Basics
Description
Biliary atresia (BA) is a congenital disease characterized by fibrosis, obstruction, and obliteration of the biliary system that is universally fatal without intervention.
Epidemiology
- BA accounts for approximately 30% of cases of neonatal cholestasis.
- BA is the most common cause of persistent cholestasis in infants and children and the most frequent indication for pediatric liver transplantation.
- The disease affects 1:8,000 to 1:18,000 live births.
Risk Factors
Genetics
- No single genetic mutation has been identified as the sole cause of BA, and there is no clear pattern of inheritance.
- Genes influencing morphogenesis may contribute to pathophysiology.
Pathophysiology
- Biliary obstruction begins at, or near, the time of birth and progresses throughout early infancy, leading to damage and ultimately scarring of liver parenchyma.
- Approximately 20% of biliary patients have at least one other major congenital anomaly (i.e., embryonal form) including splenic malformation, interrupted inferior vena cava, midline liver, situs inversus, preduodenal portal vein, and intestinal malrotation.
- More common form is the perinatal form that is not associated with malformations.
Etiology
Etiology is not completely defined, but many different pathogenic mechanisms have been proposed, including the following:
- Perinatal infection of the liver and biliary tract with potential organisms including cytomegalovirus, rotavirus, and reovirus
- Immune dysregulation
- Defective morphogenesis
- Environmental toxin exposure
- Vascular insufficiency
Diagnosis
History
- Newborns appear healthy at birth with good growth and development. However, jaundice of the skin and eyes persists beyond the 2-week interval of physiologic jaundice. Acholic stools and dark urine may be noted.
- In addition, infants with BA may present with poor weight gain, bleeding (due to vitamin K deficiency), and/or increased stool frequency.
Physical Exam
- Jaundice can be seen in the eyes, skin, or buccal mucosa.
- Infants may have hepatomegaly and splenomegaly.
- Rectal exam, including digital exam, may reveal acholic stools.
Screening
- An infant stool color card that identifies acholic and normal stool has been used in Taiwan, where it was shown to decrease the time to diagnosis in BA and improve outcomes for children with BA.
- Infants with BA have elevated direct bilirubin at 24 hours of life, suggesting a potential role for screening with this blood test.
Alert
- One of the most important factors determining outcomes in BA, including survival and need for transplantation, is the age at which a patient is referred for workup.
- The 10-year survival rate of patients diagnosed and treated prior to 60 days versus after 90 days is 73% and 11%, respectively.
Diagnostic Tests & Interpretation
Initial Lab Tests
- Conjugated hyperbilirubinemia (defined as a conjugated fraction >2 mg/dL or a conjugated bilirubin >20% of the total bilirubin) may be elevated as early as the first 24 hours of life.
- Additional laboratory findings may include mild to moderate elevations in AST, ALT, and alkaline phosphatase as well as significant elevations in γ-glutamyltransferase (GGT)
- Additional diagnostic testing should be done as clinically indicated.
- Bacterial cultures (blood, urine, stool), viral studies (hepatitis B, hepatitis C, Epstein-Barr virus, toxoplasmosis, other viruses, rubella, cytomegalovirus, herpes virus [TORCH] infections, HIV, adenovirus, enterovirus)
- Metabolic profiles (plasma amino acids, urine organic acids and urine succinylacetone, lactate/pyruvate ratio)
- Serum alpha-1-antitrypsin level and phenotype
- Thyroid function tests (TSH, free T4)
- Urine-reducing substances to evaluate for galactosemia (if infant has taken breast milk or lactose-containing formula)
- CBC, coagulation studies (prothrombin time/international normalized ratio/partial thromboplastin time [PT/INR/PTT]), total protein, albumin, and fat-soluble vitamins
Imaging
- Abdominal ultrasound
- Should be obtained to rule out choledochal cyst but has poor sensitivity and specificity for BA unless "triangular chord" sign seen (80% sensitive, 98% specific)
- May also assist in defining embryonal versus perinatal form
- Hepatobiliary iminodiacetic acid (HIDA) scan/hepatobiliary scintigraphy can be obtained to evaluate biliary excretion.
