Biliary Atresia

Introduction

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Biliary atresia is a “destructive inflammatory obliterative cholangiopathy that affects intra- and extrahepatic bile ducts.”  This disease strictly affects neonates, and there is no known analogous pathology that exists in older children or adults.  Untreated, biliary atresia leads to progressive liver cirrhosis and death by 2 years of age.  Outcomes are much better with early diagnosis and treatment, which includes the Kasai portoenterostomy and liver transplantation.  Biliary atresia accounts for about 75% of liver transplantations in those younger than 2 years.

 

Types

There are three types of biliary atresia, classified by the level of most proximal biliary obstruction (see figure 1):

  1. Type 1 (about 5%): The level of obstruction is within the common bile duct, with the gallbladder containing bile.  This type is sometimes associated with cystic change in some part of the extrahepatic biliary tree.
  2. Type 2 (about 2%): The level of obstruction is within the common hepatic duct with no bile in the gallbladder but two bile-containing lumens in the proximal remnant.
  3. Type 3 (>90%): The level of obstruction is within the porta hepatis, with no visible bile-containing proximal lumen.

Epidemiology

Biliary atresia is rare, affecting 1 in 17,000-19,000 live births.  It occurs most commonly in east Asian countries.  Evidence for classic genetic inheritance is scarce, and it rarely arises within families.  There has been no association identified between biliary atresia and infant sex, birthweight, gestational age, plurality, maternal age, gravidity, parity, maternal smoking or alcohol use, folic acid, education level, or socioeconomic status.

About 20% of cases are associated with other congenital anatomical abnormalities.  The most common of these is biliary atresia splenic malformation syndrome, which includes polysplenia, intestinal malrotation, situsinversus, and vascular/cardiac anomalies (absent inferior vena cava, preduodenal portal vein, ASD, and VSD).  In most cases (80-90%), however, it is an isolated finding.

Screening

Given the positive effect of early diagnosis and treatment on prognosis, efforts are ongoing to add biliary atresia to the newborn screen.  Thus far, attempts to develop a method of detecting conjugated bilirubin in dry blood spots have been unsuccessful.  Fortunately, type 1 biliary atresia (cystic) may be detectable on ultrasound after 20 weeks gestation, but this accounts for no more than 5% of total cases.

Pathophysiology

The pathogenesis of biliary atresia is multifactorial in nature, with the common endpoint being an obliterativecholangiopathy.   Possible mechanisms could include genetic, infective, inflammatory, and toxic factors. 

  • Genetic: Polymorphisms in the inflammatory pathway could affect the progression of fibrosis in biliary atresia, and have variable frequency in patients with this disease.  These include CFC1, ICAM1, macrophage migration inhibitory factor gene, CD14 endotoxin receptor gene, and hepcidin antimicrobial peptide gene.
  • Infectious: Rodent studies suggest a possible link between biliary atresia and infection with rotavirus (strains RRV and SA11-FM), reovirus, and cytomegalovirus.  Some serological studies in humans have suggested an increased frequency of reovirus in patients with biliary atresia.  Other studies, however, imply that viral infection is likely a secondary finding and not a specific cause.
  • Inflammatory: This mechanisms is most likely due to lymphocyte-mediated biliary inflammation, leading to bile duct damage.  The trigger for this response still remains unknown.  Additionally, inflammatory cytokines suck as IL-2, IL-12, IFN-γ, and TNFα are upregulated in patients with biliary atresia.
  • Toxic: Still unknown, yet a possibility.

Presentation

  1. Jaundice – from conjugated hyperbilirubinemia, usually the presenting sign
  2. Dark urine – caused by the excretion of water-soluble conjugates of bilirubin, may cause staining of diaper which could lead to it being mistakenly identified as colored stool
  3. Coagulopathy – responsive to IV vitamin K
  4. Failure to thrive – with excessive feeding, caused by poor absorption of long-chain fats and a catabolic state
  5. Hepatosplenomegaly and ascites – late sign, suggestive of cirrhosis and portal hypertension
  6. Pale stools– varying from white to beige, the stool color card below is used to screen infants for BA.

      
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Figure 1 of Screening for Biliary Atresia by Infant Stool Color Card in Taiwan   (Chen SM, et al).  Implementation of the card screening slightly decreased the age at first admission for suspected BA and significantly decreased the proportion of very late referrals (Tseng, 2011).

