Jaundice Clearance and Cholangitis in theFirst Year Following Portoenterostomy forBiliary Atresia

S Se1valingam, FRCS', M N Mahmud, FRCS**, C R Thambidot"ai, FRACS*, Z Zakaria, FRCS*',N Mohan, FRCS*', Isa, DCP**', M Sheila, M Med CPaeds)*'"**, 'Departments of Surgery &**'Pathology, Hospital University Kebangsaan Malaysia, '*Departments of PediatricSurgery & '"**'Pediatdcs, Institute Pediatdcs, Kuala Lumpur

Biliary atresia, POI"toEmlE,rostomy,

introduction

Biliary atresia b an idiopathic, progressive andpotentially fatal disease. If uncorrected, 90% ofpatients die before three years of agel, Biliaryatresia treated by portoenterostomy (PE) or Ka:;ai

operation has been shown to have a five-yearsUlvival of 30% to 75%1, In Malaysia, Kasaloperation currently remains the primaly treatmentfor bilialy atresia.

This article was accepted: 16 January 2002Corresponding Author: C R Thambidorai, Department of Surgery, Hospital University Kebangsaan Malaysia, Jalan TenferamCheras, 56000 Kuala Lumpur

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Cholangitis is a frequent complication followingFE in patients with biliary atresia and adverselyaffects the long-term outcome2, Cholangitisfrequently occurs within the first few months aftersurgery. In patients followed up for five yearsafter Kasai operation, most attacks of cholangitisoccurred between 1.5 to 19 tllonths after surgert,Cholangitis contributes to poor bile flow anddevelopment of liver cirrhosis.

Jaundice clearance has often been used toevaluate the success of PE. Ten-year survival ratesfrom 73% to 92% have been reported in infants inwhom jaundice cleared following PE~. Patients inwhom jaundice remained and bile flow wasinadequate, the three year survival rate fell to200/0'. We analysed the factors associated withcholangitis and persistent jaundice following PEin this study.

Materials and Methods

This is a retrospective study involving 61 patients.These patients had been followed-up for at leastone year, following Kasai operation performed atthe Institute of Pediatrics, Kuala Lumpur, fromJanuary 1992 to January 1998. The protocol forthe investigation of suspected biliary atresiaincluded blood tests to detect congenitalinfections known to cause neonatal jaundice,hypothyroiclism and alpha-1-antiuypsin deficiency.Liver function tests were done in all patients.Ultrasound and HIDA scans were performed toevaluate the biliary tree. Patients in whom biliaryatresia could not be excluded undelwent either apercutaneous transcholecystic cholangiogram oran on-table-cholangiogram (OTC). On confirmationof biliary atresia, the Kasai procedure wasperformed. The portoenterostmy was donewithout an external stoma. A 45cm. Roux en-Yintestinal segment was anastomosed, end to sideat the porta hepatitis. All patients had a liverbiopsy and biopsy of the tissue from the portalmound. Post-operatively, the patients werefollowed lip in the surgical clinic for a minimumperiod of one year and evaluated by a pecliatricsurgeon. As there was no definite policy in the

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unit with regard to use of prophylactic oralantibiotics after Kasai operation, the patientsreceiving antibiotics were not identified in thisstudy. All patients received fat-soluble vitaminsduring follow-up.

The following data were collected for eachpatient: sex, race, age at which jaundice was firstdetected, age on admission to the surgical wardand age at Kasai operation. The size of the bileductule remnant at the .porta hepatis wasmeasured (in J-l-lnicrons) from the portal moundspecimen. During the follow-up at monthlyintervals, complications including cholangitis,upper gastrointestinal bleed, liver failure andportal hypertension were noted. Portalhypertension for this study purpose was definedas the presence of one or more of the followingfeatures: splenomegaly with dilated veins in theabdominal wall, hematemesis due to documentedvarices or presence of ascites with normalalbumin levels. Liver failure was defined as lowalbumin levels «25g/L) or prolonged prothrombintime uncorrected by administration vitamin K orfailure to thrive in the presence of adequate oralintake. Jaundice clearance was defined as theabsence of clinical jaundice with a total serumbilirubin of less than 18umollL. Cholangitis wasdefined as the presence of fever and leukocytosis(without any other obvious cause) associated witheither a rise in direct bilinlbin or elevated serumlevels of liver enzymes, or passage of stools palerthan before the onset of fever. A positive bloodculture was not mandatory for the diagnosis2

•

For statistical analysis, student's t-test was used forcontinuous variables and chi-square test, forcategorical variables. Fischer's exact test was usedwhen the data were sparse.