Additional Testing
- Discussion with pediatric gastroenterologist should be obtained following evidence of persistent cholestasis.
- Liver biopsy: In BA, findings may include bile duct proliferation, bile stasis, periportal inflammation, and periportal fibrosis.
- Sweat chloride test (cystic fibrosis)
- Ophthalmology exam for Alagille syndrome (posterior embryotoxon) and congenital infections
- Spine film to evaluate butterfly vertebrae of Alagille syndrome
- Echo to evaluate cardiac anomalies in Alagille syndrome
- Urine bile acid analysis
- Intraoperative cholangiogram
- Gold standard for diagnosis of BA but is an invasive test
- Reserved for individuals with high suspicion of BA.
Differential Diagnosis
- Intrahepatic
- Infection: sepsis, UTI, gastroenteritis, TORCH infections, HIV, viral hepatitis (A, B, C, D, E), Epstein-Barr virus, adenovirus, coxsackie B virus, echovirus, enterovirus
- Systemic disease: panhypopituitarism, congestive heart failure, ischemic hepatopathy, trauma
- Metabolic: galactosemia, tyrosinemia, alpha-1-antitrypsin, cystic fibrosis, citrin deficiency, respiratory chain disorders, hereditary fructose intolerance, disorders of bile acid synthesis, storage disorders, neonatal iron storage disease
- Genetic: Alagille syndrome, Zellweger syndrome, Down syndrome, Turner syndrome
- Progressive familial intrahepatic cholestasis (i.e., PFIC 1, 2, and 3)
- Toxins and drugs: total parenteral nutrition, antibiotics, and other medications
- Miscellaneous: neonatal hepatitis, neonatal lupus, congenital hepatic fibrosis, Caroli syndrome, inspissated bile syndrome, histiocytosis X
- Extrahepatic
- Choledochal cyst
- Choledocholithiasis
- Neonatal sclerosing cholangitis
- Tumor/mass compression
- Spontaneous perforation of common bile duct
Treatment
Surgery/Other Procedures
- A hepatoportoenterostomy (Kasai procedure) is the only effective therapy for BA other than a liver transplant. The goal of the Kasai procedure is to restore bile flow from the liver to the intestine.
- Despite the Kasai procedure, 70-80% of patients with BA ultimately require liver transplantation.
- At 3 months after Kasai procedure, a total serum bilirubin <2 mg/dL is associated with low likelihood of requiring hepatic transplant within 2 years.
- A total serum bilirubin ≥6 mg/dL is associated with failure of adequate bile flow and higher likelihood of need for liver transplantation.
- Indications for transplantation include the following:
- Synthetic dysfunction of the liver
- Complications of portal hypertension (PHTN) such as life-threatening hemorrhage, ascites, and spontaneous bacterial peritonitis
- Persistent cholestasis with impaired quality of life such as intractable pruritus
- Recurrent cholangitis
Alert
- Without surgical intervention, 50-80% of patients with BA will die from biliary cirrhosis by 1 year of age and 90-100% by 3 years of age.
- If diagnosed within the first 3 months of life, surgical therapy can successfully restore bile flow from liver into the intestinal tract in 30-80% of patients.
Medication
- After the Kasai operation, patients receive
- Ursodeoxycholic acid to promote bile flow
- Supplemental fat-soluble vitamins
- Oral prophylactic antibiotics to prevent ascending cholangitis
- Corticosteroids have not been shown to improve outcomes in patients with BA.
Ongoing Care
Follow-up Recommendations
In conjunction with a GI specialist, obtain routine serum biomarkers including CBC, liver function tests, and GGT to determine progression of disease. Physicians should also monitor closely fat-soluble vitamins as well as coagulation studies to evaluate liver function including production of clotting factors and absorption of vitamin K.
Diet
- Anthropometrics should be performed consistently and frequently to evaluate growth as patients tend to have decreased fat stores and decreased lean body mass.
- For individuals with poor weight gain on breast milk or receiving standard formula supplementation, patients should use formulas enriched with medium-chain triglycerides because these fats do not require bile for absorption.
