EHBA

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EHBA

  1. 1. 81 Symposium on Hepatology and Gastroenterology Biliary Atresia: Outcome and Management Mark Davenport Department of Pediatric Surgery, King’s College Hospital, London SE5 9RS ABSTRACT Untreated, biliary atresia remains a fatal condition of the newborn. Most present within four to six weeks of conjugated jaundice and acholic stools, and, although still a challenging diagnosis to make, therein lies the opportunity of changing the course of this otherwise inexorable disease. The aim of surgery is to restore bile flow, alleviate jaundice and abbreviate the cholangiodestructive process within the liver. The Kasai portoenterostomy, introduced almost 50 years ago in Japan, aims to expose microscopic biliary ductules within the fibroinflammatory mass at the porta hepatis, and restore bile drainage into a mobilised Roux loop. About 50% of infants with BA will be able to clear their jaundice following Kasai alone, given appropriately experienced surgeons and if performed prior to the onset of overt cirrhosis. They have a reasonable expectation of long-term survival to adulthood with a good quality-of-life. The remainder may be candidates for liver transplantation (where available) although donor organ shortage and immunosuppresion-related complications remain significant problems. [Indian J Pediatr 2006; 73 (9) : 825-828] Markdav2@ntlworld.com; Mark.Davenport@kingsch.nhs.uk Key words : Biliary atresia; Kasai portoenterostomy Biliary atresia (BA) is a cholangiodestructive disease of both intra- and extrahepatic parts of the biliary system which leads to cirrhosis and ultimately liver failure and remains the commonest indication for pediatric liver transplantation throughout the Western world. The incidence of BA is higher in Japan, China and probably south Asia (~1 in 8-9 000)than in Europe and the USA (~ 1 in 12 - 15 000 live births). 1,2 In the latter countries about 10% of cases have other congenital abnormalities, and specifically a syndromic association which we have termed the Biliary Atresia Splenic Malformation (BASM) syndrome.3 This is characterised as having splenic pathology (usually polysplenia), situs inversus, cardiac and vascular anomalies such as an absence of the inferior vena cava and a pre-duodenal portal vein. There is a marked female predominance and a first-trimester illness or insult (e.g. maternal diabetes) may be causative in this sub-group. PATHOLOGY The macroscopic appearance of the extrahepatic biliary tree ranges from an inflamed, hypertrophic occluded biliary tract to an atrophic negligible remnant with absent Correspondence and Reprint requests : Dr. M. Davenport, Department of Pediatric Surgery, King’s College Hospital, Denmark Hill, London SE5 9RS, Tel.: 0044 (0) 207 346 3350; Fax : 0044 (0) 207 346 4021. Indian Journal of Pediatrics, Volume 73—September, 2006 parts. The histological appearance of the liver is characterised by portal tract inflammation, a small cell infiltrate, bile ductule plugging and proliferation and in the later stages 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 commonest classification in clinical use (Table 1). The other main macroscopic variation is that of cystic change, seen in about 5% of cases, within some part of the extrahepatic biliary tree.4 Some cysts contain mucus, while others contain bile. If it is the latter there may be some diagnostic confusion with that of a true choledochal cyst. However, in cystic biliary atresia, the wall is invariably thickened and communicates poorly with abnormal non-dilated intrahepatic ducts. This should be obvious on a cholangiogram (operative, percutaneous or ERCP). CLINICAL FEATURES All infants with biliary atresia will be jaundiced and have pale stools and dark urine. Some infants will have had an abnormal antenatal ultrasound scan (~ 5%), because of the cystic change in the biliary tree or may present because of the other congenital abnormalities.4 Clinical features of cirrhosis, such as ascites and marked hepato­ splenomegaly, are uncommon before 70-80 days of age. A small proportion of infants will present with features of a Vitamin K-dependent coagulopathy (e.g. umbilical stump bleeding, melena or intracerebral bleeding) bleeding, 825
