Biliary atresia

ARTICLE IN PRESS Current Paediatrics (2006) 16, 59–63

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Biliary atresia Erica Makin, Mark Davenport Department of Paediatric Surgery, King’s College Hospital, London SE5 9RS, UK

KEYWORDS Biliary atresia; Kasai portoenterostomy

Summary Biliary atresia (BA) remains a devastating disease of infants and is still a disease of largely unknown aetiology, although many hypotheses, including aberrant early bile duct development and perinatal viral infection, have been suggested. Although molecular biology and immmunohistochemistry have improved our understanding of some of the inflammatory elements of BA, we still do not know how such disparate elements interact and relate. Clinically, such infants present with obstructive conjugated jaundice, pale stools and dark urine in the first weeks of life. In most cases, infants should undergo excision of the bile duct remnants and biliary reconstruction (a Kasai portoenterostomy) to try to restore bile flow and alleviate jaundice. Transplantation should be reserved for those in whom this technique fails and who develop chronic liver disease and its complications. A recent UK national review suggests that over 50% of infants will be able to clear their jaundice and therefore to have a reasonable expectation of long-term survival with a good quality of life. & 2005 Elsevier Ltd. All rights reserved.

Practice points

Research directions

 Recognize the crucial difference between conju-

 Identify the mechanisms of inflammatory reaction in

  

gated and unconjugated jaundice in neonates. Investigate prolonged jaundice Kasai portoenterostomy is still the first-line therapy for BA The aetiology of BA is largely unknown The majority of individuals, even after a successful Kasai operation, will require a liver transplant at some point in their life

Corresponding author. Tel.: +44 (0) 20 7346 3350;

fax: +44 (0) 207 346 4021. E-mail addresses: [email protected], [email protected] (M. Davenport). 0957-5839/$ - see front matter & 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.cupe.2005.10.005

the liver of infants with BA

 Elucidate the real role of viruses in the aetiology of BA

 Establish effectiveness of postoperative drugs Introduction Biliary atresia (BA) can be a devastating disease in infants, invariably leading, if untreated, to cirrhosis, liver failure and death. The condition is still the most common indication for paediatric liver transplantation throughout the developed world.

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E. Makin, M. Davenport

The incidence of BA is consistently greater in Japan (1 in 96001) than in other countries (e.g. UK, 1 in 15 000 live births2), and there is usually a female preponderance. About 10% (3% in Japanese series1) of cases have other congenital abnormalities, specifically a syndromic association that we have termed ‘BA splenic malformation’ (BASM) syndrome.3 Table 1 illustrates the range of abnormalities and their incidence.

and latterly bridging fibrosis giving way to features of overt biliary cirrhosis. The lumen of the extrahepatic duct is obliterated at a variable level, and this forms the basis for the most common classification in clinical use:

 type 1 (5%)—the level of obstruction is within the common bile duct (so the gallbladder contains bile);

 type 2 (3%)—the level is within the common hepatic

Aetiology

duct. The gallbladder will not contain bile, but a

The cause of BA is not known with any degree of certainty, although there are a number of hypotheses, including a defect or derangement in early bile duct development (i.e. a first-trimester event), which may3 or may not4 be associated with the other congenital anomalies typical of BASM. The excretion of an abnormal and toxic component in the bile,5 perinatal infection with a variety of hepatotropic cholangiopathic viruses,6,7 an abnormality of the hepatic arterial supply8 and mucosal destruction secondary to a common pancreaticobiliary channel have also all been postulated as causes. More recent advances in the molecular pathology of BA hypothesize the involvement of a small-cell infiltrate composed largely of lymphocytes and natural killer cells, with an activation and proliferation of macrophages and the abnormal expression of cell adhesion molecules on hepatocytes and sinusoidal endothelium driving a (presumably detrimental) inflammatory reaction.

Pathology Whatever the cause, the macroscopic appearance of the extrahepatic biliary tree ranges from an inflamed, hypertrophic occluded biliary tract to an atrophic negligible remnant with absent parts (Fig. 1). The histological appearance within the liver exhibits early portal tract inflammation, a pronounced small-cell infiltrate, bile ductule plugging and proliferation within the portal triad,

Table 1

Figure 1 Operative view of a case of biliary atresia, showing a solid, atrophic gallbladder (solid arrow) and solid biliary remnant (dotted arrow). There was no common bile duct.

