- Email: [email protected]
Long-term outlook in biliary atresia
Author’s Accepted Manuscript Long-Term Outlook in Biliary Atresia Arun Kelay, Mark Davenport
www.elsevier.com/locate/sempedsurg
PII: DOI: Reference:
S1055-8586(17)30095-1 http://dx.doi.org/10.1053/j.sempedsurg.2017.09.003 YSPSU50702
To appear in: Seminars in Pediatric Surgery Cite this article as: Arun Kelay and Mark Davenport, Long-Term Outlook in Biliary Atresia, Seminars in Pediatric Surgery, http://dx.doi.org/10.1053/j.sempedsurg.2017.09.003 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Long-Term Outlook in Biliary Atresia
Arun Kelay MRCS
Specialist Registrar in Paediatric Surgery
Mark Davenport ChM FRCS (Paeds) Professor of Paediatric Surgery
Department of Paediatric Surgery, Kings College Hospital, London SE5 9RS
Correspondence: Prof Mark Davenport Department of Paediatric Surgery, Kings College Hospital, London SE5 9RS Email: [email protected] TEL: 0044 203 299 3350
1
Abstract The oldest survivors from the Kasai portoenterostomy originate in Sendai, Japan and are approaching their 60th birthday. These represent the tip of an expanding cohort of adults born with this previously fatal condition. Increasingly transition to adult-biased hepatologists and physicians will be the expectation of many with this condition. However unlike their usual patients with alcohol, drugs, virally-mediated liver disease these are different with different expectations of health and quality of life. Cure is not on the cards for most of these and they survive still with impaired bile flow and increased liver fibrosis and cirrhosis with the threat of cholangitis and portal hypertension still apparent. We review the reported statistics on long-term survival essentially from Japan and Western Europe (such as the UK and France) and the range of complications that may still beset this group.
KEYWORDS: Biliary atresia; long-term outcomes; Kasai portoenterostomy; portal hypertension; cholangitis.
2
Introduction The first survivors in those born with biliary atresia (BA) were a tiny cohort of which little was known simply due to their rarity. These were infants from the 1930s onwards who had had favourable, “correctable” biliary anatomy and undergone exploration within a reasonable period of time. Later, possibly optimistic calculation would suggest that was less than 5% of all the infants ever born with BA.
The potential for change was only realized during the 1960s and 70s as an alternative for those with the much more common “uncorrectable” BA (i.e. Type 3 BA) following the first reported successes from Sendai, Japan, and increasing experience with the management of longer-term complications of chronic liver disease. Still, it is important to realize that Morio Kasai’s portoenterostomy (KPE) represents only a palliative solution for this disease, and is still not a cure [1]. Even those who have cleared their jaundice, the earliest and best outcome, will have liver fibrosis and impaired bile flow at the very least and the possibility of living out the rest of their allotted lifespan with this native liver is still awaited.
It is even less clear what the longest-term future holds for those transplanted given that this was only available from the 1980s in the UK and USA and these early pioneers will still only be in their thirties at the most. The prospect of already old livers transplanted into younger bodies and the more subtle effects of long-term immunosuppression also remain to be elucidated. Complications such as post-transplantation lymphoproliferative disease can arise many years after the initial operation and be incredibly difficult both to diagnose and treat [2].
This article will describe the long-term outcomes for native liver survivors as revealed by multiple national studies, with particular focus on the chronology of complications and the manifestations of BA in adulthood.
Influence of Aetiology on Outcome Although BA is simply a phenotype, and an umbrella term which can incorporate a number of different pathological mechanisms the end points are probably the same – cholangiodestruction, chronic inflammation and liver fibrosis. We currently recognise at least four different major variants [3] with divergent patterns of onset and widely different outcomes. These include:
3
1. Syndromic BA a. Biliary Atresia Splenic Malformation (BASM) b. Cat-eye syndrome – associated with chromosomal 22 aneuploidy 2. Cytomegalovirus (CMV) IgM +ve associated BA 3. Cystic BA – i.e. cyst formation in otherwise obliterated biliary tree. 4.
Isolated BA - the rest and by far the majority, but almost certainly still a heterogenous group.
There are some pathological processes within this quartet which may develop unusual symptoms and have an effect in the longer term. A good example of this is hepatopulmonary syndrome (HPS) which is much more commonly observed in children with BASM who may have excellent bile flow and liver function but who require liver transplantation for profoundly cyanotic lung disease and who presumably died in a previous era [4].
By contrast, the cystic BA group is often over-represented in the long-term survivors group, from an initial starting point of perhaps 10% in large series [5, 6]. There will be a much higher proportion of these who initially clear their jaundice due to the relative preservation of ductular linkage between intra- and extrahepatic systems. This was 100% in our last cohort who came to surgery at <30 days for example [6]. They also, on the whole, come to surgery earlier perhaps due to antenatal detection, and therefore have a reduced degree of liver fibrosis ab initio. There is a large overlap between this group, defined by morphological appearance and the Japanese Association of Pediatric Surgery’s classification’s Type I and II [5].
Facts and Figures – Quantification of the Survival Cohort. Our own longest-term survivor at Kings College Hospital underwent surgery in 1974 following transfer after an unsuccessful operation elsewhere and consequent burst abdomen. He has now just reached 40 years of age and really has minimal signs of disease. Still it is the Japanese who have some of the oldest survivors post-KPE and are approaching their 60s (Figure 1): but these are exceptional and freedom from symptoms is rare. Figure 2 shows the improvement in outcome since the first description of portoenterostomy in Professor Kasai’s unit in Sendai, Japan [7]. Incidentally this is indirect evidence of the improvement in efficacy of the surgical technique in that institution – Professor Kasai’s operation is not necessarily the operation that is done today either in Japan and elsewhere.
4
The last report from Sendai, published in 2012, updates the outcomes of 277 infants undergoing a Kasai operation from 1955 to 1991 [8]. Of these, 92 (33%) survived with their native liver for more than 20 years and 72 continued to survive with a “good condition” native liver at the time of the report. Within this group, 17 had been treated for varices with sclerotherapy while 11 had undergone partial splenic embolization for hypersplenism. 20 patients developed persistent jaundice beyond 20 years and 10 were transplanted (2 later died) and 4 were listed. Two further patients died of end-stage liver disease and variceal bleeding at the ages of 28 and 29 years respectively.
Five and Ten-Year Native Liver Survival (Table 1) Ironically, the first attempt at a co-ordinated registry of outcome involving more than one unit was the American Biliary Atresia Registry and involved data submitted from over 100 institutions in the period 1976 – 89. Sadly, to our knowledge it only produced a single publication and no further data has accrued [14]. Follow-up was available for 670 children (74% of original cohort) with a mean length of follow-up of 5 years (range, 1 to 16 years). In that group the 5-year actuarial survival was 48% following a KPE.
The King’s College Hospital experience over a similar period (1973-1995) described results in 338 infants with BA [15]. The 10-year actuarial survival estimate for those born from 1980-95 following establishment of a standard KPE operation and post-operative management strategy was 41%. At that time, 57 children had survived to 10 years post-KPE, and these remain the nucleus for our own long-term survival cohort.
The largest cohort of survivors consistently followed remains that of the Japanese Biliary Atresia Registry (JBAR), first established in 1989. Thus, 458 (64%) of the earliest cohort (1989 – 1994) of 716 children reached their 5-year milestone with their native liver intact. As transplantation was not available in Japan at this time this also represents the true survival rate. Later cohorts varied between 53% and 64% [12].
By comparison with Japanese reports, Western experience has been much more bleak, certainly with respect to the outcome after a KPE. Overall survival has to some extent been compensated with the earlier use and application of transplantation (Table 1). For cultural reasons, neither Japanese nor Korean centres used cadaveric donors, and were relatively late in developing transplant programmes when the option of living donation became feasible.
The French record of following their BA patients has been excellent and their updated national study included 1004 infants treated with KPE from 1986 to 2009, showing 5-year NLS rates of about 40% [16]. Our own national experience of infants born within England and Wales following centralisation and somewhat more up to date than other countries, showed an estimated 10-year NLS rate of 44% (Figure 3) [9].
5
Canadian experience from 1985 to 2002 reported NLS rates of 26% (range 20% to 32%) at 10 years [10]; Taiwan a 10-year NLS rate of 31% [13], and France a 36% 10-year NLS rate between 1986-2009 [16].
