Presentation and treatment of biliary atresia Witt, Mauri
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1
INTRODUCTION
Biliary atresia (BA) is a rare cholestatic disease of infancy. It is characterised by an inflammatory process resulting in fibrosis and obliteration of the biliary tract, which becomes apparent within weeks after birth. The disease can affect (parts of) the extrahepatic bile ducts, but frequently the intrahepatic bile ducts are also affected. The incidence varies from 1:17.000 to 1:19.000 live births in Western Europe.1,2
There is a higher incidence in Asian countries, up to 1:6.600 in Taiwan and 1:3.401 in the small population of French Polynesia.3,4 Obliteration of the biliary tract results
in cholestasis, and if left untreated, in death from progressive liver fibrosis in two to three years.5,6 BA is classified according to the level of obstruction (Figure 17). The
most commonly used classification is as follows. In type 1 (±5% of cases), only the common bile duct is obstructed. This type is often associated with the formation of a proximal cystic element and therefore also known as the “cystic form “of BA, which may lead to diagnostic confusion with choledochal malformation.8 In type
2 (±2%), the obstruction is located at the level of the common hepatic duct. The most common form of BA is type 3 (>90%), in which the whole extrahepatic biliary tract and the porta hepatis is obstructed (Figure 1).5
Figure 1 (adapted from Hartley et al. 7): Schematic illustration of classification of biliary atresia types 1-3.
There are several phenotypes of BA, likely with different underlying aetiology.8-10
Some patients with BA have other congenital malformations. In these patients a joint aetiology of abnormal bile duct morphogenesis is likely.8,9 One of these
subgroups are patients with Biliary Atresia Splenic Malformation Syndrome (BASM). Besides BA this syndrome is associated with splenic malformation (polysplenia or asplenia), laterality defects (situs inversus, malrotation, malformation of the intra-abdominal veins) and cardiovascular anomalies, suggesting a developmental aetiology in this subgroup.8,9,11,12 Other subgroups
include the presence of other congenital anomalies, such as cat-eye-syndrome or non-syndromic anomalies such as intestinal atresia.8,9,13,14
Despite extensive research the aetiology of BA is still not known. In fact, BA might not be one disease but a spectrum of diseases all leading to fibrosis of the biliary tree. Based on human studies and animal models multiple factors contributing to isolated BA have been suggested, such as perinatal viral infections, (auto) immune mediated inflammatory obstruction, genetic factors, vascular changes, maternal factors and toxins.15-37 The theory most often suggested is a viral induced
or autoimmune mediated obstruction of the bile duct.9,20,22 Supporting evidence
for this theory was provided by several studies: REOvirus RNA, Rotavirus DNA and CMV DNA and IgM were found in up to half of all BA patients.38-46 Recent studies
presented a new theory about a plant toxin (biliatresone) that could play a role in the pathogenesis of BA. This toxin is linked to outbreaks of BA-like disease in Australian livestock and has been shown to destruct the biliary tract in zebrafish and mouse models.34,35,47-49 It is unlikely that pregnant women ingest biliatresone
but these findings might lead to identification of potential human teratogens with similar mechanisms to cause BA.48,49 Besides extrinsic factors, several single
nucleotide polymorphisms (e.g. CFC1, GPC1, ADD3, ARF6) are described as susceptibility factor for BA.17-19,36,37 However, these gene mutations are only present
in the minority of patients. Another suggested aetiologic factor of BA are vascular changes like medial layer hypertrophy of hepatic arterial branches.32
The prognosis of BA mainly depends on its timely recognition and treatment. Delay in diagnosing BA is a major problem. This is mainly due to the much higher incidence of benign and self-limiting breast milk jaundice, which is not discernible with the naked eye from the (initially) relatively mild jaundice in case of BA. In order to diagnose BA as soon as possible various diagnostic algorithms have been developed.50-52 The American Academy of Pediatrics recommended conjugated
bilirubin measurement for all infants with persisting jaundice beyond two to three weeks of age.53 Conjugated hyperbilirubinaemia is always pathologic and requires
referral for further diagnostic work up. In this way infants with cholestasis can be identified and early referral for further diagnostic procedures could be realised.