  2. 2. 82 Mark Davenport particularly in those communities where routine neonatal administration of parenteral Vitamin K is not practiced. The differential diagnosis of infants with conjugated jaundice is long and outside of the scope of this article. Some common medical causes include neonatal hepatitis, á1-antitrypsin deficiency, giant cell hepatitis, cytomegalovirus hepatitis, Alagille’s syndrome, and cystic fibrosis. There are other less common surgical causes including obstructed choledochal malformations, spontaneous perforation of the bile duct and the inspissated bile syndrome.5 Pertinent investigations include ultrasonography, liver biochemistry, viral serology, and ideally a percutaneous liver biopsy. In some centres, duodenal intubation and measurement of intralumenal bile is practised as the routine test for BA. Newer modalities such as ERCP and MRCP have been used at times, although the former is clearly highly operator-dependent and the latter not sufficiently precise in its delineation of infantile biliary anatomy to offer real advantage.6 In a number of centres, operative cholangiography remains the key investigation in demonstrating biliary patency. Occasionally this may be performed laparoscopically with good results.7 The surgical strategy for BA has evolved over the past 20 years incorporating liver transplantation (where available) as a complementary technique to the older Kasai portoenterostomy. In some cases (typically with established cirrhosis and ascites), a case may be made for primary liver transplantation but this should be an unusual occurrence if the infant presents at less than 100 days. KASAI PORTOENTEROSTOMY The aim of the procedure is to excise all visible extrahepatic biliary remnants allowing a wide portoenterostomy onto a denuded portal plate. In most cases, this will expose sufficient transected microscopic bile ductules which retain connections with the primitive intrahepatic bile ductule system to allow restoration of at least some worthwhile biliary drainage. This is clearly the object in type 3 biliary atresia, but should also be strongly considered even in those who have a visible bile­ containing bile duct (types 1 and 2). There are many differences in the detail of this operation and this coupled with its infrequency amongst pediatric surgeons may explain the wide variations seen in reported results. We believe that the liver should be mobilised fully outside of the abdominal cavity (by division of its suspensory ligaments), to ensure maximal exposure of the porta hepatis and a detailed dissection.8 The portal dissection itself must be wide extending from exposure of the origin of the umbilical vein from the left portal vein in the Rex fossa and encompassing the often bifurcating right portal pedicle. Small veins from the portal vein to the portal remnant should also be divided to expose the caudate lobe posteriorly. Most transected ductules are found in the marginal areas, recapitulating the normal biliary arrangement, and it is important to allow these to drain into a long (~40 cms) Roux loop. Modifications such as an intussusception valve, stomas or implanting the distal end of the Roux into the duodenum have no real advantages in clinical practice and have been discontinued in most centres. Some centres have reported the Kasai operation as a laparoscopic or at least laparoscopic-assisted procedure. Given that the only real measure of success in the Kasai is clearance of jaundice it is difficult to believe that this offers anything more in the necessarily, detailed procedure of hilar dissection – the key to its success. Cosmetic advantages are only temporary if the end result is a transplanted liver. There are a number of drugs which have been suggested to improve post-operative results. For instance, there are anecdotal and uncontrolled studies suggesting benefit from corticosteroids 9,10 , ursodeoxycholic acid10 and even Chinese herbs11 . However, none have been subjected to anything like acceptable scientific scrutiny. Early results from our own institution on a randomised double-blind, placebo­ controlled trial using post-operative prednisolone (2mg/ kg/day) did not show any significant clinical difference. PROGNOSTIC FACTORS AND COMPLICATIONS OF THE KASAI There are many factors, which will influence surgical outcome. Some are unalterable (e.g. degree of cirrhosis or fibrosis at presentation; absence of, 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 studies from the UK and France, children with BASM do less well in comparison to non­ syndromic infants.12,13 Reasons for increased mortality in this group are the associated malformations particularly severe congenital cardiac disease and hepatopulmonary syndrome.14,15 The age of the infant has an effect on outcome although this is not as clear-cut as was once thought. There is no real cut-off (e.g. six or eight weeks); these were simply the arbitrary values from earlier small-scale studies. There is no doubt that the fibrotic element of the hepatopathology is progressive but beyond what age an attempt at a Kasai portoenterostomy is pointless is not known. Some infants will come to surgery early with very soft, non-fibrotic livers, at 20 days for instance, but because there are few residual ductules in the porta hepatis their Kasai’s will fail. In contrast, our own series did show jaundice-free survival in infants (admittedly a lower proportion) coming to surgery beyond 100 days.16 Indian Journal of Pediatrics, Volume 73—September, 2006826
