2009 The Authors. Journal compilation 2009 Paediatrics and Child Health Division (Royal Australasian College of Physicians)

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1 Outcome of biliary atresia in Malaysia: A single-centre study 1. Way-Seah Lee 1,*, 2. Pei-Fan Chai 1, 3. Kean-Seng Lim 1, 4. Li-Han Lim 1, 5. Lai-Meng Looi 2, 6. Trndivanam Muthurangam Ramanujam 3 Article first published online: 28 APR 2009 DOI: /j x 2009 The Authors. Journal compilation 2009 Paediatrics and Child Health Division (Royal Australasian College of Physicians) Issue Journal of Paediatrics and Child Health Volume 45, Issue 5, pages , May 2009 Additional Information(Show All) Abstract Article References Cited By Keywords: biliary atresia; Malaysia; outcome Abstract Aim: This study aimed to determine the outcome of the operation of children with biliary atresia (BA) at a tertiary paediatric referral centre in Malaysia. Methods: A prospective study on all patients with BA referred to the University of Malaya Medical Centre (UMMC), Kuala Lumpur, from 1996 to 2005 was conducted. Survival with native liver, liver transplantation (LT) or death at 2 years of age was determined. Results: The median age at referral of the 57 patients with BA seen at University of Malaya Medical Centre was 62 days. Kasai procedure was not performed in nine patients who were all referred late (median age of referral 180 days). The median age at hepatoportoenterostomy (HPE) of the remaining 48 patients was 70 days. A total of 53 (93%) patients had type 3 BA, while only 1 (2%) patient had BA splenic malformation. At 2 years, the survival rate with native liver for the 48 patients who had HPE was 37%, while the overall survival (native liver and LT) rate was 40%. Two of the four patients who had LT survived with a liver graft at 2 years. Conclusions: The 2-year survival with native liver following corrective surgery for BA in UMMC, Malaysia, compares favourably with other international figures, but the overall survival rate was adversely affected by a lack of timely LT.

2 The outcome of BA in Malaysia may be further improved by increasing the awareness among child-health professionals on the importance early referral for appropriate surgery in infants suspected of having BA. Biliary atresia (BA) is a progressive, obliterative fibroinflammatory cholangiopathy of infancy. 1,2 The initial treatment for BA is to create a hepatoportoenterostomy (HPE), 3 which should be performed before the infant is 2 months of age to successfully re-establish bile flow. 4 For many infants, however, delayed recognition of the disease and delayed referral for surgery remain as major obstacles to optimal timing for this initial surgical intervention. 4 6 Although longterm survival has improved with early surgery, most patients (70 80%) eventually develop end-stage biliary cirrhosis and require liver transplantation (LT). 7,8 Factors predicting the effectiveness of the HPE procedure include age at surgery, 9 the anatomical pattern of BA, the presence of concomitant situs anomalies, 10 the experience of the surgical centre 11 and the degree of hepatic fibrosis at the time of HPE. 12 There are very few reports on the epidemiology and outcome of BA from Asia outside Japan and Taiwan LT is limited in Malaysia. Up until 2005, only a total of 80 Malaysians had LT. 16 Of these, only 16% had the grafts from cadaveric donors. 16 The overall 1-year survival was 69%. 16 The objectives of the present study are to ascertain the epidemiology, short- to medium-term outcome and the effect of limited LT on the outcome of BA seen at single institution in Malaysia. Key Points 1. The 2-year survival rate of 37% with native liver following corrective surgery for biliary atresia in University of Malaya Medical Centre, Malaysia, compares favourably with other international figures. 2. However, the lack of timely liver transplantation in those who had unsuccessful corrective surgery adversely affected the overall survival rate, which was 40%. This is low compared with other similar figures from other parts of the world. 3. As the median age for surgery was relatively late at 70 days, the overall outcome of biliary atresia in University of Malaya Medical Centre, Malaysia, may be further improved by increasing the awareness among child-health professionals in Malaysia on the importance of early referral for appropriate surgery in I nfants suspected of having biliary atresia. Methodology This is a prospective, descriptive study conducted at the Department of Paediatrics, University of Malaya Medical Centre (UMMC), Kuala Lumpur. Patients with BA referred to the department from January 1996 to December 2005 were included. All patients with BA have been followed up at University of Malaya Medical Centre U (MMC) since their first referral. The present study was approved by the Ethical Review Committee of UMMC. Diagnosis of BA BA was diagnosed based on diagnostic criteria established by McKiernan et al. and Fischler et al. 17,18 Atresia of hepatobiliary tree was confirmed either via an operative cholangiogram performed through the gall bladder or a demonstration of atretic gall bladder and/or extrahepatic biliary tree, intraoperatively by the surgeon. The classification of BA was based on the classification of Japanese Association of Pediatric Surgeons. 19 BA type 1