1
In the Netherlands a guideline on hyperbilirubinaemia in infants has been implemented in 2008, which includes measuring total and conjugated bilirubin in every child with persisting jaundice at the age of three weeks, irrespective of being breast- or formula-fed. A website dedicated to this guideline was constructed to aid medical caregivers as well as parents from children with hyperbilirubinaemia (www.babyzietgeel.nl).
When a conjugated hyperbilirubinaemia has been demonstrated, the differential diagnosis is still elaborate. However, in case of BA surgical therapy is urgently indicated. The initial symptoms may be mild but delay in diagnosis could have major consequences for the prognosis of the disease. Different diagnostic procedures are used to diagnose the cause of neonatal cholestasis and/or exclude BA, including biochemical, serological and imaging strategies. In most centres abdominal ultrasound is performed as the first imaging modality.9,54 Some
centres use endoscopic retrograde cholangiopancreatography (ERCP) as primary diagnostic tool, but most centres perform liver biopsy and rely on histological findings to decide to proceed to an operative cholangiogram.9,55-57 Portal tract
fibrosis, ductular proliferation, oedema and cholestasis with bile plugs are suspect histological findings for BA.5 The gold standard for the definitive diagnosis still is
demonstration of interrupted continuity between the liver and the intestine via a peroperative cholangiogram.
The clinical outcome of BA has been greatly improved by the development of surgical restoration of bile flow via the Kasai portoenterostomy (or one of its variants) since the 60’s of the last century. During this procedure the whole fibrotic extrahepatic biliary tract is resected. Subsequently a jejunal Roux-en-y loop is anastomosed to the exposed remaining ductules at the porta hepatis (Figure 2). This procedure ideally re-establishes bile flow and thereby achieves complete clearance of jaundice. The Kasai procedure is successful (defined as a total bilirubin < 20 mmol within six months after Kasai) in ~50% of cases.2,58,59
However, destruction and obliteration of the intrahepatic bile ducts, either primary or secondary to extrahepatic bile duct obstruction, is not amenable to a surgically successful Kasai procedure. It has been proven difficult to predict at the time of surgery in which patients the procedure will be clinically successful for sustained restoration of bile flow. If bile drainage is not achieved within weeks to months postoperatively, the development of end-stage cholestatic liver disease usually requires liver transplantation (LTx) within six months to two years of age.5
Despite the success of Kasai hepatoportoenterostomy, BA progresses in 70% of children in whom biliary drainage was achieved via the Kasai procedure.5 If portal
hypertension and end-stage liver failure occur, LTx is the only life-saving option.60
BA constitutes 50-75% of paediatric indications for liver transplantation throughout the Western world.5,61-63
One of the most important prognostic factors for surgical outcome after the Kasai procedure is age at surgery. Large studies have shown that young age at the time of Kasai surgery (before 30 or 60 days) results in higher sufficient bile flow rates and longer transplant-free survival, when compared to surgery at later age.64-70 This
was also confirmed by Dutch data: surgery before 60 days of age was associated with significantly higher four-year-transplant-free-survival rate compared to surgery after 60 days of age (56% vs. 34% respectively, p=0.003).71 However, only
56% of the patients in The Netherlands underwent surgery before 60 days of age.71
In several other countries this percentage amounts to 69%.72 This underlines the
importance of early identification of the disease, so that timely surgery can be performed. Apart from age at Kasai surgery, centralisation of treatment of BA has been associated with better surgical results and longer transplant-free survival in several countries.59,73-75
Insufficient recognition of the early symptoms of neonatal cholestasis could play a major role in the delayed diagnosis of BA. BA presents shortly after birth with persistent jaundice, usually followed later by pale stools and dark urine. The disease is very difficult to distinguish from physiological jaundice (usually only the first week of life) and breast milk jaundice (can extend until two to three months of life). Because of the relatively high incidence of breast milk jaundice the first symptoms of BA are often not considered alarming by parents and primary caregivers, especially not in breastfed new-borns. Acholic stools are present in the majority of patients but may not be noticed by the parents or primary caregivers or even considered to be normal, again especially in breastfed new-borns. However, acholic stools, due to the absence of bile pigment in the stools, are an alarm symptom for bile not reaching the intestine, what could be due to biliary atresia – the one and only cholestatic disease of infancy that needs immediate surgical intervention. Careful observation of the stool colour could therefore assist to improve early referral to diagnose or exclude BA.
