GCSF Adjunct Therapy for Biliary Atresia
GCSF Adjunct Therapy for Biliary Atresia
The Investigators propose to test the hypothesis that GCSF therapy enhances the clinical
 outcome of Kasai operated Biliary Atresia (BA) patients. In this study, Investigators will
 conduct a dose determination for GCSF use in post Kasai subjects to support a future phase 2
 efficacy study. The first 3 post Kasai BA subjects with liver biopsy-confirmed BA will be
 given 5 ug/kg/d of GCSF in 3 daily subcutaneous doses starting on post Kasai day 3. A second
 group of 3 subjects will be assigned to the 10 ug/Kg/d dose after the 5ug/kg/d dose has been
 proven to be safe. The levels of circulating hematopoietic stem cells and a 1-month safety
 profile will be analyzed.
In BA, neonatal fibrous obliteration of the biliary tract obstructs biliary drainage and
 promotes biliary fibrosis. BA is the leading cause of pediatric chronic end-stage liver
 disease and pediatric liver transplantation. Relief of cholestasis by the Kasai
 portoenterostomy is only partly successful with continued progression of fibrosis to hepatic
 insufficiency and, for long term survival, with eventual need for liver transplantation in
 the majority of the patients. In animal models of liver injury, GCSF enhances hematopoietic
 stem cell HSC mobilization and engraftment in the liver with associated improved liver repair
 response and attenuated hepatic necrosis and fibrosis. Randomized controlled trials of GCSF
 intervention for chronic liver failure in adult patients with acute hepatic decompensation
 showed improved short-term survival and hepatic indices such the model for end-stage liver
 disease (MELD) scores.

 The Investigators propose that post Kasai GCSF therapy attenuates biliary fibrosis and
 progression to cirrhosis. The objectives are meant to demonstrate that Kasai-GCSF sequential
 therapy improves biliary drainage, and delays the progression of hepatic insufficiency.
 Toward this goal, Investigators will first evaluate in post Kasai subjects the maximum
 tolerated dose of GCSF in mobilizing circulating CD34+ hematopoietic stem cells, with the
 limiting dose based on GCSF-related severe adverse effects. A one-month safety of GCSF will
 be tested with the 2 standard doses of 5 ug/kg/d and 10 ug/kg/d.
Inclusion Criteria:

 1. Completed the preliminary work up for cholestasis with suspected or inconclusive
 diagnosis of BA

 2. Gestational Age > 36wks

 3. Weight > 2 Kg

 4. Age >-2 weeks-<180 days at diagnosis

 5. Serum Direct Bilirubin > 2 mg/dL GGT > 100 U/L

 6. Kasai operated patients for Type 3 or 4 anatomy of BA

 7. Cholangiogram/porta hepatis findings diagnostic of BA

 8. Liver biopsy supporting BA diagnosis

 Exclusion Criteria:

 1. Having access to liver transplantation for immediate Kasai failure

 2. Prior Kasai patients

 3. Major cardiac, renal, CNS malformations with poor prognosis

 4. Intracranial hemorrhage

 5. History of recent TPN use within the last 2 weeks of surgery

 6. GI tract obstruction

 7. Laparoscopic Kasai repair