  3. 3. 83 Biliary Atresia : Outcome and Management OUTCOME OF SURGERY FOR BILIARY ATRESIA - RECENT RESULTS An excellent outcome following portoenterostomy can be characterised 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 actually achieve this is fiercely debated. There are two criteria which should be looked for in any report: clearance of jaundice (to a defined level) and the proportion that retain their own liver. The former crystallises the desired effect of the Kasai in reversing cholestasis (and is also highly predictive of ultimate outcome), the later is unequivocal and may be used to compare results from disparate centres. Table 2 illustrates published outcome from around the world.1, 12, 13, 15, 17-19 There is clearly the risk of publication bias in single centre reports – no one wants to publish poor results. With this in mind, probably the most reliable reports are from the national outcome studies of England and France 2, 12,13 which are probably representative of the European experience, and that of the Biliary Atresia Registry from Japan.1 In our own recent study based on experience in England and Wales, the clearance of jaundice rate was 57% with a 4-year estimated native liver survival of 51%. Long-term results (i.e. 10 years or greater) are less readily available as Kasai’s operation was not readily performed or even available to vast numbers of infants born in the 1970s and early 1980s. Nevertheless our own figures would suggest that about 45% will reach their teenage years with their own livers,15 and up to 15% will have a truly long-term, symptom-free, hospital-free, normal liver biochemistry existence.20 Nevertheless even in these children apparently “cured” of their biliary atresia, liver histology when looked at is still very abnormal.21 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 now born with biliary atresia. Aside from end-stage liver disease (i.e. increasing jaundice, ascites, failure to thrive etc.), there are two main complications which may follow a Kasai and to some extent are treatable. These are cholangitis and portal hypertension. Cholangitis occurs most commonly in the year following primary surgery in about 30 - 60% of children. Paradoxically, it only occurs in children with some degree of bile flow. Infants who have had no effect from a Kasai do not suffer from cholangitis, principally because no connections have been established between the residual intrabiliary bile ducts and the Roux loop. Clinically, cholangitis is characterised by worsening jaundice, fever and acholic stools. The diagnosis may be confirmed by blood culture or by percutaneous liver TABLE 1. Classification of Biliary Atresia (derived from Japanese Association of Pediatric Surgeons) Definition Type 1 (~5%) Level of obstruction is within the common bile duct. Gallbladder contains bile. Type 2 (~ 3%) Level is within the common hepatic duct. The gallbladder will not contain bile but a transection of the proximal remnant should show two distinct bile-containing lumens. Type 3 (>90%) Obstruction is within the porta hepatis. No visible bile-containing proximal lumen. TABLE 2. Recent Results in Biliary Atresia Series & country Period N Clearance jaundice Native liver survival Notes 5 yr 10 yr Hung et al. (Taiwan)17 1976 - 2000 141 61% 35% 31% Single centre Davenport et al. (UK)12 1999 - 2002 148 57%* 51%* n/a UK national study Chardot et al. (France)13 1986 - 1996 472 n/a 52% 27% French national study Altman et al. (USA)18 1972 - 1996 266 n/a 45% 35% Two-centre study from advent of Kasai operation in USA Nio et al. (Japan)1 1989 - 1994 735 57%** 52 – 64%** 53% Japanese national study Davenport et al. (UK)15 1973 - 1995 338 n/a 50 - 60%*** 41% Single centre study from advent of Kasai operation in UK Karrer et al. (Denver)20 1973 - 1985 98 n/a n/a 24% Single centre study from advent of Kasai operation in USA * < 20 mol/L and 4 year native liver survival ** < 2 mg/% (=34 µmol/L) and by year cohort *** by year cohort Indian Journal of Pediatrics, Volume 73—September, 2006 827
  4. 4. 84 Mark Davenport biopsy, but it is important to realise that actual microbiological confirmation in uncommon and early empirical treatment with broad-spectrum antibiotics effective against gram-negative organisms is indicated. Recalcitrant cholangitis can be a problem in some children and be associated with parenchymal cyst formation, too short a Roux loop or problems with loop drainage. Radioisotope scans may uncover a dysfunctional Roux loop and lead to surgical revision or internal diversion of a large cystic space. Alternatively, long-term antibiotic therapy should overcome the tendency to recurrent sepsis. Portal hypertension has been shown in virtually all infants at the time of the Kasai operation. However subsequent portal hypertension depends both on the degree of established fibrosis and, most importantly, the response to surgery. In those who fail and need early transplantation about 30% will have had a significant variceal bleed. In those who respond well to initial Kasai, but who have established