1. Biliary Atresia By
Eric Pang

2. Case JRM CC: Hyperbilirubinemia HPI
12 day old M w/ elevated indirect bilirubin now w/ decreasing indirect bili but rising direct bili and elevated GGT

3. H&P cont…. Allergies: none Meds: none Birth Hx: Surgical Hx: none
1 wk premature
8lbs 15 oz
Feeding well
Surgical Hx: none
Family Hx: none
PE:
59th percentile weight
17th percentile height
Markedly icteric sclera
Yellow stools

4. H&P cont…. Labs: Imaging:
WBC: 13.2
Alk Phos: 203
ALT and AST: 1137
Total Bilirubin: 16.3
Imaging:
U/S is normal except for horseshoe kidney
At this time examination was suspicious for biliary atresia but decision was made to f/u w/ hepatology in 1 wk

5. 1 week later… Condition was unchanged Labs were similar:
Conjugated bilirubin 4
Unconjugated bilirubin 10.5
Repeat U/S:
“no clear evidence of gallbladder or extrahepatic bile ducts”
Plan: HIDA and liver biopsy 1 wk later

6. 1 week later Liver Biopsy Report:
Microscopic DescriptionH&E-stained sections show liver with well-sampled portal tracts. The tracts are expanded, with central fibrous areas containing portal veins and hepatic arteries and looser connective tissue around the periphery containing prominent ductular proliferation.  There is mild pericholangitis as well as admixed inflammation with lymphocytes and occasional eosinophils.  There is bile duct plugging as well as intracanalicular and intrahepatic cholestasis

7. Patient HIDA scan

8. HIDA scan report (normal)

9. Biliary Atresia
An occlusive panductular cholangiopathy affecting both intra and extrahepatic bile ducts
Commonly classified into 3 types
Types 1 and 2 w/ some preservation of structures
Type 3 is the most common w/ grossly abnormal bile ducts
Site 1

10. - note there are subclassifications to classify the distal bile ducts…
- note there are subclassifications to classify the distal bile ducts….about 20% of type 3 have patent CBD and a normal gallbladder (type a) which will look normal on US

11. Biliary Atresia Splenic Malformation Syndrome
Known association of polysplenia w/ biliary atresia
Found to have etiologic relationship w/ maternal diabetes
Often w/ other anomalies (ie – absent IVC, situs inversus)
Theoretically due to a common embryologic insult vs. a genetic defect

12. BA Diagnosis Key Features
Conjugated jaundice persisting beyond 14 days of age
Initially appear healthy but will eventually develop failure to thrive 2/2 to malabsorption of fat (and subsequently vit A,D,E, and K)
U/S is useful to r/o other possible diagnosis
Liver biopsy/ERCP/laparoscopy have utility as well

13. Kasai Procedure

14. Kasai Portoenerostomy
Briefly:
Involves resection of gallbladder and extrahepatic biliary tree exposing the porta hepatitis
Construction of a large portoenterostomy encompassing the margins of the resection

15. Pt taken to the OR for Kasai w/ Dr. Healey
FINDINGS: Liver felt rubbery and dense, but not fibrotic. It was mildly cholestatic. There was a streak gallbladder which, when transected, had an obliterated lumen. We were unable to do a cholangiogram due to the lack of lumen. There was atresia of the entire extrahepatic biliary tree with no recognizable biliary structures in the area of the common bile duct or extrahepatic ducts. At the portal plate, however, there was some bile seen in the area of the right biliary remnant.

16. Adjuvant therapy postoperatively
There isn’t a strong body of evidence supporting benefits from adjuvant drug therapies but 2 classes of drugs are widely used nonetheless
Steroids and ursodeoxycholic acid

17. Clinical Question
In patients with biliary atresia who have undergone Kasai procedures, does the adjuvant administration of steroids or ursodeoxycholic acid vs. placebo have benefits in time to liver transplant or clearance of jaundice?