20-Year Survivors The Bicêtre series from Paris identified 63 (23%) from 271 patients who had survived with their native liver for >20 years [17]. They were able to show that initial anatomy was still hugely influential as different operations were performed for different situations. Thus, a hepatic portocholecystostomy was undertaken in those with patent gallbladder, cystic and common bile ducts, whilst cystojejunostomy was performed in patients with cystic BA. The remaining Type III BA underwent KPE. They found that 20-year NLS was better in those infants who had undergone portocholecystostomy or cystojejunostomy, at 35% and 40%, respectively. In the remaining patients with a KPE, just 19% survived to 20 years. In the national cohort, the 20-year NLS declined to 30% [16].
Remarkably, The Canadian national study identified age at initial surgery as still able to influence long-term outcome [10]. Surgery at <90 days of age was associated with a 20-year NLS of 28% in contrast to 13% for surgery >90 days of age, though this cut-off is still extreme and unrepresentative of when the vast majority of these infants present. Interestingly, 20-year NLS did not seem to improve from the earlier period (19681977) to the later period (1977-1983) of the study [10].
The national Netherlands review identified an improvement over time in 20-year NLS rates from 20% (10 of 49) between 1977 and 1982, rising to 32% (18 of 55) in the subsequent 1983-1988 period [18]. From the overall cohort of 104, 28 (27%) were surviving with their native liver at 20 years of age. Normal liver function tests and the absence of any clinical and ultrasonographic features of cirrhosis were present in 6 (21%) of these survivors.
Chronic Liver Disease There is a cohort of native liver survivors who display no clinical manifestations of chronic liver disease (CLD) whatsoever. In one long-term study from Kings College Hospital, we identified 28 adolescents with a median age of 13 (range 10 – 22) years who represented 11% of 244 infants treated between 1979 and 1991 [19]. All had a normal clinical examination with no features of portal hypertension and normal laboratory indices for liver function and coagulation. There had been no episodes of gastrointestinal (GI) bleeding during follow-up and surveillance oesophagogastroduodenoscopy (OGD) was performed in thirteen (45%) patients with no abnormal findings. Whether this will last until they reach three score years and ten is a moot point however as there were 59 follow-up liver biopsies (for a variety of reasons) taken at a median of 27 (range 3 – 123) months of age which showed mild to moderate liver fibrosis in 32 (54%) and
6
overt cirrhosis in 24 (41%). Only three adolescent patients originally born with Type 3 BA had no evidence of fibrosis in their biopsies (obtained at median follow-up of 36 months).
A similar proportion of “normal” native liver survivors were reported from the Denver series. Thus, 19 of 23 native liver survivors >10 years post-KPE were anicteric with normal synthetic liver function and represented 19% of the original cohort of 98 children [20].
What are Adult (>20-year) Native Liver Survivors Like? Progression of the intrahepatic component of the biliary pathology accounts for the cumulative attrition noted as survivors advance beyond 20 years of age. So, in the Bicêtre series, there was a fall in the proportion of those with normal serum bilirubin levels (52% vs 33%) and normal liver function tests (27% vs 21%) [17]. Cirrhosis was considered to be present in all but two of 63 patients over the age of 20, as assessed by any combination of clinical (hard hepatomegaly associated with splenomegaly), sonographic (nodular liver and features of portal hypertension) or histologic features.
Complications of Long-Term Survival Fundamentally, the root cause of problems remains that of inadequate bile flow in the setting of a fibrotic or cirrhotic liver. The actual mode of reconstruction, i.e. the Roux loop in most, is seldom a problem and there is no evidence that its obvious unphysiological delivery of bile into the proximal jejunum is a cause of long-term nutritional or developmental deficiencies. The same biliary reconstruction technique is used widely in choledochal malformations and no consequences have become apparent over a 40-year period of its use [21].
Cholangitis Cholangitis is a consequence of the creation of the bilioenteric conduit and is almost certainly ascending in nature. Pathogens are derived from intestinal flora and include E. coli, K. pneumoniae and P. aeruginosa [22]. Presenting features include fever, abdominal pain and worsening or recurrence of obstructive jaundice with acholic stools. There should be changes in bilirubin and liver enzyme levels together with acute changes in white cell count, and inflammatory markers such as C-reactive protein (CRP).
Most episodes of cholangitis will have presented within the first two years post-KPE and in some this can be recurrent and a reason for transplantation despite perhaps normal liver function between episodes. During adolescence and beyond the incidence is markedly reduced but other causative factors may come into play. An unexpected episode of cholangitis in someone with good liver function should prompt an investigation
7
package aimed at defining any obstruction in the Roux loop. The usual site of this is as it goes through the mesocolon, leading to a redundant pool of bile in the right upper quadrant [23]. Radioisotope hepatobiliary imaging, percutaneous cholangiography and where available single or double-balloon enteroscopy should be able to define Roux loop functionality and anatomy leading to corrective surgery.
In others, recurrent cholangitis appears to represent a failing liver possibly with anatomically definable intrahepatic bile lakes. These are more difficult to treat. Thus cholangitis occurred in 13 (22%) of 60 Japanese long-term survivors beyond the age of 20 [23]. There really were no distinguishing features in this group with regard to initial type of BA, age at KPE or presence of portal hypertension. Instead most displayed predisposing factors such as intrahepatic bile lake formation (n = 6) and/or hepatolithiasis (n = 4). Only three patients had normal imaging.
In the Bicêtre long-term series, 19 (30%) developed at least one episode of acute cholangitis between 17 and 30 years of age, successfully managed with antibiotics [17]. Interestingly none of these patients had undergone KPE, rather they had had portocholecystostomy, cystojejunostomy or cholecystojejunostomy. Gallstones were present in two of these patients, one of whom had hepatolithiasis and relapsing bacterial cholangitis, and was treated with a partial hepatectomy. The bilioenteric anastomosis was the site of gallstone formation in the second patient requiring operative removal.
It is important to note that late-onset cholangitis may precipitate liver failure, prompting expedited transplantation. This can be a fatal event in the long-term survivor, as illustrated by two patients from the Yokohama cohort who died of liver failure secondary to cholangitis at 21 and 22 years of age, respectively [25].
Is there anything that can be done to forestall the effects of recurrent cholangitis? Variations in the construction of the Roux-en-Y limb of the portoenterostomy including incorporation of an anti-reflux valve [26,27] and/or lengthening of the jejunal component [28,29] have consistently failed to show efficacy at reducing the incidence of cholangitis, perhaps reflecting its multifactorial aetiology.
Prophylactic long-term antibiotics have been also advocated to reduce the recurrence of cholangitis in this population but the evidence is scant. To date, only one randomised controlled trial has investigated the value of this but in a much younger age-group [30].
8
Portal Hypertension and Oesophageal Varices Raised portal venous pressure reflects the progression of liver fibrosis and higher preoperative values at the time of KPE are significantly correlated with a more advanced age at surgery [31] and therefore about half of this population could reasonably be defined as having portal hypertension at the time of KPE. Whether this persists, increases or decreases depends upon the response to surgery.
Established portal hypertension stimulates portosystemic shunting with formation of oesophageal, gastric, anorectal and ectopic (e.g. Roux loop) varices together with splenomegaly and hypersplenism. Oesophageal varices were detected in 88 (70%) of 125 children post-KPE who underwent OGD at a median of 13 months of age [30] though the proportion who will become symptomatic and bleed will be much less.
Obvious portal hypertension is still apparent in many of those reaching adulthood. So, 44 (70%) of 63 longterm survivors in the Bicêtre series showed clinical (splenomegaly), ultrasonographic or endoscopic features of portal hypertension [17]. Gastrointestinal bleeding had occurred in 3 beyond the age of 20, reflecting the progressive nature of the underlying disease. In this group, surgical portosystemic shunts had been created in 13 patients with no further bleeding at a mean follow-up of 15 years (range 4 - 22 years).
11 (37%) of 30 survivors from the Sendai series developed portal hypertension, although only 5 required intervention [32]. This initially included splenectomy and proximal splenorenal shunting for severe portal hypertension up to 1985, after which point partial splenic embolisation (PSE) was employed for clinically significant hypersplenism.
Malignant Transformation With the almost invariable development of chronic liver disease in BA then malignant transformation of the native liver is a real possibility. This is usually hepatocellular carcinoma (HCC) though to date it remains a rare complication.
