsy? A) Percutaneous B) Open, separate procedure in conjunction with cholangiogram C) Open in conjunction with cholangiogram and Kasai (if cholangiogram is positive)

14 Liver Biopsy

15 Continuation of Case Upon exploring the abdomen of the infant presumed to have biliary atresia, you find a small gallbladder that appears to have a lumen. How will you proceed? What will you do if you identify hypoplastic ducts on cholangiogram?

16 Patterns of Atresia

17 Intraoperative Cholangiogram

18 Biliary Atresia Inflammatory cholangiopathy of the newborn Incidence - 1 in 10,000 live births On occasion associated with congenital anomalies Polysplenia syndrome multiple spleens, malrotation, preduodenal portal vein, bilobar lungs, situs inversus, IVC anomalies Fibrosis and obliteration of the biliary tract Biliary cirrhosis 100% mortality without treatment

19 Treatment Kasai Portoenterostomy Liver Transplantation

20 Kasai Portoenterostomy First described by Kasai in 1950 s Roux-en-Y Hilar plate to mucosal anastomosis Multiple modifications Diverting stomas Refluxing valve Gallbladder

21 Biliary Atresia Extended Dissection

22 Hilar Dissection

23 Divided Fibrous Plate in Hilum EXTENDED DISSECTION AREAS P.V. H.A.

24 Roux-En-Y in Hilum

25 Polysplenia Syndrome

26 Polysplenia Syndrome

27 Cystic Variant of Biliary Atresia Ladd s Correctable variant biliary atresia In utero detection in 40% Surgical intervention at earlier age Better prognosis surgery at earlier age Caponcellia et al, JPS, 2008

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29 Operative Considerations Which length roux limb do you routinely use? A) <20 cm B) cm C) cm D) cm E) >50 cm Do you consider any modifications of the Roux such as a anti-refluxing valve? A) yes B) no

30 Kasai Portoenterostomy Outcome Outcome Bile drainage without the progression to end-stage liver disease Age at intervention Experience and operative technique of surgeon Size of bile ducts in porta hepatis Acquired versus Congenital variants Immunosuppression/anti-inflammatory agents Revision of Kasai

31 Question What do you believe is the optimal age for performing a successful Kasai procedure? A) <30 days B) <45 days C) <60 days D) <90 days E) It does not matter

32 Survival vs Age at Operation Age at Operation (days) # Cases 10 yr Survival # (%) (34) (24) (26) > Karrar, et al. Arch Surg 131:493, 1996.

33 Survival vs Age at Operation 743 patients with biliary atresia diagnosed in France from with median follow up of 7 years Survival rate with native liver decreased at all time points as age increased Age at Kasai (n) 2y SNL (n) 5y SNL (n) 10y SNL (n) 15y SNL (n) 30d (59) 66% (35) 58% (21) 43% (6) - (0) 31-45d (131) 66% (79) 41% (37) 41% (20) 41% (4) 46-60d (162) 58% (89) 42% (45) 36% (18) 33% (2) 61-75d (159) 57% (82) 36% (39) 32% (24) 29% (7) 76-90d (90) 52% (43) 26% (17) 20% (8) 17% (6) >90d (84) 42% (31) 27% (15) 20% (9) 13% (2) Serinet et al, et al. Pediatrics, 2009.

34 Question Does your practice have 1-2 surgeons that perform the majority of the Kasai procedures? A) Yes B) No

35 Question How many Kasai procedures do you perform per year? A) 0 B) 1-2 C) 3-5 D) >5

36 % SURVIVAL UK Study - Center Effect YEARS POST KASAI Group A (>5 cases) Group B (< 5 cases) McKiernan PJ et al, Lancet, 2000