18. Steroids In theory, steroids are beneficial in multiple ways
Anti-inflammatory effect of steroids
Increase bile salt independent fraction of bile flow
Have been several studies examining benefit but only one RCT trial…

19. Prospective 2 center, double blind, randomized, placebo-controlled trial
Published in 2007 in Hepatology out of King’s College London SOM and St. James’ University Hospital
Meant to examine effect of post-Kasai portoenterostomy corticosteroids w/ primary endpoints being clearance of jaundice (tbili < 20umol/L) and the proportion of infants retaining their native livers at 6 and 12 mo

20. Infants w/ type 3 isolated biliary atresia were included in the study
exclusion criteria included those w/ splenic malformation, severe cardiac anomalies, close contact w/ or evidence of infection, cirrhosis, or type 1/2 biliary atresia
operative procedures were performed by 1 of 2 surgeons in a standardized fashion, post operative nutritional schedules, abx administration, and medication administration were scripted as well.
Administered prednisilone 2mg/kg/day POD 7-21 and 1mg/kg/day POD
73 infants were enrolled (36 to steroids and 37 to placebo group)

21. Findings:
No significant difference for clearance of jaundice at 1,6, or 12 mo
No significant difference for transplantation at 6 or 12 mo 

23. Subgroup analysis for infants <70 days old at time of surgery showed significantly more clearance of jaundice in pt operated on <70 days of age (64 v 116, P<0.01) but effect was not sustained at later sampling and there was no significant different in need for subsequent transplantation

24. Conclusions:
Steroids w/out significant benefit as far as achieving normal bilirubin or reducing the need for liver transplant
Does reduce bilirubin for younger patients (<70 day old at age of surgery) but only at 1mo w/out longer term effects

25. Areas for improvement:
Small N could have underpowered the study
Short course of steroids
Low dose

26. Systematic review and metanalysis published in 2012 in the Canadian Journal of Gastroenterology
Looked at studies between Jan 1969 and June 2010 using Medline, PubMed, EMBASE and Cochrane databases

27. Out of 16 observational studies only 4 met criteria for inclusion:
compared 2 groups of infants who underwent Kasai
Sufficient data to calculate OR and RR
Outcomes included normalization serum bili at 6 mo post op and early liver transplant

28. Out of 16 observational studies only 4 met criteria for inclusion:
compared 2 groups of infants who underwent kasai
Sufficient data to calculate OR and RR
Outcomes included normalizaiton serum bili at 6 mo PO and early liver transplant

31. Results:
160 subjects in observational studies and 73 patients in the single RCT
No significant difference for normalization of serum bilirubin at 6mo
Showed some effect in delaying transplant but not statistically significant

32. Retrospective study published in 2010 in the American Journal of Surgery out of Seattle Children’s Hospital
Utilized the Pediatric Health Information System which include data from 43 children hospitals
Searched using ICD-9 coding for the Kasai procedure and the diagnosis of biliary atresia
Aimed to look at relationship of postop steroids w/ length of hospital stay

33. Identified 516 patients
Of which 46% received perioperative steroids (defined as being w/in 4 days of surgery)
lengths of stay was 14.5 ± 19.7 for those who did not receive steroids vs ± 16.3 days for those who did receive steroids.
Postoperative steroid use was significantly associated with a 3.5-day decrease in postoperative length of stay

34. Limitations of study include:
Use of database rely on accurate documentation, no information in database concerning dosages or schedules, labs and subsequent liver transplantation data were not available, could be skewed population
Does suggest that postoperative steroids may be beneficial in terms of time to discharge

35. Steroids or No Steroids?
Pros
Possible benefit in pt w/ Kasai procedures done early
Observational studies in the past have suggested benefit in both time to transplant and clearance of jaundice
Possible decrease is post operative hospital stay length

36. Steroids or No Steroids
Cons
Possible side effects
No RCT proving benefit

37. The bottom line for steroids
A large prospective study examining high dose steroid use for postoperative management of biliary atresia patients is necessary
Currently there is a RCT being done sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases which may help elucidate this topic further
Treatment dose is 4mg/kg starting 1-3 days post op
Estimated 140 pts to be enrolled
Target date of completion was 1/2013….