1
To ensure the recognition of pathologic stool colours by parents and medical caregivers, the Infant Stool Colour Card (ISCC) has been developed and successfully implemented in Taiwan.65,70 The ISCC consists of seven photographs
of different coloured stool samples (Figure 3). The pictures 1-3 are regarded as abnormal; these are white, clay-coloured and light yellowish stools. The four other colours, yellow to greenish, are considered to be normal. Parents and caregivers were asked to observe the stool colour of their infant using this card. This ISCC screening program significantly decreased the mean age at which Kasai surgery was performed. The percentage of BA patients undergoing Kasai surgery within 60 days increased from 49% to 66% (p<0.02).70 According to epidemiological
expectations, the surgery at earlier age has remarkably improved outcomes. The five-year-transplant-free-survival rate increased from 27% to 64% (p<0.001).70
Recently this Infant Stool Colour Card has been introduced in several countries including Brazil, Japan, Switzerland and Canada. It has proven to be a simple, cost-effective, sensitive and specific screening method for BA in infants.65,70,76-82 There
is presently no screening program for acholic stools in The Netherlands. Whether Dutch parents and primary healthcare doctors recognise acholic stools adequately and whether implementation of the ISCC in the Netherlands could improve the recognition of acholic stools is unknown.
Figure 3: Infant Stool Colour Card
Apart from neonatal jaundice, acholic stools and dark-coloured urine, another presenting symptom of BA can be Vitamin K deficiency bleeding (VKDB), especially in breastfed infants. Because of insufficient amounts of Vitamin K in breast milk, breastfed infants are at higher risk to develop VKDB.83,84 Therefore, many countries
implemented prophylactic regimens of Vitamin K to prevent VKDB. VKDB can be classified according to the time of presentation:early (<24 hours of age), classic (first week after birth), and late (between one week and six months of age).85 In
late VKDB, the bleeding is often located intracranial, which is associated with high mortality and morbidity.85-90 Vitamin K absorption is strongly dependent on
the presence of bile acids in the intestinal lumen. During cholestasis, absent or diminished intestinal availability of bile acids results in malabsorption of vitamin K and other fat-soluble vitamins. The Dutch prophylactic regimen of a single oral dose of 1 mg vitamin K at birth, followed by a recommended daily oral supplementation of 25 μg vitamin K from week two until the end of week 13 in breastfed infants was proven to be insufficient to prevent VKDB in breastfed infants with BA.86
Eighty-three per cent of breastfed patients with BA presented with VKDB and 43% with intracranial haemorrhage, which is associated with high mortality and morbidity.86-89 Based on these data the nationwide guideline regarding Vitamin K
prophylaxis has been adapted in 2011. The daily dose of 25 µg of vitamin K orally was raised to 150 µg a day for all breastfed infants from day eight till the 12th week
of life.90 Whether this increase in daily dose of vitamin K has been successful in
preventing VKDB in breastfed children with (still unrecognised) cholestasis has remained unclear.
As mentioned previously, even after a surgically successful Kasai procedure, BA progresses in the majority of patients.5 Progression of the disease leads to
on-going fibrosis, cirrhosis and finally to end-stage liver disease. Several factors related to native liver survival up to the age of two or four have been identified in epidemiological studies, such as type of BA, associated malformations, early life KPE and postoperative use of antibiotics and ursodeoxycholic acid (UDCA).7,91-102
Up to 50% of BA patients need LTx before the age of two years.73,103,104 This suggests
that the prognosis after having reached the age of two years with native liver seems favourable. However, neither the long-term prognosis of patients with at least two years of NLS nor factors associated with sustained survival with native liver have been studied yet.
A frequent feature of cirrhosis and of end-stage liver disease is the development of oesophageal varices. Oesophageal varices can rupture spontaneously, leading to severe upper gastrointestinal tract bleedings with significant morbidity and even mortality. To decrease morbidity and mortality of varices several preventive strategies have been developed, including screening and primary prophylaxis, either by beta blockade or band ligation. However, the efficacy of screening for oesophageal varices or primary prophylaxis for patients with BA has not been conclusively demonstrated.105-107
To address several of the unresolved questions of BA, we used data from a nationwide registry, the Netherlands Study group on Biliary Atresia Registry (NeSBAR). NeSBAR is an on-going joint effort of the Dutch Society for Paediatrics - Section Gastroenterology, Hepatology and Nutrition, and the Dutch Society for Paediatric Surgeons. The registry contains the patient data of all BA patients, born since January 1 1987, and treated in the six specialised academic centres in The Netherlands. All centres offered primary surgical treatment and subsequent follow-up. From all centres a paediatric surgeon and a paediatric gastroenterologist were involved in NeSBAR, ensuring reliable data entrance. One or two PhD students involved in the project regularly collected data.