Results

Characteristics of the study group

There were 39 (64%) Malay infants, 16 (26%)Chinese and 6 (10%) Indians. Sex ratio was equalamong the three races. Mean age on admission tothe Institute of Pediatrics was 66.90 +/- 23.36 days

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and mean age at PE was 75.85 +/- 24.05 days. Atthe time of PE, 20 patients 03%) were less than60 days old (Group 1), 24 (39%) were between 60to 89 days of age (Group 2), 14 (23%) werebetween 90 to 120 days of age (Group 3) and 3patients (5%) were more than 120 days old(Group 4). Although not statistically significant,there was a tendency for Malay and Indianpatients to present at an older age. At the time ofpresentation to Institute Pediatrics, all patientshad pale stools and dark- coloured urine. Thirtypatients (45%) had splenomegaly and theincidence of splenomegaly was the same in allage groups (about 45%). None of the patients hadclinical ascites on admission. All patients hadelevated total and direct bilirubin levels. Meanalbumin level was 41.1 +/- 5.14 gram/L andalkaline phosphatase levels varied between 98U/L - 885 U/L with a mean of 398.2 +/- 256.6 U/L.

At the end of the one-year follow-up, 33 patients(54%) had jaundice clearance, 35 patients (57%)had cholangitis, 35 patients (57%) had portalhypertension, eight patients 03%) had liverfailure and six patients (10%) developedgastrointestinal bleeding due to oesophagealvarices. Six patients (10%) had died. Of the sixpatients who died, five died of liver failure andone of cholangitis.

When the patients were grouped according toage at operation (Groups 1 - 4) there was nostatistical difference in the rate of jaundiceclearance between the various groups. Themean age of patients who had jaundiceclearance was 75.45 +/- 23.15 days compared to76.32 +/- 25.49 days in those with persistentjaundice. (p>0.05) However, patients operatedafter 90 days of age had a clearance rate of only28% compared to patients operated before 90days of age, who had a 72% jaundice clearancerate. Among the 33 patients who achievedclearance, the mean clearance time was 85 +/­39 days (2.85 +/- 1.38 months) after surgery.There were six patients who took six months toachieve jaundice clearance.

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Among the 35 patients with postoperativecholangitis, 8 patients had more than one episodeof cholangitis while 27 patients had only oneepisode, during one year of follow-up. Eighteenpatients developed cholangitis within threemonths after PE, 14 patients between three to sixmonths and in 3 patients cholangitis occurred sixmonths after surgery. Cholangitis developed in23% of Group 1 patients compared to 77% in theother groups. However, there was no statisticaldifference in the rate of cholangitis between thevarious age groups. The mean age at the time ofPE for patients who developed cholangitis was80.29 +/- 26.48 days compared to 69.88 +/- 19.24days in those with no cholangitis. (p>0.05). It wasalso noted that patients with post-operativecholangitis had a significantly lower jaundiceclearance rate (37%) compared to patients whodid not develop cholangitis (77%). (p<0.05). Thiswas more obvious among infants with 'earlyonset' cholangitis, which is defined as cholangitisoccurring within three months after PES, Ninetyone percent of such infants had persistentjaundice, On the contraty, when cholangitisoccurred more than three months after PE, only23.5% of infants had persistent jaundice.

Patients were divided into two groups based onsize of the biliary ductules, assessed fr01ll thetissue taken in the portal mound: 38 patients(62%) had ductule size more than or equal to 150 I'and 23 patients 08%) had size less than 150 1'.The mean ductule size among those with jaundiceclearance was 240.26 +/- 118 J.l and in thosewithout jaundice clearance was 122.61 +/- 95.64 J.l(p<O.Ol). Patients' with ductule size more than orequal to 150 ( had a significantly higher jaundiceclearance rate (76%), compared to patients withductule size less tban 150 J.l who had only 17%jaundice clearance rate (p<0.05). Patients withductule size more tlun or equal to 150 ( also hada significantly lower cholangitis rate (45%),compared to patients with ductule size less than150 1', 78% of whom had cholangitis. (p<0.05).On further analysis, 47.1% of patients with earlyonset cholangitis had ductule size less than 150 I'

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compared to 26.4% of patients who developedcholangitis more than three months after PE(p>O.05). Multivariate analysis showed the ductulesize to be an independent predictor of cholangitisand jaundice clearance. However, the jaundiceclearance rate as well as the size of the portalductules did not show any temporal relation tothe age of patients at PE.

Discussion

Our study has shown that after PE, 54% ofpatients studied had jaundice clearance. Fifty­seven percent of patients developed post­operative cholangitis within one year of surgery.A significant proportion of patients with 'earlyonset' cholangitis (cholangitis occurring withinthree months after PE) had persistent jaundice.Although jaundice clearance rates decreased withincreasing postnatal age at PE, the relationshipwas not directly linear. Patients who had biliaryductules at the porta < 150 P in size, were morelikely to have persistent jaundice and also todevelop cholangitis within the first year followingPE. The lower rate of jaundice clearance when thediameter of the bilialy ductules was <150 p, hasbeen documented previously3.