We reported malignant transformation in 5 (0.8%) children and adolescents with type 3 BA arising from a cohort of 387 managed at Kings College Hospital between 1990 and 2008 [33]. Three of these children had developed suspicious nodules with an arterialized pattern on CT imaging (Fig. 4). Alpha-feto protein (AFP) levels were variable and well-differentiated HCC was confirmed within the explanted liver. In the other two cases the findings of HCC foci were incidentally made at the time of transplant (aged 2 and 17 years old). Other centres have reported cases in adolescents and one young adult [34-37] (TABLE 2).
9
Hepatoblastoma [37] and cholangiocarcinoma [38] in addition to HCC, have also been identified in explanted livers of BA survivors requiring transplantation, but only during childhood.
Background cirrhosis, nodular regeneration and reactive hyperplasia can make differentiation between benign and malignant nodules extremely difficult. We advocate screening for malignant transformation in all our children and young people with BA including regular US and serial serum AFP levels. Suspicious findings on US will mandate further cross-sectional imaging including CT which may identify arterialization of the lesion(s) aiding in the assessment of potential malignancy. It must be noted however, that small HCC lesions (< 11 mm) can be missed on US [33] and the serum AFP may well be entirely normal even with sizeable tumours [33, 38].
Complete tumour excision represents the only curative treatment option, and almost always this implies liver transplantation given the co-existent cirrhotic liver disease. Adjuvant chemotherapy is usually not indicated in the absence of extrahepatic disease [33].
Growth and Development 49 (78%) of the 63 native liver survivors from Bicêtre, France reached an adult height at or above the mean [17]. All male patients progressed through normal pubertal development. The female cohort also completed normal puberty with the exception of two female patients - one who had suffered from bacterial meningitis with subsequent primary amenorrhoea, and another noted to have ventricular dilatation and developmental delay.
The Sendai series found that 29 of 30 survivors beyond the age of 20 displayed physical growth within the normal range [32]. Normal puberty occurred in all male patients, and all but two female patients. These consisted of one girl with Turner’s syndrome and another with primary amenorrhoea secondary to severe liver dysfunction. None of these patients had evidence of developmental delay.
Pregnancy There is an increasing cohort of female native liver survivors who wish to start their own families. Pregnancy is a particularly challenging period for cirrhotic patients as shown from a previous report from our centre [39] where a MELD score of > 6 and a UKELD score > 46 were associated with increased maternal and fetal risk. A platelet count of < 110 x 109/l was also found to be a good predictor for presence of varices during pregnancy. The last published report from the Sendai BA series described 14 pregnancies with 11 who completed live-born deliveries [40]. Women with a previous history of cholangitis and/or variceal
10
bleeding tend to be the ones with liver-related complications during pregnancy but even those with biochemically normal liver function could be challenged.
Multidisciplinary support including hepatology and obstetric teams familiar with the problems of pregnancy in cirrhosis is vital and in our unit we advise second trimester elective endoscopy to assess the presence and degree of varices to gauge the risk of bleeding. Even then progression of liver failure necessitating transplantation and/or recurrent cholangitis may occur pre- or postnatally [25, 41].
It is worth re-iterating that the offspring of mothers born with BA have been invariably normal. A nationwide survey of Japanese centres did not reveal any abnormalities in the infants born to mothers with BA [41].
Quality of Life (QoL) There has been a paucity of studies determining the quality of life in native liver survivors of BA, although this is becoming an additional focus for investigation as this cohort expands. In a unique comparison study of UK and Japanese young people ( > 10 years) Howard et al. used the SF-36 questionnaire and its Japanese equivalent to assess long-term quality of life in 55 patients (30 Japanese and 25 British) [7]. This was unable to show any significant differences between the two groups and with respect to their normative populations in terms of physical functioning. The British cohort tended to outperform their Japanese equivalent in both perception of “general health” and ‘vitality’ within the well-being domain.
Quality of Life of 25 Dutch young adult native liver survivors at a median age of 23 years was found to be generally comparable to age-matched controls [42]. However, their general health perception was lower than both controls and patients post-transplant. The education level, marital and employment status of this group was also found to be commensurate with that of a reference group aged 18 - 30 years old [43], and similar to the findings in a Japanese study [32]. Of 63 French native liver survivors > 20 years; 17 were in university education and 21 in regular employment [15]; 20 (32%) were married or in stable relationships, and 10 have become parents [17].
In conclusion, such results suggest that native liver survivors can achieve a QoL similar to healthy peers extending through adolescence to young adulthood.
Transplantation in Young People and Adults Born with Biliary Atresia Unfortunately the right-side of the native liver survival curves in BA is never flat and there is an on-going need for transplantation as they move into full adult life. This can create many problems as it is a natural
11
hiatus in the caring paradigm for many “children’s diseases” such as these BA native liver survivors as it is for cystic fibrosis native lung survivors. The problem is probably that of unfamiliarity with the nature of the disease rather than unwillingness. Adult hepatologists will have seldom seen large numbers of young adults with the condition and perhaps judge them to different standards.
We recently reviewed our experience with 36 young persons who underwent LT between 1999 and 2014 at a median age of 16.6 (11.2 - 27.2) years [unpublished data]. The most common indications for listing were cholangitis (31%), synthetic failure (20%) and recurrent variceal bleeding (15%). It was noticeable that there were differences in the pre-transplant period depending on age. Thus, admission to an intensive care unit was more common for those >18 years (40% vs 6%) and they also spent longer on the waiting (10 vs 6 months). Unfortunately, you can wait too long so those with bilirubin levels of >100 µmol/l at time of LT were associated with poor survival (19% vs 0%,).
Conclusion Decades of Japanese experience and our experience with centralization in the UK suggests that 40-45% of infants and children with BA will have sufficiently good restoration of bile flow, resolution of jaundice and attenuation of the underlying liver fibrotic pathology to reach their teenage years given the current indications and availability of transplantation. While this may be somewhat optimistic it is attainable.
Nevertheless, true “cure” is a more elusive concept and the likelihood is that these survivors have the potential for considerable morbidity due to cirrhosis, recurrent cholangitis and portal hypertension. Hepatobiliary malignancy is possible but does not seem to be the threat it is in other metabolic liver conditions such as tyrosinaemia. They do require life-long monitoring and management with a fastidious approach to the care of their liver and appropriate escalation in care if the signs suggest a need for transplantation. All things considered they should probably be looked after in units with sufficient multidisciplinary skills to enable an appropriately smooth transition. They have come this far, they need to go further.
12
References
1. Kasai M, Suzuki S. A new operation for “non correctable” biliary atresia: portoenterostomy. Shijitsu 1959; 13: 457-81. 2. Dreyzin A, Lunz J, Venkat V, et al. Long-term outcomes and predictors in pediatric liver retransplantation. Pediatr Transplant 2015; 19: 866-74. 3. Davenport M. Biliary atresia: clinical aspects. Semin Pediatr Surg. 2012; 21: 175-841. 4. Davenport M, Tizzard SA, Underhill J, et al. The biliary atresia splenic malformation syndrome: a 28-year single-center retrospective study. J Pediatr 2006; 149: 393-4001. 5. Nio M, Wada M, Sasaki H, et al. Does hepatic hilum morphology influence long-term prognosis in type I/I cyst biliary atresia? Pediatr Surg Int. 2015; 31: 931-61. 6. Caponcelli E, Knisely AS, Davenport M. Cystic biliary atresia: an etiologic and prognostic subgroup. J Pediatr Surg 2008;43: 1619-241. 7. Howard ER, MacLean G, Nio M, et al. Survival patterns in biliary atresia and comparison of quality of life of long-term survivors in Japan and England. J Pediatr Surg 2001; 36 :892-7. 8. Nio M, Wada M, Sasaki H, et al.T. Risk factors affecting late-presenting liver failure in adult patients with biliary atresia. J Pediatr Surg 2012; 47: 2179–2183. 9. Davenport M, Ong E, Sharif K, et al. Biliary atresia in England and Wales: results of centralization and new benchmark. J Pediatr Surg 2011; 46: 1689-94. 10. Schreiber RA, Barker CC, Roberts EA, et al. Biliary atresia: the Canadian experience. J Pediatr 2007; 151: 659-65. 11. Serinet MO, Broue P, Jacquemin E, et al. Management of patients with biliary atresia in France: results of a decentralized policy 1986-2002. Hepatology 2006; 44: 75-84. 12. 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. 13. Hung PY, Chen CC, Chen WJ, et al. Long-term prognosis of patients with biliary atresia: a 25 year summary. J Pediatr Gastroenterol Nutr 2006; 42: 190-5. 14. Karrer FM, Lilly JR, Stewart BA, Hall RJ. Biliary atresia registry, 1976 to 1989. J Pediatr Surg 1990; 25: 1076-80 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. Chardot C, Buet C, Serinet MO, et al. Improving outcomes of biliary atresia: French national series 19862009. J Hepatol 2013; 58: 1209-17. 17. Lykavieris P, Chardot C, Sokhn M, et al. Outcome in adulthood of biliary atresia: a study of 63 patients who survived for over 20 years with their native liver. Hepatology 2005; 41: 366-71.