Differential Diagnosis of Neonatal Cholestasis

  • Obstructive
                
    • Biliary atresia
    • Choledochal cysts
    • Bile duct paucity
    • Neonatal sclerosing cholangitis
    • Inspissated bile syndrome
    • Gallstones/biliary sludge
    • Cystic fibrosis
    • Caroli disease
  • Intrahepatic
            
    • Viral infection: HSV, CMV, HIV, Parvovirus B19, other
    • Bacterial infection: sepsis, UTI, syphilis
    • Genetic/metabolic disorders: alpha-1 antitrypsin deficiency, tyrosinemia, galactosemia, progressive familial intrahepatic cholestasis, Alagille syndrome, other
    • Endocrine disorders: hypothyroidism, hypopituitarism
    • Toxic: drugs, parenteral nutrition
    • Systemic: shock, heart failure, neonatal lupus

 

Work-Up

  1. Liver function tests – indicating cholestasis (elevated conjugated bilirubin, alkaline phosphatase, and GGT) but normal synthetic function (normal albumin and prothrombin time)
  2. Rule out other etiologies - viral, alpha-1 antitrypsin deficiency, and cystic fibrosis
  3. Ultrasound – showing enlarged liver, absence of biliary dilation, absent/contracted gallbladder
  4. Percutaneous liver biopsy – portal tract fibrosis, edema, ductular proliferation, and cholestasis (bile plugs)
  5. Endoscopic retrograde cholangiopancreatography (ERCP) or operative cholangiography if diagnosis is still unclear

Kasai Portoenterostomy

The Kasai portoenterostomy (see figure 2 above) was first described in the 1950s, with the aim of facilitatingcomplete clearance of jaundice and restoring excretory and synthetic liver function.  Regardless of biliary atresia type or level of obstruction, theentire extrahepatic biliary tree is excised, and the porta hepatis is transected at the level of the liver capsule.  A jejunal Roux loop is anastomosed to the cut surface of the liver, creating the wide portoenterostomy and facilitating biliary drainage. 

Check out a video to the procedure below, courtesy of YouTube and Stanford University Medical Center.

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Success of this procedure is usually determined within 6 months postoperatively, and depends on the patient’s age at surgery (better outcomes if <100 days of age), degree of cirrhosis or fibrosis, absence or paucity of microscopic bile ductules, and center experience.  Once a procedure is determined to be successful, more than 80% of patients survive more than 10 years with their native liver.  As a rule, patients with biliary atresia splenic malformation syndrome have a poorer prognosis postoperatively than those with isolated biliary atresia.

Post-Procedure Management & Issues:

  • Ursodiol to promote hydrophilic bile acids (no benefits shown in BA yet)
  • Glucocorticoids to decrease bilirubin levels (no consistent benefit shown)
  • Malnutrition in BA due to cholestasis, chronic inflammation and absence of gall bladder
                            
    • Increased caloric and protein intake (treat like failure to thrive)
    • Supplemental NG feeds (G tubes increase portal hypertension)
    • Fat-soluble vitamin supplementation; patients are more deficient in FSV levels when their total serum bilirubin is >2 mg/dL; current methods of supplementation were shown to leave 58% of patients with insufficient levels of FSVs (Shneider BL et al, 2012).

Complications of HPE:

  • Ascending cholangitis, many experienced before 2 yoa and occurs in 30-50% of children; characterized by worsening jaundice, fever and acholic stools.  Diagnosis confirmed by blood culture or percutaneous liver biopsy.  Treatment includes early broad-spectrum antibiotics against gram-negative organisms.  Recommendation is one year of bactrim or neomycin as prophylaxis; as mentioned above, recurrent cholangitis may lead to fibrosis and necessitate a liver transplant
  • Chronic inflammation leads to biliary cirrhosis, causing portal hypertension which manifests as variceal bleeding and ascites. The recurrence of the latter two symptoms also necessitates a liver transplant.
  • Some degree of cirrhosis is also present in most cases, which is a risk factor for the development of malignancy (hepatoblastoma, hepatocellular carcinoma, and cholangiocarcinoma).  Yearly screening of serum alpha-feto-protein is part of the care of these patients.
  • Most patients with BA will need a liver transplant for any of the following reasons: failure of the HPE, refractory growth, portal hypertension and liver dysfunction. The survival rate of those needing liver transplant is 70-80% at 10 years.