37 Question Do you use postoperative corticosteroids? A) Yes B) No

38 Corticosteroids and Biliary Atresia Randomized, double-blind, placebo-controlled trial of corticosteroids after Kasai portoenterostomy for biliary atresia. Davenport et al, Hepatology, 2007 Low dose steroid (2mg/kg for day7-21, 1mg/kg day 21-28) No benefit Postoperative high-dose corticosteroids do not improve mid term survival with native liver in biliary atresia. Petersen C, et al, Am J Gastro, 2008 Higher dose (10mg/kg for 5 days, then 1mg/kg for 4 weeks) No benefit

39 Childhood Liver Disease Research and Education Network (ChiLDREN) Biliary Atresia Research Consortium Objectives Prospective Data Collection Clinical Research Studies Benchwork Research Opportunities Supported by NIDDK U01

40 Steroids in Biliary Atresia Randomized Trial (START) ChiLDREN Consortium Randomized, multicenter trial of 140 infants receiving corticosteroids vs placebo after Kasai No improvement in bile drainage (59 vs 49%) No difference in transplant-free survival at 24 months (58 vs 59%) No difference in adverse events (81 vs 80%) Significant increase in adverse events at 30 days (37 vs 19%, p = 0.008) Bezerra et al, JAMA, 2014

41 Question Do you routinely use postoperative antibiotics? If so, for what duration? A) No B) Yes, <6 months C) Yes, 6-12 months D) Yes, >1 year

42 Bu et al 2003 (Taiwan) Randomized trial of 36 infants with biliary atresia with 1 episode of cholangitis 9 treated with TMP/SMZ for mean 14.6 mo 52% recurrence at 40 month follow up (p = 0.042) 9 treated with neomycin for mean 14.7 mo 42% recurrence at 40 month follow up (p = 0.011) 18 with no prophylaxis 100% recurrence at 39 month follow up

43 Question Do you ever perform revisions of a Kasai procedure? A) Yes B) No

44 Question If you perform revisions, what postoperative timeframe would you consider? A) No B) Yes, <1 month C) Yes, <3 months D) Yes, <6 months E) Yes, <1 year

45 Kasai Revision Revision of Kasai is often seen as a hindrance to future transplant Reported complications from adhesiolysis, blood loss, operative time, posttransplant management Hasegawa et al patients underwent Kasai revision for poor bile drainage. Conclusion: revision was an appropriate option if patients had not yet developed liver fibrosis or cirrhosis Haber at al, 2006 Case report of successful revision at 4 months of age, initial age of Kasai was 21 days with resolution of cholestasis and normalization of bilirubin Recurrence of cholestasis at 3.5 months Symptom free at 14 months of age

46 Kasai Revision Retrospective analysis of 181 patients with biliary atresia since 1983, 24 underwent revision Kasai 75% of revisions achieved adequate biliary drainage with normalized conjugated bilirubin 87% overall survival 46% survival with native liver Operative time longer at transplant 500 vs 310 min (p = 0.03) and increased blood loss 10 year survival the same after transplant 89 vs 87% Bondoc et al, Annals of Surgery, 2012

47 Kasai Revision Select groups of biliary atresia patients may be considered for Kasai revision, thereby avoiding or delaying liver transplant. Current criteria for revision consideration Successful initial Kasai Recurrent jaundice and/or cholangitis resistant to maximal medical therapy

48 Outcome after Kasai Author Location # Cases Years JF Survival Kasai Japan % Lilly USA % Grosfeld USA % Dorney Australia % Ryckman USA % Lin Taiwan %

49 Contemporary Consortium Outcomes Country Years # Centers Japan United Kingdom US (BARC) France England/Wales Patients Median Age at HPE Days Survival with Native Liver % years years years years years Overall Survival %

50 Portoenterostomy and Laparoscopy Laparoscopic approach - multiple reports in early 2000 s benefits appeared limited Prospective single arm trial by team in Peterson group in Germany evaluating approach Stopped after interim analysis of first 12 patients At six months, successful Kasai in 42% of patients treated laparoscopically versus 82% of controls At two years, 83% laparoscopic approach transplanted versus 64% open surgery