13
18. de Vries W, Homan-Van der Veen J, Hulscher JB, et al. Twenty-year transplant-free survival rate among patients with biliary atresia. Clin Gastroenterol Hepatol 2011;9: 1086-91. 19. Hadžić N, Davenport M, Tizzard S, et al. Long-term survival following Kasai portoenterostomy: is chronic liver disease inevitable? J Pediatr Gastroenterol Nutr. 2003; 37: 430-3. 20. Karrer FM, Price MR, Bensard DD, et al. Long-term results with the Kasai operation for biliary atresia. Arch Surg 1996; 131: 493-6. 21. Ford KE, Cooper LR, Davenport M. Growth in children with choledochal malformations: effect of the Roux loop. Pediatr Surg Int 2015; 31: 1015-9. 22. Wu ET, Chen HL, Ni YH, et al. Bacterial cholangitis in patients with biliary atresia: impact on short-term outcome. Pediatr Surg Int 2001;17:390-395 23. Houben C, Phelan S, Davenport M. Late-presenting cholangitis and Roux loop obstruction after Kasai portoenterostomy for biliary atresia. J Pediatr Surg 2006; 41: 1159-64. 24. Nio M, Sano N, Ishii T, et al. Cholangitis as a late complication in long-term survivors after surgery for biliary atresia. J Pediatr Surg 2004; 39: 1797-9. 25. Shinkai M, Ohhama Y, Take H, et al. Long-term outcome of children with biliary atresia who were not transplanted after the Kasai operation: >20-year experience at a children’s hospital. J Pediatr Gastroenterol Nutr 2009; 48: 443-50. 26. Nakajo T, Hasizume K, Saeki M, et al. Intussusception-type antireflux valve in the Roux-en-Y loop to prevent ascending cholangitis after hepatic portojejunostomy. J Pediatr Surg 1990;25: 311-4. 27. Ogasawara Y, Yamataka A, Tsukamoto K, et al. The intussusception antireflux valve is ineffective for preventing cholangitis in biliary atresia: a prospective study. J Pediatr Surg 2003; 38:1826-1829. 28. Muraji T, Tsugawa C, Nishijima E, et al. Surgical management for intractable cholangitis in biliary atresia. J Pediatr Surg. 2002;37 : 1713-5. 29. Chuang JH, Lee SY, Shieh CS, et al. Reappraisal of the role of the bilioenteric conduit in the pathogenesis of postoperative cholangitis. Pediatr Surg Int 2000; 16: 29-34. 30. Bu LN, Chen HL, Chang CJ, et al. Prophylactic oral antibiotics in prevention of recurrent cholangitis after the Kasai portoenterostomy. J Pediatr Surg 2003;38: 590-3. 31. Shalaby A, Makin E, Davenport M. Portal venous pressure in biliary atresia. J Pediatr Surg 2012; 47:3636. 32. Nio M, Ohi R, Shimaoka S, et al. The outcome of surgery for biliary atresia and the current status of long-term survivors. Tohoku J Exp Med 1997; 181: 235-44. 33. Hadžić N, Quaglia A, Portmann B, et al. Hepatocellular carcinoma in biliary atresia: King’s College Hospital experience. J Pediatr 2011; 159: 617-22. 34. Hirzel AC, Madrazo B, Rojas CP. Two rare cases of hepatocellular carcinoma after Kasai procedure for biliary atresia: a recommendation for close follow-up. Case Rep Pathol 2015; 2015: 982679. Published
14
online 2015 Aug 3. doi: 10.1155/2015/982679 35. Hol L, van den Bos IC, Hussain SM, et al. Hepatocellular carcinoma complicating biliary atresia after Kasai portoenterostomy. Eur J Gastroenterol Hepatol 2008; 20: 227-31. 36. Aggarwal S, Vadada D, Sharma V. A rare complication in an adult patient after Kasai portoenterostomy for biliary atresia. Arab J Gastroenterol 2012; 13: 148-9. doi: 10.1016/j.ajg.2012.08.010. Epub 2012 Sep 15. 37. Amir AZ, Sharma A, Cutz E, et al. Hepatoblastoma in explanted livers of patients with biliary atresia. J Pediatr Gastroenterol Nutr 2016; 63: 188-94. 38. Yoon HJ, Jeon TY, Yoo SY, et al. Hepatic tumours in children with biliary atresia: single-centre experience in 13 cases and review of the literature. Clin Radiol 2014; 69: 113-9. 39. Westbrook RH, Yeoman AD, O’Grady JG, et al. Model for end-stage liver disease score predicts outcome in cirrhotic patients during pregnancy. Clin Gastroenterol Hepatol 2011; 9: 694-699. 40. Sasaki H, Nio M, Hayashi Y, et al. Problems during and after pregnancy in female patients with biliary atresia. J Pediatr Surg 2007; 42: 1329-32. 41. Shimaoka S, Ohi R, Saeki M, et al. Problems during and after pregnancy of former biliary atresia patients treated successfully by the Kasai procedure. J Pediatr Surg 2001; 36: 349-51. 42. de Vries W, Lind RC, Sze YK, et al. Overall Quality of Life in adult biliary atresia survivors with or without liver transplantation: results from a national cohort. Eur J Pediatr Surg 2016; 26: 349-56. 43. Lind RC, de Vries W, Keyzer CM, et al. Health status and quality of life in adult biliary atresia patients surviving with their native livers. Eur J Pediatr Surg 2015; 25: 60-5.
15
Table 1 : 10-Year Survival Figures In Biliary Atresia – Data From National Studies (> 100 subjects)
n
Period
10 year Native liver
Actual Survival
survival England & Wales
443
1999 - 2009
40
89
Canada [10]
349
1985 - 2002
24
75 – 80
France [11]
472
1986 - 96
26
70
Japan [12]
108
1989
53
66
Taiwan [13]
141
1976 - 2000
31
40
(9)
16
Table 2: Malignant Transformation in Adolescents and Young People with Biliary Atresia
Age Hadzic (#33)
17
Gender f
Clinical Incidental
Histology (diameter) HCC
Outcome LT
(10mm) Hirzel (#34)
25
m
Incidental
HCC
LT
(25 and 12mm) Hol (#35)
19
m
Mass in cirrhotic liver.
Aggarwal (#36)
23
f
RUQ pain and jaundice.