Liver Transplantation

Even after undergoing the Kasai portoenterostomy, most patients end up requiring liver transplantation, which continues to be the cornerstone of curative therapy for biliary atresia. It is usually performed between 6 months and 2 years of age.Indications for transplantation include a failed Kasai procedure or the presence of its previously mentioned complications, persistence of cholestasis or development of cirrhosis with hepatic dysfunction.  Outcomes after liver transplantation have improved over the years, with 10-year graft survival of 73%, and 10-year patient survival of 86%.

References

  1. Bates MD, Bucuvalas JC, Alonso MH, and Ryckman FC.  Biliary Atresia: Pathogenesis and Treatment.  Seminars in Liver Disease.  1998.  18(3):281-293.
  2. Bijl EJ, Bharwani KD, Houwen RH, and de Man RA.  The long-term outcome of the Kasai operation in patients with biliary atresia: a systematic review.  The Netherlands Journal of Medicine.  2013.  71(4):170-173.
  3. Hartley JL, Davenport M, and Kelly DA.  Biliary Atresia.  Lancet.  2009.  374:1704-1713.
  4. Makin E and Davenport M.  Biliary Atresia.  Current Paediatrics.  2006.  16:59-63.
  5. Nakamura K and Tanoue A.  Etiology of biliary atresia as a developmental anomaly: recent advances.  Journal of Hepato-Biliary-Pancreatic Sciences.  2013.  20:459-464.
  6. Suchy FJ.  Neonatal cholestasis.  Pediatrics in Review.  2004.  25(11):388-396.
  7. Bondoc AJ, Taylor JA, Alonso MH, Nathan JD, Wang Y, Balistreri WF, Bezerra JA, Ryckman FC and Tiao GM. Annals of Surgery. 2012. 255(3):570-576.
  8. Canty TG. Encouraging results with a modified Sawaguchi hepatoportoenterostomy for biliary atresia. The American Journal of Surgery. 1987. 154:19-26.
  9. Caponcelli E, Knisely AS, Davenport M. Cystic biliary atresia: an etiologic and prognostic subgroup. Journal of Pediatric Surgery. 2008. 43(9):1619-1624.
  10. 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.
  11. Harpavat S, Finegold MJ, and Karpen SJ. Patients with biliary atresia have elevated direct/conjugated bilirubin levels shortly after birth. Pediatrics. 2011. 128(6):e1428-e1433.
  12. Jensen MK, Biank VF, Moe DC, Simpson PM, Li SH and Telega GW. HIDA, percutaneous transhepatic cholecysto-cholangiography and liver biopsy in infants with persistent jaundice: can a combination of PTCC and liver biopsy reduce unnecessary laparotomy? Pediatric Radiology. 2012. 42:32-39.
  13. Shneider BL, Magee JC, Bezerra JA, Haber B, Karpen SJ, Raghunathan T, Rosenthal P, Schwarz K, Suchy FJ, Kerkar N, Turmelle Y, Whitington PF, Robuck PR and Sokol RJ. Efficacy of fat-soluble vitamin supplementation in infants with biliary atresia. Pediatrics. 2012. 130(3):e607-14.
  14. Suchy FJ. Neonatal cholestasis. Pediatrics in Review. 2004. 25(11):388-396.
  15. Superina R, Magee JC, Brandt ML, Healey PJ, Tiao G, Ryckman F, Karrer FM, Iyer K, Fecteau A, West K, Burns RC, Flake A, Lee H, Lowell JA, Wang KS and the Childhood Liver Disease Research and Education Network. The anatomic pattern of biliary atresia identified at time of Kasai hepatoportoenterostomy and early postoperative clearance of jaundice are significant predictors of transplant-free survival. Annals of Surgery. 2011. 254(4):577-585.
  16. Yoon PW, Bresee JS, Olney RS, James LM and Khoury MJ. Epidemiology of biliary atresia: a population-based study. Pediatrics. 1997. 99(3):376-382.
  17. Zallen GS, Bliss DW, Curran TJ, et al. Biliary Atresia. Pediatrics in Review. 2006. 27(7):243-248.