fibrosis then variceal development can be delayed and presentation with bleeding perhaps only occurs at 2-3 years. The emergency treatment of bleeding varices is a combination of blood transfusion, correction of thrombocytopenia, and coagulopathy together with acute endoscopy to confirm the diagnosis and initiate treatment. Specific agents to lower portal pressure (e.g. the somatostatin analogue, octreotide) may also be useful where available. A sengstaken tube may occasionally be required when there is on-going bleeding to enable a clear enough view for definitive endoscopic therapy. Although injection sclerotherapy (e.g. ethanolamine) retains a role in treating varices in infants, most older children are better suited to endoscopic variceal banding.21 In children with reasonable restoration of liver function and particular those that are jaundice-free prior to the bleeding episode then endoscopic control may be the only therapy necessary. However, where varices are symptomatic of a failing liver then transplantation is the only realistic procedure with a long-term chance of success. Currently, in large centres with experienced surgeons, about 50 - 60% of all infants will clear their jaundice and achieve a normal (<20 µmol/L, <2 mg/% according to definition) bilirubin. These should do well and have a good quality of long-term survival with their native liver. In those with no effect from the Kasai (usually only too apparent within 2-3 months), then active consideration should be given to early liver transplantation. The hazards of transplantation in small infants should never be underestimated and deaths on the waiting-list are still an ever present threat. Nevertheless a 3-year survival rate of 85 - 90% post–transplantation is currently achievable and realistic for this group of children.22,23 REFERENCES 1. Nio M, Ohi R, Miyano T et al. Five and 10-year survival rates after surgery for biliary atresia: a report from the Japanese Biliary Atresia Registry. J Pediatr Surg 2003; 38: 997-1000. 2. McKiernan PJ, Baker AJ, Kelly DA. The frequency and outcome of biliary atresia in the UK and Ireland. Lancet 2000; 355: 25-29. 3. Davenport M, Savage M, Mowat AP, Howard ER. The Biliary Atresia Splenic Malformation syndrome. Surgery 1993; 113: 662 – 668. 4. Hinds R, Davenport M, Mieli-Vergani G, Hadzic N. Antenatal presentation of biliary atresia. J Pediatr 2004; 144: 43-46. 5. Davenport M, Betalli P, D’Antiga L et al. The spectrum of surgical jaundice in infancy. J Pediatr Surg 2003; 38: 1471-1479. 6. Ohnuma N, Takahashi H, Tanabe M, Yoshida H, Iwai J. The role of ERCP in biliary atresia. Gastrointest Endosc 1997; 45: 365­ 370. 7. Okasaki T, Miyano G, Yamataka A et al. Diagnostic laparoscopy-assisted cholangiography in infants with prolonged jaundice. Pediatr Surg Int 2006; 22 : 140-143. 8. Davenport M. Biliary atresia. In Robb & Smith (eds) Spitz L, Coran AG. (in press) 9. Dillon PW, Owings E, Cilley R et al. Immunosupression as adjuvant therapy for biliary atresia. J Pediatr Surg 2001; 36 : 80­ 85. 10. 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: 406-411. 11. 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: 1607-1611. 12. Davenport M, Ville de Goyet J, Stringer MD et al. Seamless management of biliary atresia. England & Wales 1999- 2002. Lancet 2004; 363 : 1354-1357. 13. 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 : 606-611. 14. Barbe T, Losay J, Grimon G et al. Pulmonary arteriovenous shunting in children with liver disease. J Pediatr 1995; 126; 571– 579. 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 : 479-485. 16. Davenport M, Puricelli V, Farrant P et al. The outcome of the older (>100days) infant with biliary atresia. J Pediatr Surg 2004; 39: 575-581. 17. Hung PY, Chen CC, Chen WJ et al. Long-term prognosis of patient with biliary atresia: a 25 year summary. J Pediatr Gastrol Nutr 2006; 42: 190-195. 18. Altman RP, Lily JR, Greenfield J et al. A multivariable risk factor analysis of the portoenterostomy (Kasai) procedure for biliary atresia: twenty-five years of experience from two centers. Ann Surg 1997; 226 : 348-353. 19. Karrer FM, Price MR, Bensard DD et al. Long-term results with the Kasai operation for biliary atresia. Arch Surg 1996; 131: 493­ 496. 20. 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 : 403-433. 21. Sasaki T, Hasagawa T, Nakajima K et al. Endoscopic variceal ligation in the management of gastroesophageal varices in postoperative biliary atresia. J Pediatr Surg 1998; 33 : 1628-1632. 22. Utterson EC, Shepherd RW, Sokol RJ et al. Biliary atresia: clinical profiles, risk factors, and outcomes of 755 patients listed for liver transplantation. J Pediatr 2005; 147: 180-185. 23. Barshes NR, Lee TC, Balkrishnan R et al. Orthotopic liver transplantation for biliary atresia: the U.S. experience. Liver Transpl 2005; 11 : 1193-1200. Indian Journal of Pediatrics, Volume 73—September, 2006828

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