17
HCC
LT
(10 cm)
HCC (3 cm)
Awaiting transplant
FIGURES Figure 1: Oldest Japanese Survivor Junko Sugai was born in 1955 with biliary atresia and operated on by Dr Kasai. At 61 years old she remains perfectly well with only minimal evidence of liver disease. Pictured here with Prof Masaki Nio, the current Chair of Surgery in Sendai, Japan.” [reprinted here with full consent of the patient]
Figure 2: Survival Curves in Sendai, Japan Survival curves for 311 patients with biliary atresia treated with portoenterostomy at Tohoku University, Sendai, Japan, between 1951 and 1998. The curves are presented in 6-year cohorts and illustrate the gradual improvement in long-term survival rates. [Reproduced with permission from # 7]
Figure 3: England and Wales 10 year Actuarial Native Liver and True Survival: Effect of Age. (A) Actuarial true and native liver survival curves (median [±95% CI]) for biliary atresia (n = 443) in England and Wales (1999-2009). (B) Infants with isolated BA (n = 318) were divided by age at surgery. No difference overall (χ = 3.3; P = 0.34) or for trend (χ2 = 0.87; P = 0.35). Specifically, no difference between 2 outermost curves (χ2 = 2.1; P = 0 .15). [Reproduced with permission from # 9]
Figure 4: Biliary Atresia and Malignant Transformation Two year old girl with arterialised nodule developing in right lobe. A) A 19 mm pale subcapsular tumour (arrow) is present. B) The tumour is composed of highly cellular population of moderately atypical hepatoid cells. Mitotic activity is evident (arrow) (H&E 200x), C) Clusters of tumour cells are present in the lumen of perilesional thin-walled vascular spaces indicating vascular invasion (H&E, 400x). [Reproduced with permission from reference #33]
18
19
20
www.elsevier.com/locate/sempedsurg
PII: DOI: Reference:
S1055-8586(17)30095-1 http://dx.doi.org/10.1053/j.sempedsurg.2017.09.003 YSPSU50702
To appear in: Seminars in Pediatric Surgery Cite this article as: Arun Kelay and Mark Davenport, Long-Term Outlook in Biliary Atresia, Seminars in Pediatric Surgery, http://dx.doi.org/10.1053/j.sempedsurg.2017.09.003 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Long-Term Outlook in Biliary Atresia
Arun Kelay MRCS
Specialist Registrar in Paediatric Surgery
Mark Davenport ChM FRCS (Paeds) Professor of Paediatric Surgery
Department of Paediatric Surgery, Kings College Hospital, London SE5 9RS
Correspondence: Prof Mark Davenport Department of Paediatric Surgery, Kings College Hospital, London SE5 9RS Email: [email protected] TEL: 0044 203 299 3350
1
Abstract The oldest survivors from the Kasai portoenterostomy originate in Sendai, Japan and are approaching their 60th birthday. These represent the tip of an expanding cohort of adults born with this previously fatal condition. Increasingly transition to adult-biased hepatologists and physicians will be the expectation of many with this condition. However unlike their usual patients with alcohol, drugs, virally-mediated liver disease these are different with different expectations of health and quality of life. Cure is not on the cards for most of these and they survive still with impaired bile flow and increased liver fibrosis and cirrhosis with the threat of cholangitis and portal hypertension still apparent. We review the reported statistics on long-term survival essentially from Japan and Western Europe (such as the UK and France) and the range of complications that may still beset this group.
KEYWORDS: Biliary atresia; long-term outcomes; Kasai portoenterostomy; portal hypertension; cholangitis.
2
Introduction The first survivors in those born with biliary atresia (BA) were a tiny cohort of which little was known simply due to their rarity. These were infants from the 1930s onwards who had had favourable, “correctable” biliary anatomy and undergone exploration within a reasonable period of time. Later, possibly optimistic calculation would suggest that was less than 5% of all the infants ever born with BA.
The potential for change was only realized during the 1960s and 70s as an alternative for those with the much more common “uncorrectable” BA (i.e. Type 3 BA) following the first reported successes from Sendai, Japan, and increasing experience with the management of longer-term complications of chronic liver disease. Still, it is important to realize that Morio Kasai’s portoenterostomy (KPE) represents only a palliative solution for this disease, and is still not a cure [1]. Even those who have cleared their jaundice, the earliest and best outcome, will have liver fibrosis and impaired bile flow at the very least and the possibility of living out the rest of their allotted lifespan with this native liver is still awaited.
It is even less clear what the longest-term future holds for those transplanted given that this was only available from the 1980s in the UK and USA and these early pioneers will still only be in their thirties at the most. The prospect of already old livers transplanted into younger bodies and the more subtle effects of long-term immunosuppression also remain to be elucidated. Complications such as post-transplantation lymphoproliferative disease can arise many years after the initial operation and be incredibly difficult both to diagnose and treat [2].
This article will describe the long-term outcomes for native liver survivors as revealed by multiple national studies, with particular focus on the chronology of complications and the manifestations of BA in adulthood.
Influence of Aetiology on Outcome Although BA is simply a phenotype, and an umbrella term which can incorporate a number of different pathological mechanisms the end points are probably the same – cholangiodestruction, chronic inflammation and liver fibrosis. We currently recognise at least four different major variants [3] with divergent patterns of onset and widely different outcomes. These include:
3
1. Syndromic BA a. Biliary Atresia Splenic Malformation (BASM) b. Cat-eye syndrome – associated with chromosomal 22 aneuploidy 2. Cytomegalovirus (CMV) IgM +ve associated BA 3. Cystic BA – i.e. cyst formation in otherwise obliterated biliary tree. 4.
Isolated BA - the rest and by far the majority, but almost certainly still a heterogenous group.
There are some pathological processes within this quartet which may develop unusual symptoms and have an effect in the longer term. A good example of this is hepatopulmonary syndrome (HPS) which is much more commonly observed in children with BASM who may have excellent bile flow and liver function but who require liver transplantation for profoundly cyanotic lung disease and who presumably died in a previous era [4].
By contrast, the cystic BA group is often over-represented in the long-term survivors group, from an initial starting point of perhaps 10% in large series [5, 6]. There will be a much higher proportion of these who initially clear their jaundice due to the relative preservation of ductular linkage between intra- and extrahepatic systems. This was 100% in our last cohort who came to surgery at <30 days for example [6]. They also, on the whole, come to surgery earlier perhaps due to antenatal detection, and therefore have a reduced degree of liver fibrosis ab initio. There is a large overlap between this group, defined by morphological appearance and the Japanese Association of Pediatric Surgery’s classification’s Type I and II [5].
Facts and Figures – Quantification of the Survival Cohort. Our own longest-term survivor at Kings College Hospital underwent surgery in 1974 following transfer after an unsuccessful operation elsewhere and consequent burst abdomen. He has now just reached 40 years of age and really has minimal signs of disease. Still it is the Japanese who have some of the oldest survivors post-KPE and are approaching their 60s (Figure 1): but these are exceptional and freedom from symptoms is rare. Figure 2 shows the improvement in outcome since the first description of portoenterostomy in Professor Kasai’s unit in Sendai, Japan [7]. Incidentally this is indirect evidence of the improvement in efficacy of the surgical technique in that institution – Professor Kasai’s operation is not necessarily the operation that is done today either in Japan and elsewhere.
4
The last report from Sendai, published in 2012, updates the outcomes of 277 infants undergoing a Kasai operation from 1955 to 1991 [8]. Of these, 92 (33%) survived with their native liver for more than 20 years and 72 continued to survive with a “good condition” native liver at the time of the report. Within this group, 17 had been treated for varices with sclerotherapy while 11 had undergone partial splenic embolization for hypersplenism. 20 patients developed persistent jaundice beyond 20 years and 10 were transplanted (2 later died) and 4 were listed. Two further patients died of end-stage liver disease and variceal bleeding at the ages of 28 and 29 years respectively.
Five and Ten-Year Native Liver Survival (Table 1) Ironically, the first attempt at a co-ordinated registry of outcome involving more than one unit was the American Biliary Atresia Registry and involved data submitted from over 100 institutions in the period 1976 – 89. Sadly, to our knowledge it only produced a single publication and no further data has accrued [14]. Follow-up was available for 670 children (74% of original cohort) with a mean length of follow-up of 5 years (range, 1 to 16 years). In that group the 5-year actuarial survival was 48% following a KPE.
The King’s College Hospital experience over a similar period (1973-1995) described results in 338 infants with BA [15]. The 10-year actuarial survival estimate for those born from 1980-95 following establishment of a standard KPE operation and post-operative management strategy was 41%. At that time, 57 children had survived to 10 years post-KPE, and these remain the nucleus for our own long-term survival cohort.
The largest cohort of survivors consistently followed remains that of the Japanese Biliary Atresia Registry (JBAR), first established in 1989. Thus, 458 (64%) of the earliest cohort (1989 – 1994) of 716 children reached their 5-year milestone with their native liver intact. As transplantation was not available in Japan at this time this also represents the true survival rate. Later cohorts varied between 53% and 64% [12].
By comparison with Japanese reports, Western experience has been much more bleak, certainly with respect to the outcome after a KPE. Overall survival has to some extent been compensated with the earlier use and application of transplantation (Table 1). For cultural reasons, neither Japanese nor Korean centres used cadaveric donors, and were relatively late in developing transplant programmes when the option of living donation became feasible.
The French record of following their BA patients has been excellent and their updated national study included 1004 infants treated with KPE from 1986 to 2009, showing 5-year NLS rates of about 40% [16]. Our own national experience of infants born within England and Wales following centralisation and somewhat more up to date than other countries, showed an estimated 10-year NLS rate of 44% (Figure 3) [9].
5
Canadian experience from 1985 to 2002 reported NLS rates of 26% (range 20% to 32%) at 10 years [10]; Taiwan a 10-year NLS rate of 31% [13], and France a 36% 10-year NLS rate between 1986-2009 [16].