3 affects the common bile duct; type 2 atresia affects the common hepatic duct; and type 3 is an occlusion at the level of the porta hepatis. 19 The operative findings of all infants who underwent Kasai's procedure were noted and recorded. Outcome measures A review on all patients was conducted at December 2007, 2 years after the last patient was recruited. All patients had a minimum duration of follow-up of 24 months after HPE. The latest outcome status was defined as alive with native liver, LT, or died. Successful HPE was defined as clearance of jaundice (serum bilirubin 20 µmol/l) within 6 months of surgery. 20 Patients who survived with the native liver at 24 months of age and who have the following features were classified as having a major morbidity: poor general health, failure to thrive (minus 2 standard deviations for weight-for-age), presence of liver cirrhosis or its complication such as portal hypertension and hypersplenism (clinical and/or laboratory evidence), LT or major restriction of lifestyle (including school activities). Patients who survived without any of the above features were classified as having no or minimal morbidity. Portal hypertension was suspected in patients with splenomegaly, hypersplenism and ascites and was confirmed by endoscopy. Statistical method Data were entered by using SPSS 11.0 (SPSS Inc., Chicago, IL, USA) for Windows XP. (Microsoft, Seattle, Washington, USA) Data are quoted as medians and range. χ 2 square tests were used for categorical data, while Student's t-test was used for comparison of numerical data. Results During the study period, 57 cases of BA were seen at the Department of Paediatrics, UMMC. Of these, 9 patients had no Kasai procedure, while the remaining 48 had Kasai procedure. (Figs 1,2) Figure 1. Outcome of 57 patients with biliary atresia, UMMC, Kuala Lumpur; Figure 2. Kaplan-Meier survival curve for survival with native liver in patients with biliary atresia. Basic epidemiological features No patients had any siblings with BA. Two patients were products of twin pregnancies. None of the other twins had BA. The median gestational age at birth was 40 weeks (range: weeks), while the median birth weight was 3.00 kg (range: kg). Most of the associated physical anomalies noted were minor (craniosynostosis, isolated cleft palate, small secundum-type of atrial septal defect and left pulmonary artery stenosis; n = 1 each). Only one patient was noted to have BA splenic malformation (BASM) and had partial situs inversus with right-sided stomach, pre-duodenal vein, malrotation of the gut and polysplenia. Age at evaluation and surgery The median age at referral was 62 days ( days, Table 1). Factors relating to delayed referral have been reported earlier. 5 Briefly, the main factors included repeated reassurance by medical and paramedical staffs, failure of hospital services at referral hospitals and initial parental reluctance for referral. 5 The median age at surgery for all

4 patients was 70 days (range: days; mean ± standard deviation = 96 ± 67 days). The median interval between initial referral to UMMC, and surgery was 8 days. Factors All No. alive with native liver at 2 years Yes (n) No (n) P Operative findings at surgery. HPE, hepatoportoenterostomy; ND, no data. Overall cohort (%) (37%) 36 (63%) ND Race Chinese Malay ND Indians ND Sex Male Female ND Type of BA Type Type ND Number of patients with HPE at age 60 days >60 days ND All (%) (44) 27 (56) ND Number of patients without HPE ND Presence of cirrhosis Yes No ND Consistency of liver Soft Firm ND Hard ND Not noted ND Presence of portal hypertension Yes No ND Median age at referral (days) Median age at HPE (days) Table 1. Demographic factors, age at referral and age at surgery, and findings at surgery as predictors of outcome of hepatoportoenterostomy in biliary atresia Types and forms of BA Of the 57 cases of BA, 56 (98%) cases had the perinatal form of BA. Only 1 (2%) patient had BASM. A total of 53 (93%) had type 3 BA, while another 4 cases (7%) had type 1. None of the patients had type 2 BA. Features of liver cirrhosis and portal hypertension