38. Ursodeoxycholic Acid

39. Ursodeoxycholic Acid Hydrophilic bile acid
Has shown biochemical, histologic, and clinical benefits in pts w/ primary biliary cirrhosis and sclerosing cholangitis in reducing need for transplant
Theory is that UDCA:
Decreases concentrations of endogenous toxic bile acids
Has an immunomosuppressive property
Has been suggested that UDCA can be beneficial in biliary atresia

40. Prospective study published in 2008 in Pediatrics out of Lille University Children’s Hospital in France
Study looked at patients who had undergone successful Kasai procedures and were treated w/ ursodeoxycholic acid for atleast 18 mo
Successful surgery was defined as the clearance jaundice 6mo post operatively
Note: no pt’s received steroids

41. Study prospectively followed 16 pt who had completed at least 1 yrs of UDCA treatment
Pt’s had UDCA dc’d when clinically deemed ready by physician and were observed for changes in clinical condition and labs.
Median treatment time at time of initial d/c was 2.6 years
Labs were drawn at time of d/c and then again at time of reexamination at 6 mo
If labs had worsened (>2x the upper limit of normal) then they were restarted on UDCA

42. Of the 16 patients:
Only 1 pt developed jaundice 3mo post d/c w/ an elevation of his bili from 10 to 57 umol/L
13 of the pt’s had elevated LFT’s (AST/ALT/GGT) and were restarted on UDCA
6 mo after restarted LFT’s were redrawn and showed statistically significant improvement at that time

44. Findings suggest UDCA therapy can have long term benefits
Weaknesses:
No control group
Only 1 pt w/ clinical change 2/2 to therapy
Did not assess histology of liver
Findings suggest UDCA therapy can have long term benefits

45. UDCA vs No UDCA? Pros Cons
Evidence supporting utility in diminishing jaundice
Few side effects and generally tolerated well
H/a, weight gain, constipation, diarrhea
Cons
Cost
For 100 capsules ($270-$770)
Clinical vs. Lab value benefits?
Again, more studies required for more definitive proof going forward.

46. Case JRM Operation was completed without complication
Currently continuing to recover from operation
LFT’s normalizing
On Bactrim/Ursodiol/Vitamin supplementation
Advancing PO + NG feeds until goal is reached
Hopefully going home soon…

47. Works Cited
Davenport, Mark. "Biliary Atresia: Clinical Aspects." Seminars in Pediatric Surgery 21 (2012): Elsevier. Web. 05 July
Davenport, Mark, Mark D. Stringer, Sarah A. Tizzard, Patricia McClean, Giorgina Mieli-Vergani, and Nedim Hadzie. "Randomized, Double-Blind, Placebo-Controlled Trial of Corticosteroids After Kasai Portoenterostomy for Biliary Atresia." Hepatology 46.6 (2007): Wiley InterScience. Web. 5 July
Lao, Oliver B., Cindy Larison, Michele Garrisson, Patrick J. Healey, and Adam B. Goldin. "Steroid Use after the Kasai Procedure for Biliary Atresia." The American Journal of Surgery (2010): Elsevier. Web. 5 July 2013.
Sarkhy, Ahmed, Richard A. Schreiber, Ruth Milner, and Collin C. Barker. "Does Adjuvant Steroid Therapy Post-Kasai Portoenterostomy Improve the Outcome of Biliary Atresia? A Systematic Review and Meta-analysis." Canadian Journal of Gastroenterology 25.8 (2011): Pulsus Group Inc. Web. 5 July <
Willot, Stephanie, Stephanie Uhlen, Laurent Michaud, Gilbert Briand, Michel Bonnevalle, Rony Sfeir, and Frederic Gottrand. "Effect of Ursodeoxycholic Acid on Liver Function in Children After Successful Surgery for Biliary Atresia." Pediatrics (2008). Pediatrics. Web. 05 July