- If patients exhibit poor weight gain on oral feedings, an enteric feeding tube for supplemental nutrition should be strongly considered.
- Due to decrease bile acid excretion, patients with BA malabsorb fat-soluble vitamins (A, D, E, and K) and likely need supplementation.
Complications
- Ascending bacterial cholangitis: Patients are predisposed to this infection after the portoenterostomy procedure given the absence of the ampulla of Vater and present with fever, elevated liver function tests, hypopigmented stools, increased pruritus, and/or increased GGT. Recurrent ascending cholangitis can lead to sclerosis and loss of remaining intrahepatic bile ducts. Antibiotic prophylaxis is helpful in preventing recurrent infections.
- Pruritus: Occurs frequently and is due to elevated circulating bile acid. Ursodeoxycholic acid, antihistamines, rifampin, naloxone, and cholestyramine may be used to alleviate itching.
- Ascites: Spironolactone, chlorothiazide, and furosemide are commonly used diuretics. However, their use should be monitored closely in order to avoid the development of hepatorenal syndrome.
- PHTN: Monitoring liver firmness, texture, and span along with splenomegaly will be helpful. Progressive thrombocytopenia suggests further splenomegaly. PHTN can also manifest as ascites, spontaneous bacterial peritonitis, portosystemic encephalopathy, portopulmonary syndrome, or GI hemorrhage from esophageal or gastric varices.
Additional Reading
- Chen SM, Chang MH, Du JC, et al. Screening for biliary atresia by infant stool color card in Taiwan. Pediatrics. 2006;117(4):1147-1154. [View Abstract]
- Cowles RA, Lobritto SJ, Ventura KA, et al. Timing of liver transplantation in biliary atresia-results in 71 children managed by a multidisciplinary team. J Pediatr Surg. 2008;43(9):1605-1609. [View Abstract]
- Davenport M, Tizzard SA, Underhill J, et al. The biliary atresia splenic malformation syndrome: a 28-year single-center retrospective study. J Pediatr. 2006;149(3):393-400. [View Abstract]
- Hartley JL, Davenport M, Kelly DA. Biliary atresia. Lancet. 2009;374(9702):1704-1713. [View Abstract]
- Karrer FM, Bensard DD. Neonatal cholestasis. Semin Pediatr Surg. 2000;9(4):166-169. [View Abstract]
- Mack CL. The pathogenesis of biliary atresia: evidence for a virus-induced autoimmune disease. Semin Liver Dis. 2007;27(3):233-242. [View Abstract]
- Shneider BL, Brown MB, Haber B, et al. A multicenter study of the outcome of biliary atresia in the United States, 1997 to 2000. J Pediatr. 2006;148(4):467-474. [View Abstract]
- Sokol RJ, Mack C, Narkewicz MR, et al. Pathogenesis and outcome of biliary atresia: current concepts. J Pediatr Gastroenterol Nutr. 2003;37(1):4-21. [View Abstract]
Codes
ICD09
- 751.61 Biliary atresia
- 576.8 Other specified disorders of biliary tract
- 789.1 Hepatomegaly
- 789.2 Splenomegaly
ICD10
- Q44.2 Atresia of bile ducts
- K83.1 Obstruction of bile duct
- R16.0 Hepatomegaly, not elsewhere classified
- R16.1 Splenomegaly, not elsewhere classified
SNOMED
- 77480004 Congenital biliary atresia (disorder)
- 433237003 Cholestasis in newborn (disorder)
- 80515008 Large liver (disorder)
- 16294009 Splenomegaly (disorder)
FAQ
- Q: How soon should parents contact their primary care provider when they see pale-colored stools?
- A: The first time they notice these stools are acholic.
- Q: What should a physician do if he or she is concerned about persistent jaundice?
- A: Obtain a thorough history, perform a thorough physical exam, and measure both total and direct bilirubin. If there is significant conjugated bilirubinemia, contact your local pediatric gastroenterologist and begin neonatal cholestasis diagnostic workup, ruling out the most immediately dangerous etiologies (including potentially fatal metabolic diseases and infections) as well as common etiologies such as BA.