Cholangitis is the most common complicationseen following PE and is known to have anegative impact on the long-term results2A . Thereported incidence of cholangitis ranges between40 - 60%. IEarly- onset' cholangitis is said to resultfrom insufficient volume of bile flow and apartially obstructed biliary tree2,s. The pooreroutcome following PE in patients who developcholangitis is likely to be due to progressivedamage to the biliary ductules and hepaticparenchyma with each attack of cholangitis.

The lack of linear relationship between age at PEand i) jaundice clearance rate, ii) incidence ofcholangitis and iii) the size of the remnant portalductules has also been noted in other studies6

.11

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A single ceoter study based on 205 patients hasshown that sparsity or absence of ductules at theporta hepatis and absence of portal inflanunation

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were predictors of poor outcome following PE6•

These histological features may represent theIlburnt outll end result of the disease process.Macroscopic appearance at portoenterostomy(MAP), based on liver consistency, size of portalremnants, grade of portal hypertension andassociated extrahepatic anomalies have been usedto calculate a .MAP score. MAP score has shownstatistically significant correlation with postnatalage at PE but the actual degree of associationbetweeo the two was only moderate". Althoughincreased bile excretion and short-term goodoutc01ne were related to early operation, therewas a plateau effect in which decreasing age hada diminishing effect on outcomeG,8. Data frombiliary atresia registry also showed similar effece.This implies that factors other than age at PE maydetermine the degree of liver damage8-10 and it ispostulated that although biliary atresia is aprogressive disease, the progression with age isnot uniform and there is an unknown effect ofprenatal period in the evolution of the diseaseH.

In conclusion, our study has reiterated that thesize of the bilialy ductules in the porta hepatisgives a good indication of jaundice clearance rateand the incidence of cholangitis followiog PE.Even though PE at an early age gives betterjaundice clearance and reduces the incidence ofcholangitis, age alone is not an accurate predictorof outcome. Prospective and multi-center basedlocal studies on a bigger patient population areneeded to identify other indicators of successfuloutcome following PE. This may help to definethe indications for primary liver transplantation inthe local population.

Acknowledgements

This article is a part of the dissertation submittedfor the Master of Surgery program, UniversityKebangsaan Malaysia (UKM) in 1999. The authorslike to express their gratitude to Professors F.Meah, A. Qureshi aod A. ]asmi of the Departmentof Surgery and Prof. K Rampal of the Departmentof Social and Preventive Medicine, UKM for theirvaluable suggestions.

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2. Wu, ET, Chen HL, Ni YE. Bacterial cholangitis inpatients with biliary atresia: Impact on short-termoutcome. Ped. Surg. Int 2001; 17: 390-5.

3. Ballisteri WF, Bore KE, Ryckman Pc. Biliary atresiaand other disorders of the extrahepatic bile ducts.In: Suchy Fj, Sokol R], Ballisteri WF(eds). Liverdiseases in children, Philadelphia: LippincottWilliams & Wilkins, 2001; 253-74.

4. Kimura K,Inomata Y. Biliary atresia. In: DonnellanW, Burrington JD, Kimura K, Schafer JC, White JJ(cds). Abdominal surgery of infancy andchildhood, Luxembourg: Harwood Academicpublishers, 1996; 32/1-32/13.

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6. Tan CEL, Davenport M, Driver M et al. Does themorphology of the extrahepatic biliary remnants inbiliary atresia influence survival? A review of 20Scases.] Pediatr Surg 1994; 29, 1459-64.

7. Miyano T, Fujimoto T, Ohya T, Shimomura H.Current concept of the treatment of biliary atresia.World]. Surg 1993; 17, 332-6.

8. Davenport M, Howard ER. Macroscopic appearanceat portoenterostomy - A prognostic variable inbilialY atresia. J. Pediatr Surg 1996; 31:1387- 90.

9. Karrer FM, LillyJR, Stewart 13A. 13iliary Atresia registry1976 to 1989. ]. PediaU·. Surg 1990; 25, 1076-81.

10. Schweizer P, Schweizer M, Schellinger K, KirschnerHJ, Schttenhclm C. Prognosis of extrahepatic bileduct atresia after hepatoenterostomy. Pediatr Surg1nt 2000, 16,351-5.

11. Maksoud JG, Fauza DO, Silva M et at. Managementof biliaty atresia in the liver transplantation era: AIS-year, single center experience. J Pediatr. Surg1998, 33'. 115-8.

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