Biliary atresia splenic malformation syndrome.

Component

Frequency (%)

Polysplenia, double spleen, etc. Asplenia Situs inversus Preduodenal portal vein

90 10 50 40–60

Absent inferior vena cava

40–50

Malrotation Cardiac anomalies

30–40 30–40

Annular/short pancreas Immotile cilia syndrome Abnormal maternal history

5 o2 40

 From the King’s College Hospital series (1997–2005; unpublished data).

Notes

Other variants include congenital portocaval shunt Consequent azygous venous drainage of the lower body into the superior vena cava All types, including Fallot’s tetralogy, hypoplastic left heart, valvular anomalies and septal defects

For example, maternal diabetes (10% of cases), first-trimester drug ingestion

ARTICLE IN PRESS Biliary atresia



transection of the proximal remnant should show two distinct bile-containing lumens; type 3 (490%)—there is no visible bile-containing proximal lumen, and the obstruction is within the porta hepatis.

The other main macroscopic variation is that of cystic change, seen in about 5% of cases, within some part of the extrahepatic biliary tree. Some cysts contain mucus, whereas others contain bile. If the latter occurs, there may be some diagnostic confusion with a true choledochal cyst. In cystic BA, however, the wall is invariably thickened and communicates poorly with abnormal, non-dilated intrahepatic ducts. This should be obvious on a cholangiogram (operative, percutaneous or endoscopic retrograde cholangiopancreatography.

Clinical features All infants with BA will be jaundiced and have pale stools and dark urine—if looked for! This is due to the inability to excrete conjugated (i.e. water-soluble) bilirubin into the gastrointestinal tract, excreting instead into the urine and darkening its colour. Some infants (5%) will have had an abnormal antenatal ultrasound scan with cystic change in the biliary tree9 or may present because of other abnormalities (typically the cardiac abnormalities associated with BASM or malrotation).3 Most infants presenting within 80 days will not show clinical features of cirrhosis or irretrievable liver damage, such as ascites, splenomegaly or heterogeneity on the liver ultrasound.9 A small proportion of infants will present with features of vitamin-K-dependent coagulopathy and bleeding, particularly in those communities where the practice of neonatal administration of parenteral vitamin K is not routine. The differential diagnosis of conjugated jaundice in infants is long and needs perseverance to work out. Surgical causes, other than BA, are uncommon but may include obstructed choledochal malformations, spontaneous perforation of the bile duct and inspissated bile syndrome.10 Common medical causes include neonatal hepatitis, a1antitrypsin deficiency, giant-cell hepatitis, cytomegalovirus hepatitis and cystic fibrosis. Biliary hypoplasia may be a feature of Alagille’s syndrome (abnormal ‘elfin’ facies, butterfly vertebrae, pulmonary stenosis) and can cause diagnostic confusion. In larger specialist centres, a prelaparotomy diagnosis of BA is possible in over 80% of cases.10 Important diagnostic elements should include ultrasonography, the biochemical exclusion of a1-antitrypsin deficiency and cystic fibrosis, viral serology and ideally a percutaneous liver biopsy. In many centres, however, particularly those in Japan, duodenal intubation and measurement of intraluminal bile remains the key investigation, rather than biopsy. If the diagnosis is still in doubt, other techniques such as endoscopic retrograde cholangiopancreatography can be performed in order to delineate the biliary tree, thus avoiding a laparotomy.11 Magnetic retrograde cholangiopancreatography does not currently appear to offer much advantage over standard ultrasonography, although with new-generation scanners this may change. Radioisotope

61 hepatobiliary imaging (e.g. using iminodiacetic acid derivatives (IDA)) still lacks sufficient discrimination in borderline cases to be really useful.