20-Year Survivors The Bicêtre series from Paris identified 63 (23%) from 271 patients who had survived with their native liver for >20 years [17]. They were able to show that initial anatomy was still hugely influential as different operations were performed for different situations. Thus, a hepatic portocholecystostomy was undertaken in those with patent gallbladder, cystic and common bile ducts, whilst cystojejunostomy was performed in patients with cystic BA. The remaining Type III BA underwent KPE. They found that 20-year NLS was better in those infants who had undergone portocholecystostomy or cystojejunostomy, at 35% and 40%, respectively. In the remaining patients with a KPE, just 19% survived to 20 years. In the national cohort, the 20-year NLS declined to 30% [16].
Remarkably, The Canadian national study identified age at initial surgery as still able to influence long-term outcome [10]. Surgery at <90 days of age was associated with a 20-year NLS of 28% in contrast to 13% for surgery >90 days of age, though this cut-off is still extreme and unrepresentative of when the vast majority of these infants present. Interestingly, 20-year NLS did not seem to improve from the earlier period (19681977) to the later period (1977-1983) of the study [10].
The national Netherlands review identified an improvement over time in 20-year NLS rates from 20% (10 of 49) between 1977 and 1982, rising to 32% (18 of 55) in the subsequent 1983-1988 period [18]. From the overall cohort of 104, 28 (27%) were surviving with their native liver at 20 years of age. Normal liver function tests and the absence of any clinical and ultrasonographic features of cirrhosis were present in 6 (21%) of these survivors.
Chronic Liver Disease There is a cohort of native liver survivors who display no clinical manifestations of chronic liver disease (CLD) whatsoever. In one long-term study from Kings College Hospital, we identified 28 adolescents with a median age of 13 (range 10 – 22) years who represented 11% of 244 infants treated between 1979 and 1991 [19]. All had a normal clinical examination with no features of portal hypertension and normal laboratory indices for liver function and coagulation. There had been no episodes of gastrointestinal (GI) bleeding during follow-up and surveillance oesophagogastroduodenoscopy (OGD) was performed in thirteen (45%) patients with no abnormal findings. Whether this will last until they reach three score years and ten is a moot point however as there were 59 follow-up liver biopsies (for a variety of reasons) taken at a median of 27 (range 3 – 123) months of age which showed mild to moderate liver fibrosis in 32 (54%) and
6
overt cirrhosis in 24 (41%). Only three adolescent patients originally born with Type 3 BA had no evidence of fibrosis in their biopsies (obtained at median follow-up of 36 months).
A similar proportion of “normal” native liver survivors were reported from the Denver series. Thus, 19 of 23 native liver survivors >10 years post-KPE were anicteric with normal synthetic liver function and represented 19% of the original cohort of 98 children [20].
What are Adult (>20-year) Native Liver Survivors Like? Progression of the intrahepatic component of the biliary pathology accounts for the cumulative attrition noted as survivors advance beyond 20 years of age. So, in the Bicêtre series, there was a fall in the proportion of those with normal serum bilirubin levels (52% vs 33%) and normal liver function tests (27% vs 21%) [17]. Cirrhosis was considered to be present in all but two of 63 patients over the age of 20, as assessed by any combination of clinical (hard hepatomegaly associated with splenomegaly), sonographic (nodular liver and features of portal hypertension) or histologic features.
Complications of Long-Term Survival Fundamentally, the root cause of problems remains that of inadequate bile flow in the setting of a fibrotic or cirrhotic liver. The actual mode of reconstruction, i.e. the Roux loop in most, is seldom a problem and there is no evidence that its obvious unphysiological delivery of bile into the proximal jejunum is a cause of long-term nutritional or developmental deficiencies. The same biliary reconstruction technique is used widely in choledochal malformations and no consequences have become apparent over a 40-year period of its use [21].
Cholangitis Cholangitis is a consequence of the creation of the bilioenteric conduit and is almost certainly ascending in nature. Pathogens are derived from intestinal flora and include E. coli, K. pneumoniae and P. aeruginosa [22]. Presenting features include fever, abdominal pain and worsening or recurrence of obstructive jaundice with acholic stools. There should be changes in bilirubin and liver enzyme levels together with acute changes in white cell count, and inflammatory markers such as C-reactive protein (CRP).
Most episodes of cholangitis will have presented within the first two years post-KPE and in some this can be recurrent and a reason for transplantation despite perhaps normal liver function between episodes. During adolescence and beyond the incidence is markedly reduced but other causative factors may come into play. An unexpected episode of cholangitis in someone with good liver function should prompt an investigation
7
package aimed at defining any obstruction in the Roux loop. The usual site of this is as it goes through the mesocolon, leading to a redundant pool of bile in the right upper quadrant [23]. Radioisotope hepatobiliary imaging, percutaneous cholangiography and where available single or double-balloon enteroscopy should be able to define Roux loop functionality and anatomy leading to corrective surgery.
In others, recurrent cholangitis appears to represent a failing liver possibly with anatomically definable intrahepatic bile lakes. These are more difficult to treat. Thus cholangitis occurred in 13 (22%) of 60 Japanese long-term survivors beyond the age of 20 [23]. There really were no distinguishing features in this group with regard to initial type of BA, age at KPE or presence of portal hypertension. Instead most displayed predisposing factors such as intrahepatic bile lake formation (n = 6) and/or hepatolithiasis (n = 4). Only three patients had normal imaging.
In the Bicêtre long-term series, 19 (30%) developed at least one episode of acute cholangitis between 17 and 30 years of age, successfully managed with antibiotics [17]. Interestingly none of these patients had undergone KPE, rather they had had portocholecystostomy, cystojejunostomy or cholecystojejunostomy. Gallstones were present in two of these patients, one of whom had hepatolithiasis and relapsing bacterial cholangitis, and was treated with a partial hepatectomy. The bilioenteric anastomosis was the site of gallstone formation in the second patient requiring operative removal.
It is important to note that late-onset cholangitis may precipitate liver failure, prompting expedited transplantation. This can be a fatal event in the long-term survivor, as illustrated by two patients from the Yokohama cohort who died of liver failure secondary to cholangitis at 21 and 22 years of age, respectively [25].
Is there anything that can be done to forestall the effects of recurrent cholangitis? Variations in the construction of the Roux-en-Y limb of the portoenterostomy including incorporation of an anti-reflux valve [26,27] and/or lengthening of the jejunal component [28,29] have consistently failed to show efficacy at reducing the incidence of cholangitis, perhaps reflecting its multifactorial aetiology.
Prophylactic long-term antibiotics have been also advocated to reduce the recurrence of cholangitis in this population but the evidence is scant. To date, only one randomised controlled trial has investigated the value of this but in a much younger age-group [30].
8
Portal Hypertension and Oesophageal Varices Raised portal venous pressure reflects the progression of liver fibrosis and higher preoperative values at the time of KPE are significantly correlated with a more advanced age at surgery [31] and therefore about half of this population could reasonably be defined as having portal hypertension at the time of KPE. Whether this persists, increases or decreases depends upon the response to surgery.
Established portal hypertension stimulates portosystemic shunting with formation of oesophageal, gastric, anorectal and ectopic (e.g. Roux loop) varices together with splenomegaly and hypersplenism. Oesophageal varices were detected in 88 (70%) of 125 children post-KPE who underwent OGD at a median of 13 months of age [30] though the proportion who will become symptomatic and bleed will be much less.
Obvious portal hypertension is still apparent in many of those reaching adulthood. So, 44 (70%) of 63 longterm survivors in the Bicêtre series showed clinical (splenomegaly), ultrasonographic or endoscopic features of portal hypertension [17]. Gastrointestinal bleeding had occurred in 3 beyond the age of 20, reflecting the progressive nature of the underlying disease. In this group, surgical portosystemic shunts had been created in 13 patients with no further bleeding at a mean follow-up of 15 years (range 4 - 22 years).
11 (37%) of 30 survivors from the Sendai series developed portal hypertension, although only 5 required intervention [32]. This initially included splenectomy and proximal splenorenal shunting for severe portal hypertension up to 1985, after which point partial splenic embolisation (PSE) was employed for clinically significant hypersplenism.
Malignant Transformation With the almost invariable development of chronic liver disease in BA then malignant transformation of the native liver is a real possibility. This is usually hepatocellular carcinoma (HCC) though to date it remains a rare complication.
We reported malignant transformation in 5 (0.8%) children and adolescents with type 3 BA arising from a cohort of 387 managed at Kings College Hospital between 1990 and 2008 [33]. Three of these children had developed suspicious nodules with an arterialized pattern on CT imaging (Fig. 4). Alpha-feto protein (AFP) levels were variable and well-differentiated HCC was confirmed within the explanted liver. In the other two cases the findings of HCC foci were incidentally made at the time of transplant (aged 2 and 17 years old). Other centres have reported cases in adolescents and one young adult [34-37] (TABLE 2).