5 Features of liver cirrhosis and portal hypertension were common at laparotomy. Macroscopic features of cirrhosis on the surface of the liver were noted in the majority of patients (n = 44, 77%). The consistency of the liver, noted in 37 patients, was firm and/or hard in the majority of patients (n = 27 of 37, 73%). In addition, features of portal hypertension (increase in vascularity or tortuosity of veins at the splenic hilum) were noted in 7 (13%) and absent in 47 (87%) patients at laparotomy. Patients with no HPE (n = 9) HPE was not performed in 9 (16%) patients who were all referred late (Fig. 1). The median age at referral 180 days (range: days), while the median age at laparotomy was 200 days (range: days). All patients had features of advanced liver cirrhosis and portal hypertension. All have since died of progressive liver cirrhosis and its complications (median age of death, 14 months; range: 6 20 months). Unsuccessful HPE (n = 27) HPE was performed in 48 (84%) patients. It was unsuccessful in 27 (56%) patients (median age at operation, 80 days: range: days). One infant died of early post-operative anastomic leak and bleeding. The remaining 26 patients had persistent jaundice after HPE. A total of four patients had LT (see Liver Transplant (LT)). All the remaining 22 patients who did not have LT have since died (median age of death: 14 months; range: 3 25 months). The only one patient with BASM had an unsuccessful HPE. Successful HPE HPE was successful in 21 patients, representing 37% of the total cohort (n = 57) or 44% of all who had a HPE (n = 48). The median age at surgery was 58 days ( days). All patients were free of jaundice at the time of review. Three of the four infants with type 1 BA had a successful HPE. LT A total of four patients had LT. Of these, two of the transplant surgeries were performed in Malaysia, while another two were at neighbouring countries. All received liver grafts from live donor; three were from living-related donors, while one was from living non-related donor. Two patients died soon after LT because of primary non-function of graft. Two patients survived the LT with functioning grafts at 13 months and 8 years after LT, respectively. Outcome at 24 months As on December 2007, 21 (37%) patients survived with their native liver (Table 2). The median duration of follow-up for the survivors was 8 years (range: 24 months to 11 years). Of these, 16 patients were alive with their native liver without major morbidity. The remaining five patients had major morbidity with various degree of portal hypertension. The actuarial 24-month survival rate with native liver was 37%, while the overall actuarial 24-month survival rate (native liver and LT) was 40%. n % Alive, no residual morbidity Alive, major morbidity 5 9 Alive, with liver transplant 2 3 Died, without hepatoportoenterostomy 9 16 Died, unsuccessful hepatoportoenterostomy Died, after liver transplant 2 4 Total Table 2. Overall final status of 57 infants with biliary atresia

6 Predictors of successful Kasai procedure Various demographic, clinical and laboratory parameters were analysed to determine the presence of any predictor for a successful outcome following HPE (Tables 1,3). Patients who had liver cirrhosis or portal hypertension at surgery, a lower albumin level, a higher aspartate transferase level and prothrombin ration on admission were predictors of non-survival with native liver at 2 years of age. Patients who were referred earlier and, therefore, had surgery at an earlier age were more likely to survive with their native liver at 2 years of age (Fig. 2). Two-thirds (65%, 13 of 20 patients) of the infants who underwent HPE before 60 days of age survived with native liver at 2 years compared with 22% in those operated after 60 days (P = 0.028, odds ratio 5.50). On further analysis, patients who were operated before 45 days had an 87% success rate. This dropped progressively to 57% between 46 and 60 days, and 0% in those who were operated after 120 days. Parameters Mean ± Sandard deviation Alive with native liver at 2 years Yes No (n = 21) (n = 36) P Size of liver (cm, below right costal margin) 3.6 ± ± Size of spleen (cm, below left costal margin) 1.0 ± ± Haemoglobin (g/l) 107 ± ± White cell count ( 10 9 /L) 16.0 ± ± Platelet ( 10 9 /L) 491 ± ± Total bilirubin (µmol/l) 166 ± ± Conjugated bilirubin (µmol/l) 126 ± ± Albumin (g/l) 35 ± 3 32 ± Alkaline phosphatase (IU/L) 619 ± ± Aspartate transferase (IU/L) 180 ± ± Alanine transferase (IU/L) 156 ± ± γ Glutamyl transferase (IU/L) 647 ± ± Prothrombin ratio 1.01 ± ± International normalised ratio 1.01 ± ± Table 3. Clinical and laboratory parameters on admission as predictors of outcome of Kasai procedure in biliary atresia Comparison of outcome between the present cohort and other published series To benchmark the outcome of BA from this institution, results of the present study were compared with those of other similar studies. 8,13,14,20 23 Compared with the US multicentre (Biliary Atresia Research Consortium, BARC) study, the present study compares unfavourably. 20 Two significant factors adversely affected the overall outcome of the present study as compared with the BARC cohort were age at surgery and the number of children who underwent LT. The BARC cohort had a much earlier age at HPE than the present study (mean age at surgery 53 days for BARC cohort, 83 days for the present study; Table 4). In addition, LT was limited in the present study with only 7% of children in the present study who underwent LT compared with 40% of the BARC cohort. 20 Characteristics US BARC cohort (n = 104) UMMC cohort (n = 57) 1. US BARC, United States Biliary Atresia Research Consortium; UMMC, University of Malaya Medical Centre, Kuala Lumpur.