51 Portoenterostomy and Laparoscopy Although approach remains controversial, conclusive answer has not been reached Yamatika et al How hilar plate transected some fibrous remnant versus into parenchyma itself Unanswered and being studied in ChiLDREN s network

52 Kasai Portoenterostomy Outcome 33% long-term drainage 33% improvement but progress to end-stage liver disease and require transplant in childhood 33% minimal response and require transplant in infancy

53 LONG-TERM FOLLOW-UP - 15 YRS POST KASAI

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55 Liver Transplantation Biliary atresia number one indication for pediatric liver transplantation Led to the development of reduced sized grafts and living related liver transplantation

56 Indications for Liver Transplantation Failed HPE Progressive hepatocellular decompensation Nutritional failure Portal hypertension with hemorrhage Successful HPE Progressive hepatocellular insufficiency Portal hypertension Recurrent cholangitis Hepatocellular carcinoma

57 Question A 95 day old female who was born at 34 weeks arrives from overseas with signs of cholestasis and a presumptive diagnosis of biliary atresia. You agree with the preoperative diagnosis and are asked to evaluate him for a Kasai procedure. What factors will you assess, and what will you tell this child's family regarding the outcomes of the Kasai in this scenario?

58 Liver Transplantation vs KasaiTiming In the early 90 s some suggested primary liver transplantation Donor Shortage Higher morbidity and mortality in transplant recipients 20-30% of infants with good response to Kasai Kasai first, if it fails liver transplantation If cirrhosis at presentation, primary transplantation

59 Failed Kasai

60 % SURVIVAL Liver Transplant Survival Progress over Time MONTHS POST TRANSPLANT Starzl Pediatric Surgery, 1979 CHMC Data SPLIT -2007

61 Health Status of Children Alive 10 Years after Pediatric Liver Transplantation Performed in the US and Canada: Report of the Studies of Pediatric Liver Transplantation Experience Vicky L. Ng, et al. Studies of Pediatric Liver Transplantation (SPLIT) Research Group *

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63 References Moyer V, Freese DK, Whitington PF, Olson AD, Brewer F, Colletti RB, et al. Guideline for the evaluation of cholestatic jaundice in infants: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Journal of pediatric gastroenterology and nutrition. 2004;39(2): 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 Oct;43(10): Wu ET, Chen HL, Ni YH, Lee PI, Hsu HY, Lai HS, et al. Bacterial cholangitis in patients with biliary atresia: impact on short-term outcome. Pediatr Surg Int Jul;17(5-6): Serinet M-O, Wildhaber BE, Broue P, Lachaux A, Sarles J, Jacquemin E, et al. Impact of Age at Kasai Operation on Its Results in Late Childhood and Adolescence: A Rational Basis for Biliary Atresia Screening. PEDIATRICS May 1;123(5):

64 References Bu L-N, Chen H-L, Chang C-J, Ni Y-H, Hsu H-Y, Lai H-S, et al. Prophylactic oral antibiotics in prevention of recurrent cholangitis after the Kasai portoenterostomy. Journal of Pediatric Surgery Apr;38(4): Haber BA, Erlichman J, Thayu M, Flake AW, Rand EB. Successful revision of portoenterostomy in an infant with biliary atresia. Journal of Pediatric Surgery Jul;41(7):e1 3. Bondoc AJ, Taylor JA, Alonso MH, Nathan JD, Wang Y, Balistreri WF, et al. The beneficial impact of revision of Kasai portoenterostomy for biliary atresia: an institutional study. Ann Surg Mar;255(3): Bezerra JA, Spino C, Magee JC, Shneider BL, Rosenthal P, Wang KS, et al. Use of Corticosteroids After Hepatoportoenterostomy for Bile Drainage in Infants With Biliary Atresia: The START Randomized Clinical Trial. JAMA May 7;311(17):1750.