Kasai portoenterostomy The aim of the surgery is to excise all extrahepatic biliary remnants, allowing a wide portoenterostomy on to a portal plate, denuded of all tissue. In the majority of cases, this will expose sufficient transected microscopic bile ductules that retain connections with the primitive intrahepatic bile ductule system to allow the restoration of at least a degree of biliary drainage. This should be the object not only in patients with type 3 BA, but also in those who do have proximal bile containing ducts (types 1 and 2). As with many operations, there are many differences in the detail, which may explain the wide variations seen in reported results. At King’s College Hospital, we have developed the original Kasai technique and believe the following are crucial elements. The liver should be fully mobilized by dividing its ligaments so that the organ can be everted outside the abdominal cavity. This step allows full exposure of the porta hepatis and facilitates the subsequent detailed dissection. This manoeuvre impairs venous return to the heart by kinking the cava and may need a concomitant increase in intravenous volume support. The dissection itself must be wide. There are three key portal plate landmarks: exposure of the origin of the umbilical vein from the left portal vein in the fossa of Rex; exposure of the usual extrahepatic bifurcation of the right portal pedicle; and division of small veins to the plate directly from the portal vein to expose the caudate lobe posteriorly. It is important to realize that actually excising liver parenchyma (‘coring’) does not improve bile drainage, presumably because any divided ductules simply become obliterated by subsequent scar tissue. A portoenterostomy using a retrocolic Roux loop completes the surgery (Fig. 2). There is a whole range of possible pharmacological therapies that have been suggested to improve postoperative results. None, however, has been subjected to anything like acceptable scientific scrutiny. For example, there are anecdotal small-number studies suggesting a benefit from corticosteroids,12 ursodeoxycholic acid13 and even Chinese herbs.14 An interim analysis from our institution on a doubleblind, randomized placebo trial using postoperative prednisolone has, however, failed to show any significant clinical difference.

Prognostic factors and complications of the Kasai procedure There are many factors that will influence surgical outcome in BA. Some are unalterable (e.g. degree of cirrhosis or fibrosis at presentation; absence or paucity of microscopic bile ductules at the level of section), and some are subject to change (e.g. surgical experience, untreated cholangitis). In large centres with experienced surgeons, about 50–60% of all infants will clear their jaundice and achieve a normal (o20 mmol/l) bilirubin level.15,16 These infants should do well and have a good quality of long-term survival with their

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E. Makin, M. Davenport

Clearance of jaundice (< 20 µmol/L) = 52%

native liver survival (%)

1.0 0.8

N = 126

0.6 0.4 0.2 Native liver survival~ 50% 0.0 0.0

1.0

2.0

3.0 4.0 Age (years)

5.0

6.0

7.0

Figure 3 Outcome of 126 infants treated by Kasai portoenterostomy (1999–2004). Complete clearance of jaundice was achieved in 65 (52%) infants. Five-year native liver survival is 50%.

Figure 2 Schematic figure of a Roux loop reconstruction and portoenterostomy.

native liver.17 In those with no effect from the Kasai procedure (usually apparent within 2–3 months), active consideration should be given to early liver transplantation. Fig. 3 illustrates the current results from a recent cohort of infants treated at our institution. Children with BASM do less well in comparison with nonsyndromic infants, which has been shown in large studies from the UK.3,16 One of the reasons for the increased mortality in this group is related to the associated malformations, especially severe congenital cardiac disease and sudden death seen with hepatopulmonary syndrome.18 This complication is associated with BASM and appears to be caused by vasoactive substances derived from the mesenteric circulation bypassing sinusoidal inactivation.18 The age of the infant has an effect on outcome, although this is not as clear-cut as was once thought. It is not a linear effect, and it is difficult to determine a real variation in outcome at anywhere up to 80 days of age. Beyond that, fibrosis does begin to be detrimental, although even beyond 100 days the Kasai procedure can have advantages and even long-term jaundice-free survival.9 There are two significant complications following a Kasai portoenterostomy, these being cholangitis and portal hypertension. Cholangitis occurs most commonly in the year following primary surgery in about 30–50% of children.15 Paradoxically, it only occurs in children with some degree of bile flow and not in those with early failure. Clinically, it is characterized by worsening jaundice, fever and acholic stools. The diagnosis may be confirmed by blood culture or by percutaneous liver biopsy, but it is important to treat suspected cases early with broad-spectrum antibiotics effective against Gram-negative organisms. Recalcitrant cholangitis can be a problem in some children. This can be associated with parenchymal cyst formation, and some authors have advocated percutaneous aspiration or internal drainage to overcome putative defects in bile drainage.19 A