1
The aim of this thesis was to assess the results of current strategies to diagnose and treat biliary atresia and to determine targets for improvement in the chain of care (Figure 4).
Figure 4: Chain of care of BA.
Firstly, we aimed to assess the efficacy of current strategies to diagnose biliary atresia, and to explore novel avenues to improve early diagnosis. The relatively late diagnosis of BA in the Netherlands, compared to other countries could be due to insufficient recognition of the warning signs for neonatal cholestasis, such as acholic stools. In chapter 2 we determined if insufficient recognition of acholic stools by parents, caregivers and/or health care professionals could be a factor in the late diagnosis of BA in the Netherlands. We analysed whether Dutch parents and primary healthcare doctors were able to recognise acholic stool from other stool colours and, whether, depending on their initial judgement, they would seek medical help or refer the patients for further medical investigation. Since we also aim to define targets for improvement we analysed whether recognition of discoloured stools by parents could be improved by the use of the ISCC.
The fraction of breastfed infants who had a severe vitamin K deficiency at the time they were diagnosed with BA, i.e. as a presenting symptom, was profoundly higher than in other countries, such as Denmark. It had been demonstrated previously that this phenomenon was related to insufficient prophylactic regimen in the Netherlands. In 2011 the Dutch guideline of Vitamin K prophylaxis for breastfed infants was adapted towards a regimen that was unique in the world. However, the efficacy of this new regimen was not known. We therefore compared the incidence of VKDB as a presenting symptom under the new regimen with two other prophylactic regimens. For this purpose, we again collaborated with the Danish biliary atresia registry, where prophylaxis consists of a single intramuscular dose of 1 mg vitamin K at birth for all new-borns. In chapter 3 we compared the incidence and severity of VKDB in breastfed patients with BA who had received one of the three prophylactic regimens: 1 mg orally at birth, followed by a daily oral dose of 25 μg (Netherlands, < February 2011), 1 mg orally at birth, followed by a daily oral dose of 150 μg vitamin K (Netherlands > March 2011); and a single IM dose of 1 mg vitamin K at birth (Denmark, > July 2000).
Diagnosis Kasai portoenterostomyFollow-up Referral to
Tx center
Whether VKDB as a presenting symptom is related to the severity of liver disease is not known. In chapter 4 we analysed whether the presence of VKDB at initial presentation of patients with biliary atresia is predictive for the later development of end-stage liver failure and therefore induce an earlier need for LTx. The (unfortunate) increased incidence of VKDB in The Netherlands, together with a national registry NeSBAR with follow-up for over 30 years, offered a unique possibility to address this question.
Even upon initial clearance of jaundice after Kasai surgery, BA still ultimately progresses in the majority of patients. Progression of the disease leads to fibrosis, cirrhosis and end-stage liver disease. A well-known complication of cirrhosis and end-stage liver disease is the development of portal hypertension and oesophageal varices (EV). Variceal bleeding is associated with significant morbidity and even mortality. In adult patients with cirrhosis, screening for oesophageal varices is recommended as primary prophylaxis. In children with liver disease evidence for screening, primary and secondary prophylaxis is far from conclusive. In chapter 5 we analysed the incidence, severity and clinical characteristics of BA patients who experienced EV bleeding during follow-up after KPE.
If liver fibrosis and cirrhosis progresses and end-stage liver disease occur, LTx becomes the only option. Most patients require LTx before the age of two years. In chapter 6 we analysed the follow-up of all BA patients with at least two years of NLS. We analysed whether early-life factors were associated with continued NLS after two years of age and studied the indications and timing of LTx in BA patients after two years of NLS. We aimed to provide long-term prognostic information for parents, caregivers and healthcare professionals regarding those BA patients who reached the age of two years with their native livers.
In chapter 7 the different experimental elements and chapters of this thesis are discussed in relation to the overall aim. Based on our results we also offer several strategies to further improve the outcome of patients with biliary atresia.
1
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