9
Hepatoblastoma [37] and cholangiocarcinoma [38] in addition to HCC, have also been identified in explanted livers of BA survivors requiring transplantation, but only during childhood.
Background cirrhosis, nodular regeneration and reactive hyperplasia can make differentiation between benign and malignant nodules extremely difficult. We advocate screening for malignant transformation in all our children and young people with BA including regular US and serial serum AFP levels. Suspicious findings on US will mandate further cross-sectional imaging including CT which may identify arterialization of the lesion(s) aiding in the assessment of potential malignancy. It must be noted however, that small HCC lesions (< 11 mm) can be missed on US [33] and the serum AFP may well be entirely normal even with sizeable tumours [33, 38].
Complete tumour excision represents the only curative treatment option, and almost always this implies liver transplantation given the co-existent cirrhotic liver disease. Adjuvant chemotherapy is usually not indicated in the absence of extrahepatic disease [33].
Growth and Development 49 (78%) of the 63 native liver survivors from Bicêtre, France reached an adult height at or above the mean [17]. All male patients progressed through normal pubertal development. The female cohort also completed normal puberty with the exception of two female patients - one who had suffered from bacterial meningitis with subsequent primary amenorrhoea, and another noted to have ventricular dilatation and developmental delay.
The Sendai series found that 29 of 30 survivors beyond the age of 20 displayed physical growth within the normal range [32]. Normal puberty occurred in all male patients, and all but two female patients. These consisted of one girl with Turner’s syndrome and another with primary amenorrhoea secondary to severe liver dysfunction. None of these patients had evidence of developmental delay.
Pregnancy There is an increasing cohort of female native liver survivors who wish to start their own families. Pregnancy is a particularly challenging period for cirrhotic patients as shown from a previous report from our centre [39] where a MELD score of > 6 and a UKELD score > 46 were associated with increased maternal and fetal risk. A platelet count of < 110 x 109/l was also found to be a good predictor for presence of varices during pregnancy. The last published report from the Sendai BA series described 14 pregnancies with 11 who completed live-born deliveries [40]. Women with a previous history of cholangitis and/or variceal
10
bleeding tend to be the ones with liver-related complications during pregnancy but even those with biochemically normal liver function could be challenged.
Multidisciplinary support including hepatology and obstetric teams familiar with the problems of pregnancy in cirrhosis is vital and in our unit we advise second trimester elective endoscopy to assess the presence and degree of varices to gauge the risk of bleeding. Even then progression of liver failure necessitating transplantation and/or recurrent cholangitis may occur pre- or postnatally [25, 41].
It is worth re-iterating that the offspring of mothers born with BA have been invariably normal. A nationwide survey of Japanese centres did not reveal any abnormalities in the infants born to mothers with BA [41].
Quality of Life (QoL) There has been a paucity of studies determining the quality of life in native liver survivors of BA, although this is becoming an additional focus for investigation as this cohort expands. In a unique comparison study of UK and Japanese young people ( > 10 years) Howard et al. used the SF-36 questionnaire and its Japanese equivalent to assess long-term quality of life in 55 patients (30 Japanese and 25 British) [7]. This was unable to show any significant differences between the two groups and with respect to their normative populations in terms of physical functioning. The British cohort tended to outperform their Japanese equivalent in both perception of “general health” and ‘vitality’ within the well-being domain.
Quality of Life of 25 Dutch young adult native liver survivors at a median age of 23 years was found to be generally comparable to age-matched controls [42]. However, their general health perception was lower than both controls and patients post-transplant. The education level, marital and employment status of this group was also found to be commensurate with that of a reference group aged 18 - 30 years old [43], and similar to the findings in a Japanese study [32]. Of 63 French native liver survivors > 20 years; 17 were in university education and 21 in regular employment [15]; 20 (32%) were married or in stable relationships, and 10 have become parents [17].
In conclusion, such results suggest that native liver survivors can achieve a QoL similar to healthy peers extending through adolescence to young adulthood.
Transplantation in Young People and Adults Born with Biliary Atresia Unfortunately the right-side of the native liver survival curves in BA is never flat and there is an on-going need for transplantation as they move into full adult life. This can create many problems as it is a natural
11
hiatus in the caring paradigm for many “children’s diseases” such as these BA native liver survivors as it is for cystic fibrosis native lung survivors. The problem is probably that of unfamiliarity with the nature of the disease rather than unwillingness. Adult hepatologists will have seldom seen large numbers of young adults with the condition and perhaps judge them to different standards.
We recently reviewed our experience with 36 young persons who underwent LT between 1999 and 2014 at a median age of 16.6 (11.2 - 27.2) years [unpublished data]. The most common indications for listing were cholangitis (31%), synthetic failure (20%) and recurrent variceal bleeding (15%). It was noticeable that there were differences in the pre-transplant period depending on age. Thus, admission to an intensive care unit was more common for those >18 years (40% vs 6%) and they also spent longer on the waiting (10 vs 6 months). Unfortunately, you can wait too long so those with bilirubin levels of >100 µmol/l at time of LT were associated with poor survival (19% vs 0%,).
Conclusion Decades of Japanese experience and our experience with centralization in the UK suggests that 40-45% of infants and children with BA will have sufficiently good restoration of bile flow, resolution of jaundice and attenuation of the underlying liver fibrotic pathology to reach their teenage years given the current indications and availability of transplantation. While this may be somewhat optimistic it is attainable.
Nevertheless, true “cure” is a more elusive concept and the likelihood is that these survivors have the potential for considerable morbidity due to cirrhosis, recurrent cholangitis and portal hypertension. Hepatobiliary malignancy is possible but does not seem to be the threat it is in other metabolic liver conditions such as tyrosinaemia. They do require life-long monitoring and management with a fastidious approach to the care of their liver and appropriate escalation in care if the signs suggest a need for transplantation. All things considered they should probably be looked after in units with sufficient multidisciplinary skills to enable an appropriately smooth transition. They have come this far, they need to go further.
12
References
1. Kasai M, Suzuki S. A new operation for “non correctable” biliary atresia: portoenterostomy. Shijitsu 1959; 13: 457-81. 2. Dreyzin A, Lunz J, Venkat V, et al. Long-term outcomes and predictors in pediatric liver retransplantation. Pediatr Transplant 2015; 19: 866-74. 3. Davenport M. Biliary atresia: clinical aspects. Semin Pediatr Surg. 2012; 21: 175-841. 4. Davenport M, Tizzard SA, Underhill J, et al. The biliary atresia splenic malformation syndrome: a 28-year single-center retrospective study. J Pediatr 2006; 149: 393-4001. 5. Nio M, Wada M, Sasaki H, et al. Does hepatic hilum morphology influence long-term prognosis in type I/I cyst biliary atresia? Pediatr Surg Int. 2015; 31: 931-61. 6. Caponcelli E, Knisely AS, Davenport M. Cystic biliary atresia: an etiologic and prognostic subgroup. J Pediatr Surg 2008;43: 1619-241. 7. Howard ER, MacLean G, Nio M, et al. Survival patterns in biliary atresia and comparison of quality of life of long-term survivors in Japan and England. J Pediatr Surg 2001; 36 :892-7. 8. Nio M, Wada M, Sasaki H, et al.T. Risk factors affecting late-presenting liver failure in adult patients with biliary atresia. J Pediatr Surg 2012; 47: 2179–2183. 9. Davenport M, Ong E, Sharif K, et al. Biliary atresia in England and Wales: results of centralization and new benchmark. J Pediatr Surg 2011; 46: 1689-94. 10. Schreiber RA, Barker CC, Roberts EA, et al. Biliary atresia: the Canadian experience. J Pediatr 2007; 151: 659-65. 11. Serinet MO, Broue P, Jacquemin E, et al. Management of patients with biliary atresia in France: results of a decentralized policy 1986-2002. Hepatology 2006; 44: 75-84. 12. 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. 13. Hung PY, Chen CC, Chen WJ, et al. Long-term prognosis of patients with biliary atresia: a 25 year summary. J Pediatr Gastroenterol Nutr 2006; 42: 190-5. 14. Karrer FM, Lilly JR, Stewart BA, Hall RJ. Biliary atresia registry, 1976 to 1989. J Pediatr Surg 1990; 25: 1076-80 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. Chardot C, Buet C, Serinet MO, et al. Improving outcomes of biliary atresia: French national series 19862009. J Hepatol 2013; 58: 1209-17. 17. Lykavieris P, Chardot C, Sokhn M, et al. Outcome in adulthood of biliary atresia: a study of 63 patients who survived for over 20 years with their native liver. Hepatology 2005; 41: 366-71.