7 Characteristics US BARC cohort (n = 104) UMMC cohort (n = 57) Sex (female, %) % with biliary atresia splenic malformation (n) 11 (11) 2 (1) Age at initial evaluation (mean, days) Age at Kasai procedure Mean (days) % <60 days % 60 days Survival rate (%) with native liver at 2 years % underwent liver transplantation (n) 40 (42) 7 (4) Overall survival rate (%) at 2 years (native liver and liver transplant) Table 4. Comparison of outcome of biliary atresia between the US BARC Cohort and the present study However, the result of surgery for BA of the present study is similar to other published studies (Table 5), although the minimum duration of follow-up for the present study was 2 years. The 37% 2-year survival rate with native liver for the present study is comparable with figures from Taiwan (35%, 5-year survival with native liver), 24 France (43%, 4 years), 21 Canada (33%, 5 years), 22 and Switzerland (37%, 4 years). 23 However, the overall survival rate of the present study was unfavourable because of a lack of availability of timely LT. Discussion Prognostic factors predicting the outcome of surgery in BA include the timing of surgery, associated anomalies and experience of centre. 24 The age of Kasai procedure is the single most widely quoted prognostic variable affecting the outcome of BA. 4,9 Late referral for surgery in BA is a common occurrence in many countries. 5,6,25,26 In the present study, the overall median age at HPE was 70 days. One of the factors contributing to a delay in surgery was the time between referral and surgery. In this study, the median interval between first referral and eventual surgery was 10 days, same as those quoted by McKiernan et al. from the United Kingdom and Ireland study (10 days at large referral centres, 14 days at smaller centres). 17 The reasons for this delay in surgery were the lack of adequate manpower in paediatric surgery and operating time in UMMC during the study period. During most of the study period, there was only one consultant paediatric surgeon who had to take on other paediatric surgical work. The 37% 24-month survival rate with native liver observed in the present study is comparable with figures from Canada (33%, 5-year survival), 22 Switzerland (37%, 4-year survival), 23 or Taiwan (35%, 5-year survival). 25 A total of nine (16%) patient in this study did not have a HPE. All were referred late and were found to have advanced cirrhosis on laparotomy. The decision of whether to proceed with HPE depends on the findings by the surgeon at laparotomy and is often a difficult one. LT operation may be complicated by bleeding from adhesions from previous upper abdominal surgery, for example, HPE for BA. Thus, primary LT may be an option preferred instead of proceeding with the HPE in the presence of advance liver cirrhosis, as LT, in this circumstance, is often unavoidable. 27 However, it is obvious that primary LT in those with late referral is not a feasible option in Malaysia. LT is not routinely available in Malaysia. In the present study, only 7% of the 56 patients with BA had a liver graft. This is a low figure compared with 40% from the BARC cohort and 37% from the European BA registries. 20,28 Liver graft in Malaysia is

