N-Acetylcysteine in Biliary Atresia After Kasai Portoenterostomy

Biliary atresia (BA) is a disease characterized by fibro-obliteration of extrahepatic bile
ducts leading to impaired bile flow (Sokol et al., 2007). BA is treated with the Kasai
portoenterostomy (KP), an operation which connects the liver directly to the intestine in
attempt to relieve bile back-up and promote bile flow. KPs have variable success. KPs
occasionally normalize bile flow and stop disease progression (Jimenez-Rivera et al., 2013).
More commonly, however, bile flow never completely normalizes after KP. This can be detected
by elevated total bilirubin (TB) or conjugated bilirubin (Bc) serum concentrations, or, when
TB and Bc are normal, elevated total serum bile acids (TSBA) concentrations (Bezerra et al.,
2014; Shneider et al., 2015; Venkat et al., 2014). Impaired flow leads to fibrosis,
cirrhosis, and eventual need for liver transplantation. Given these uneven results, therapies
are urgently needed to enhance the KP's success.

The investigators hypothesize that N-acetylcysteine (NAC) will improve outcomes after KP,
because NAC is a precursor for the powerful choleretic molecule glutathione (Ballatori and
Truong, 1989, 1992, Ballatori et al., 1986, 1989). The hypothesis assumes that better bile
flow will lead to better outcomes. This is supported by previous reports demonstrating that
good bile flow correlates with slower disease progression in BA. For example, a recent study
showed infants with good bile flow after KP were significantly less likely to develop
failure-to-thrive, ascites, hypoalbuminemia, or coagulopathy in the first two years of life
(Shneider et al., 2015). Furthermore, these infants had significantly higher transplant-free
survival in the same time period. In this study, TB <2.0 mg/dL within three months of KP was
used as the marker for good bile flow.

NAC has a number of properties that make it an especially attractive potential therapeutic
agent. First, glutathione creates an osmotic gradient in the bile duct lumen which drives
one-third of total bile flow in humans (the other drivers are bile acids and
secretin/bicarbonate) (Ballatori and Truong, 1989, 1992, Ballatori et al., 1986, 1989).
Second, NAC is a Food and Drug Administration-approved therapy for another serious liver
condition in neonates and children (acetaminophen overdose). It has also been used for other
liver and non-liver indications in neonates, with few reported adverse events (Ahola et al.,
2003; Flynn et al., 2003; Jenkins et al., 2016; Kortsalioudaki et al., 2008; Mager et al.,
2008; Soghier and Brion, 2006; Squires et al., 2013; Wiest et al., 2014). Third, glutathione
is an anti-oxidant, which could scavenge the free radicals contributing to cirrhosis.
Preclinical studies are also promising, with glutathione's strong choleretic properties best
established in rat flow studies and NAC's hepatoprotective effects documented in rescuing
different mouse models of cholestasis (Ballatori et al., 1986; Galicia-Moreno et al., 2009,
2012; Tahan et al., 2007).

To test the hypotheses, the investigators will administer intravenous NAC continuously for
seven days and determine the number of subjects with normal TSBAs (0-10 umol/L) within 24
weeks of KP. In addition, markers of BA progression, such as abnormal laboratory results,
failure-to-thrive, and occurrence of complications related to chronic liver disease, will be
described over the first two years of life. Finally, all adverse events occurring during NAC
infusion and in the 21 days after its completion will be recorded. The study employs the
two-stage "minimax" Phase 2 clinical trial design, a design commonly used in oncological
trials to determine whether a particularly therapy has sufficient activity to warrant a
larger Phase 3 trial (Simon, 1989). The two-stage "minimax" design offers two distinct
advantages compared to other designs: (i) early termination if the drug is not efficacious;
and (ii) small sample sizes, because historical controls rather than a separate control arm
are used.

Inclusion Criteria:

1. Age less than or equal to 90 days at time of KP (standard age range in which KPs are
performed)

2. BA diagnosis made by intraoperative cholangiography and KP performed at Texas
Children's Hospital, Texas Medical Center Campus

3. Legal guardian(s) sign consent after understanding risks and investigational nature of
study

Exclusion Criteria:

1. Decompensated liver disease (INR >1.3) despite parenteral Vitamin K administration)

2. KP not performed for any reason (i.e., normal intraoperative cholangiography, or liver
found to be too diseased intraoperatively to proceed with KP)

3. Active respiratory infection

4. Renal impairment, as defined by having an eGFR < 60 mL/min/1.73m2 or creatinine
clearance < 60 mL/min
(https://www.niddk.nih.gov/health-information/communication-programs/nkdep/laboratory-
evaluation/glomerular-filtration-rate-calculators/children-conventional-units)

5. Presence of severe concurrent illnesses, such as pulmonary (i.e., bronchopulmonary
dysplasia), neurological, cardiovascular, metabolic, endocrine, and renal disorders,
which may be congenital or acquired, that would interfere with the conduct and results
of the study