brief course of high-dose steroids has also been advocated by some institutions. Portal hypertension has been shown in virtually all infants at the time of the Kasai operation, but subsequent portal hypertension depends both on the degree of established fibrosis and, most importantly, on the response to surgery. There is a relationship with biochemical liver function and variceal development. In those infants where the Kasai fails to clear jaundice to any degree and need early transplantation, about 30% will have had a significant variceal bleed. In those who respond well to the initial Kasai procedure but who have established fibrosis, variceal development may be delayed, presentation with bleeding perhaps occurring only at 2–3 years of age. Although injection sclerotherapy retains a role in treating varices in infants, most older children are better suited to endoscopic variceal banding. Where liver function is poor, liver transplantation needs to be actively considered.

Conclusion and recent results An excellent outcome following portoenterostomy can be characterized as clearance of jaundice (to normal levels), abbreviation of hepatic fibrosis (i.e. absence of clinical portal hypertension) and avoidance of ascending cholangitis. Just how many patients actually achieve this is fiercely debated. In the recently published experience from the three designated centres in England and Wales, the rate of clearance of jaundice was 57%.16 The next unequivocal criterion of success is the 5-year native liver survival rate, which therefore regards need for transplant and death as end-points. Recent figures have ranged from 32% to 62% in national registries.1,2,16,20 Longterm results (i.e. 10 years or greater) are less readily available as Kasai’s operation was not readily performed on or even available to infants born in the 1970s and early 1980s. Nevertheless, our own figures would suggest that about 45% will reach adulthood with their own liver.15 Furthermore, about 15% will have a truly long-term,

ARTICLE IN PRESS Biliary atresia symptom-free, hospital-free, normal-liver-biochemistry existence, although even in those ‘cured’ of their BA, liver histology, when looked at, is still very abnormal.17 The prospect of native liver survival to adulthood is therefore probably only available to a minority, and a successful liver transplant procedure at some later point in life should probably be a realistic aim for most infants born with BA.

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63 9. Davenport M, Puricelli V, Farrant P, et al. The outcome of the older (4100 days) infant with biliary atresia. J Pediatr Surg 2004;39:575–81. 10. Davenport M, Betalli P, D’Antiga L, et al. The spectrum of surgical jaundice in infancy. J Pediatr Surg 2003;38:1471–9. 11. Ohnuma N, Takahashi H, Tanabe M, Yoshida H, Iwai J. The role of ERCP in biliary atresia. Gastrointest Endosc 1997;45:365–70. 12. Dillon PW, Owings E, Cilley R, et al. Immunosupression as adjuvant therapy for biliary atresia. J Pediatr Surg 2001;36: 80–5. 13. Meyers R, Book LS, O’Gorman M, et al. High dose steroids, ursodeoxycholic acid and chronic intravenous antibiotics improve bile flow after Kasai procedure in infants with biliary atresia. J Pediatr Surg 2004;38:406–11. 14. Iinuma Y, Kubota M, Yag M, et al. Effects of the herbal medicine Inchinko-to on liver function in post-operative patients with biliary atresia—a pilot study. J Pediatr Surg 2003;38:1607–11. 15. Davenport M, Kerkar N, Mieli-Vergani G, et al. Biliary atresia—the King’s College Hospital experience (1974–1995). J Pediatr Surg 1997;32:479–85. 16. Davenport M, Ville de Goyet J, Stringer MD, et al. Seamless management of biliary atresia. England & Wales 1999–2002. Lancet 2004;363:1354–7. 17. Hadzic N, Tizzard S, Davenport M, Mieli-Vergani G. Long-term survival following Kasai portoenterostomy: is chronic liver disease inevitable? J Pediatr Gastro Nutr 2003;37:403–33. 18. Barbe T, Losay J, Grimon G, et al. Pulmonary arteriovenous shunting in children with liver disease. J Pediatr 1995;126: 571–9. 19. Islam S, Dasika N, Hirschl RB, et al. A novel approach to the management of late-onset liver failure in biliary atresia. J Pediatr Surg 2004;39:371–4. 20. Chardot C, Carton M, Spire-Bendelac N, et al. Prognosis of biliary atresia in the era of liver transplantation: French national study from 1986 to 1996. Hepatology 1999;30:606–11.