13
18. de Vries W, Homan-Van der Veen J, Hulscher JB, et al. Twenty-year transplant-free survival rate among patients with biliary atresia. Clin Gastroenterol Hepatol 2011;9: 1086-91. 19. Hadžić N, Davenport M, Tizzard S, et al. Long-term survival following Kasai portoenterostomy: is chronic liver disease inevitable? J Pediatr Gastroenterol Nutr. 2003; 37: 430-3. 20. Karrer FM, Price MR, Bensard DD, et al. Long-term results with the Kasai operation for biliary atresia. Arch Surg 1996; 131: 493-6. 21. Ford KE, Cooper LR, Davenport M. Growth in children with choledochal malformations: effect of the Roux loop. Pediatr Surg Int 2015; 31: 1015-9. 22. Wu ET, Chen HL, Ni YH, et al. Bacterial cholangitis in patients with biliary atresia: impact on short-term outcome. Pediatr Surg Int 2001;17:390-395 23. Houben C, Phelan S, Davenport M. Late-presenting cholangitis and Roux loop obstruction after Kasai portoenterostomy for biliary atresia. J Pediatr Surg 2006; 41: 1159-64. 24. Nio M, Sano N, Ishii T, et al. Cholangitis as a late complication in long-term survivors after surgery for biliary atresia. J Pediatr Surg 2004; 39: 1797-9. 25. Shinkai M, Ohhama Y, Take H, et al. Long-term outcome of children with biliary atresia who were not transplanted after the Kasai operation: >20-year experience at a children’s hospital. J Pediatr Gastroenterol Nutr 2009; 48: 443-50. 26. Nakajo T, Hasizume K, Saeki M, et al. Intussusception-type antireflux valve in the Roux-en-Y loop to prevent ascending cholangitis after hepatic portojejunostomy. J Pediatr Surg 1990;25: 311-4. 27. Ogasawara Y, Yamataka A, Tsukamoto K, et al. The intussusception antireflux valve is ineffective for preventing cholangitis in biliary atresia: a prospective study. J Pediatr Surg 2003; 38:1826-1829. 28. Muraji T, Tsugawa C, Nishijima E, et al. Surgical management for intractable cholangitis in biliary atresia. J Pediatr Surg. 2002;37 : 1713-5. 29. Chuang JH, Lee SY, Shieh CS, et al. Reappraisal of the role of the bilioenteric conduit in the pathogenesis of postoperative cholangitis. Pediatr Surg Int 2000; 16: 29-34. 30. Bu LN, Chen HL, Chang CJ, et al. Prophylactic oral antibiotics in prevention of recurrent cholangitis after the Kasai portoenterostomy. J Pediatr Surg 2003;38: 590-3. 31. Shalaby A, Makin E, Davenport M. Portal venous pressure in biliary atresia. J Pediatr Surg 2012; 47:3636. 32. Nio M, Ohi R, Shimaoka S, et al. The outcome of surgery for biliary atresia and the current status of long-term survivors. Tohoku J Exp Med 1997; 181: 235-44. 33. Hadžić N, Quaglia A, Portmann B, et al. Hepatocellular carcinoma in biliary atresia: King’s College Hospital experience. J Pediatr 2011; 159: 617-22. 34. Hirzel AC, Madrazo B, Rojas CP. Two rare cases of hepatocellular carcinoma after Kasai procedure for biliary atresia: a recommendation for close follow-up. Case Rep Pathol 2015; 2015: 982679. Published
14
online 2015 Aug 3. doi: 10.1155/2015/982679 35. Hol L, van den Bos IC, Hussain SM, et al. Hepatocellular carcinoma complicating biliary atresia after Kasai portoenterostomy. Eur J Gastroenterol Hepatol 2008; 20: 227-31. 36. Aggarwal S, Vadada D, Sharma V. A rare complication in an adult patient after Kasai portoenterostomy for biliary atresia. Arab J Gastroenterol 2012; 13: 148-9. doi: 10.1016/j.ajg.2012.08.010. Epub 2012 Sep 15. 37. Amir AZ, Sharma A, Cutz E, et al. Hepatoblastoma in explanted livers of patients with biliary atresia. J Pediatr Gastroenterol Nutr 2016; 63: 188-94. 38. Yoon HJ, Jeon TY, Yoo SY, et al. Hepatic tumours in children with biliary atresia: single-centre experience in 13 cases and review of the literature. Clin Radiol 2014; 69: 113-9. 39. Westbrook RH, Yeoman AD, O’Grady JG, et al. Model for end-stage liver disease score predicts outcome in cirrhotic patients during pregnancy. Clin Gastroenterol Hepatol 2011; 9: 694-699. 40. Sasaki H, Nio M, Hayashi Y, et al. Problems during and after pregnancy in female patients with biliary atresia. J Pediatr Surg 2007; 42: 1329-32. 41. Shimaoka S, Ohi R, Saeki M, et al. Problems during and after pregnancy of former biliary atresia patients treated successfully by the Kasai procedure. J Pediatr Surg 2001; 36: 349-51. 42. de Vries W, Lind RC, Sze YK, et al. Overall Quality of Life in adult biliary atresia survivors with or without liver transplantation: results from a national cohort. Eur J Pediatr Surg 2016; 26: 349-56. 43. Lind RC, de Vries W, Keyzer CM, et al. Health status and quality of life in adult biliary atresia patients surviving with their native livers. Eur J Pediatr Surg 2015; 25: 60-5.
15
Table 1 : 10-Year Survival Figures In Biliary Atresia – Data From National Studies (> 100 subjects)
n
Period
10 year Native liver
Actual Survival
survival England & Wales
443
1999 - 2009
40
89
Canada [10]
349
1985 - 2002
24
75 – 80
France [11]
472
1986 - 96
26
70
Japan [12]
108
1989
53
66
Taiwan [13]
141
1976 - 2000
31
40
(9)
16
Table 2: Malignant Transformation in Adolescents and Young People with Biliary Atresia
Age Hadzic (#33)
17
Gender f
Clinical Incidental
Histology (diameter) HCC
Outcome LT
(10mm) Hirzel (#34)
25
m
Incidental
HCC
LT
(25 and 12mm) Hol (#35)
19
m
Mass in cirrhotic liver.
Aggarwal (#36)
23
f
RUQ pain and jaundice.
17
HCC
LT
(10 cm)
HCC (3 cm)
Awaiting transplant
FIGURES Figure 1: Oldest Japanese Survivor Junko Sugai was born in 1955 with biliary atresia and operated on by Dr Kasai. At 61 years old she remains perfectly well with only minimal evidence of liver disease. Pictured here with Prof Masaki Nio, the current Chair of Surgery in Sendai, Japan.” [reprinted here with full consent of the patient]
Figure 2: Survival Curves in Sendai, Japan Survival curves for 311 patients with biliary atresia treated with portoenterostomy at Tohoku University, Sendai, Japan, between 1951 and 1998. The curves are presented in 6-year cohorts and illustrate the gradual improvement in long-term survival rates. [Reproduced with permission from # 7]
Figure 3: England and Wales 10 year Actuarial Native Liver and True Survival: Effect of Age. (A) Actuarial true and native liver survival curves (median [±95% CI]) for biliary atresia (n = 443) in England and Wales (1999-2009). (B) Infants with isolated BA (n = 318) were divided by age at surgery. No difference overall (χ = 3.3; P = 0.34) or for trend (χ2 = 0.87; P = 0.35). Specifically, no difference between 2 outermost curves (χ2 = 2.1; P = 0 .15). [Reproduced with permission from # 9]
Figure 4: Biliary Atresia and Malignant Transformation Two year old girl with arterialised nodule developing in right lobe. A) A 19 mm pale subcapsular tumour (arrow) is present. B) The tumour is composed of highly cellular population of moderately atypical hepatoid cells. Mitotic activity is evident (arrow) (H&E 200x), C) Clusters of tumour cells are present in the lumen of perilesional thin-walled vascular spaces indicating vascular invasion (H&E, 400x). [Reproduced with permission from reference #33]
18
19
20