8 almost always from living relatives. In addition, LT surgery is not always successful. This is aptly illustrated in the present study where two patients who had LT surgery died of primary non-function of the graft soon after the surgery. In addition, it is known that HPE may still be successful in infants with late referral. Charcot et al. reported a 5-year survival rate with native liver of 25% in those with HPE after 90 days. 29 Davenport et al. reported a 5-year survival rate with native liver of 45% in those operated after 100 days. 30 Thus, the medium-term survival in infants who had Kasai procedure after days was reasonable. This may obviate the need for LT. It is uncertain whether performing corrective surgery in the nine infants in this study who did not have HPE would have changed their eventual outcome. All these nine infants were referred exceedingly late, at a median age of 180 days. However, in the absence of a readily available and affordable LT in Malaysia for these infants, primary corrective surgery should be the first option, even in those who were referred later than 90 days. In those where the primary corrective surgery for BA was unsuccessful, the eventual outcome is poor. The median age of survival in those who had an unsuccessful surgery but did not have LT was 14 months, similar to those who did not have a HPE. There is a need for close follow-up in these patients for complications of liver cirrhosis. Utterson et al. advocated an anticipatory approach for patients with BA who had a failed HPE. 27 Thus, counselling of the parents about the necessity of LT and the preparation of the child for transplant surgery needs to be commenced as early as possible, preferably within the first 12 months of age. It is likely that many of the patients who had initial successful portoenterostomy may need LT eventually. 31 Lykavieris et al. followed up 271 patients with BA who were operated between 1968 and Twenty years after surgery, less than 18% of patients with BA who were treated with HPE did not require LT. 31 It is obvious that there was considerable delay in referral and surgery in the present cohort. 5,6 We have previously argued that, because there is limited availability of LT in Malaysia, efforts to improve the outcome of BA should ideally address the issue of late referral. 5 Conclusion In conclusion, the survival with native liver following corrective surgery for BA in Malaysia compares favourably with other international figures. But the overall outcome was adversely affected by a lack of LT. References References 1.Campbell KM, Bezerra JA. Biliary atresia. In: WalkerWA, GouletO, KleinmanRE, ShermanPM, ShneiderBL, SandersonI R, eds.pediatric Gastrointestinal Disease: Pathophysiology, Diagnosis, Management. Hamilton, ON: BC Decker, 2004; Schreiber RA, Kleinman RE. Biliary atresia. J. Pediatr. Gastroenterol. Nutri. 2002; 35: S11 13

9 3. Kasai M, Suzuki S. A new operation for non-correctible biliary atresia: hepatic portoenterostomy. Shujitsu 1959; 13: Mieli-Vergani G, Howard ER, Portman B, Mowat AP. Late referral for biliary atresia missed opportunities for effective surgery.lancet 1989; 333: Lee WS. Pre-admission consultation and late referral in infants with neonatal cholestasis. J. Paediatr. Child Health 2008; 44: Wadhwani SI, Turmelle YP, Nagy R, Lowell J, Dillon P, Shepherd RW. Prolonged neonatal jaundice and the diagnosis of biliary atresia: a single center analysis of trends in age at diagnosis and outcome. Pediatrics 2008; 121: e Lykavieris P, Chardot C, Sokhn M, Gauthier F, Valayer J, Bernard O. Outcome in adulthood of biliary atresia: a study of 63 patients who survived for over 20 years with their native liver. Hepatology 2005; 41: Davenport M, De Goyet JDV, Stringer MD et al. Seamless management of biliary atresia in England and Wales ( ).Lancet 2004; 363: Karrer FM, Price MR, Bensard DD et al. Long term results with the Kasai operation for biliary atresia. Arch. Surg. 1996; 131: Davenport M, Savage M, Mowat AP et al. Biliary atresia splenic malformation syndromes: an etiologic and prognostic subgroup.surgery 1993; 113: Kobayashi H, Stringer MD. Biliary atresia. Sem. Neonatol. 2003; 8: Shteyer E, Ramm GA, Xu C, White FV, Shepherd RW. Outcome after portoenterostomy in biliary atresia: pivotal role of degree of liver fibrosis and intensity of stellate cell activation. J. Pediatr. Gastroenterol. Nutri. 2006; 42: Nio M, Ohi R, Miyano T, Saeki M, Shiraki K, Tanaka K. Five- and 10-year survival rates after surgery for biliary atresia: a report from the Japanese biliary atresia registry. J. Pediatr. Surg. 2003; 38: Hung PY, Chen CC, Chen WJ et al. Long-term prognosis of patients with biliary atresia: a 25-year summary. J. Pediatr. Gastroenterol. Nutri. 2006; 42: Tiao MM, Tsai SS, Kuo HW, Chen CL, Yang CY. Epidemiological features of biliary atresia in Taiwan, a national study J. Gastroenterol. Hepatol. 2008; 23: Hooi LS, Mansor LY. Second report of National Transplant Registry 2005, Malaysia. Natl. Transpl. Registry, Malaysia 2006; 2: McKiernan PJ, Baker AJ, Kelly DA. The frequency and outcome of biliary atresia in the UK and Ireland. Lancet 2000; 355: 25 9.

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