Presentation and treatment of biliary atresia Witt, Mauri
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of biliary atresia
Geneeskunde Isala, Fiscaal adviesbureau mr. J. Voerman, Noord Negentig, Chipsoft, Erbe B.V., University of Groningen, University Medical Center Groningen, Zeldzame Ziekten Fonds, UMCG Doelmatigheidsfonds, Astellas Pharma B.V., Hypotheekvisie Zwolle Frank van Eijk
Their support is gratefully acknowledged. Cover design: Jorn Lemmen & Mauri Witt Layout: Loes Kema
Printed by: GVO drukkers & vormgevers B.V.
Copyright © Mauri Witt, Zwolle the Netherlands 2018
All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form without written permission of the
Presentation and treatment
of biliary atresia
Proefschrift
ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen
op gezag van de
rector magnificus prof. dr. E. Sterken
en volgens besluit van het College voor Promoties. De openbare verdediging zal plaatsvinden op
maandag 26 november 2018 om 16.15 uur door
Mauri Witt
geboren op 5 september 1989 te Rotterdam
Beoordelingscommissie
Prof. dr. R.J. Porte Prof. dr. E. Heineman Prof. dr. E.H.H.M. Rings
CHAPER 2 Early detection of neonatal cholestasis: inadequate assessment of stool colour by parents and youth healthcare doctors.
Eur J Pediatr Surg 2016 Feb;26(1):67-73.
29
CHAPTER 3 Prophylactic Dosing of Vitamin K to Prevent Bleeding
Pediatrics 2016 May;137(5):10.1542/peds.2015-4222. 43
CHAPTER 4 Prognosis of biliary atresia after initial presentation with
vitamin K deficiency bleeding.
Submitted
55
CHAPTER 5 Variceal Bleeds in Patients with Biliary Atresia
Eur J Pediatr Surg 2017 Jun 28. 69
CHAPTER 6 Prognosis of Biliary Atresia after two-year Survival with
Native Liver: a Nationwide Cohort Analysis.
J Pediatr Gastroenterol Nutr. 2018 Aug 8.
83
CHAPTER 7 Summary, general discussion and future perspectives 97
Nederlandse samenvatting 107
Dankwoord 115
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
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
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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cholangiopancreatography in the diagnosis of biliary atresia in infants younger than 100 days. J Pediatr Gastroenterol Nutr. 2009;49(4):435-441.
58. Davenport M, De Ville de Goyet J, Stringer MD, et al. Seamless management of biliary atresia in england and wales (1999-2002). Lancet. 2004;363(9418):1354-1357.
59. 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(9):1689-1694.
60. Nietgen GW, Vacanti JP, Perez-Atayde AR. Intrahepatic bile duct loss in biliary atresia despite portoenterostomy: A consequence of ongoing obstruction? Gastroenterology. 1992;102(6):2126-2133.
61. European Liver Transplant Registry. http://www.eltr.org/spip.php?article178. Accessed January/22, 2012.
62. Scheenstra R, Peeters PM, Verkade HJ, Gouw AS. Graft fibrosis after pediatric liver transplantation: Ten years of follow-up. Hepatology. 2009;49(3):880-886.
63. Ng VL, Fecteau A, Shepherd R, et al. Outcomes of 5-year survivors of pediatric liver transplantation: Report on 461 children from a north american multicenter registry. Pediatrics. 2008;122(6):e1128-35.
64. Serinet MO, Wildhaber BE, Broue P, et al. Impact of age at kasai operation on its results in late childhood and adolescence: A rational basis for biliary atresia screening. Pediatrics. 2009;123(5):1280-1286.
65. Hsiao CH, Chang MH, Chen HL, et al. Universal screening for biliary atresia using an infant stool colour card in taiwan. Hepatology. 2008;47(4):1233-1240.
66. Schreiber RA, Barker CC, Roberts EA, et al. Biliary atresia: The canadian experience. J Pediatr. 2007;151(6):659-65, 665.e1.
67. Chardot C, Buet C, Serinet MO, et al. Improving outcomes of biliary atresia: French national series 1986-2009. J Hepatol. 2013;58(6):1209-1217.
68. Tiao MM, Tsai SS, Kuo HW, Chen CL, Yang CY. Epidemiological features of biliary atresia in taiwan, a national study 1996-2003. J Gastroenterol Hepatol. 2008;23(1):62-66.
69. Carvalho E, Santos JL, Silveira TR, et al. Biliary atresia: The brazilian experience. J Pediatr (Rio J). 2010;86(6):473-479.
1
70. Lien TH, Chang MH, Wu JF, et al. Effects of the infant stool colour card screening program on 5-year outcome of biliary atresia in taiwan. Hepatology. 2011;53(1):202-208.
71. de Vries W, de Langen ZJ, Groen H, et al. Biliary atresia in the netherlands: Outcome of patients diagnosed between 1987 and 2008. J Pediatr. 2011.
72. Chiu CY, Chen PH, Chan CF, Chang MH, Wu TC, Taiwan Infant Stool Colour Card Study Group. Biliary atresia in preterm infants in taiwan: A nationwide survey. J Pediatr. 2013;163(1):100-3.e1.
73. Davenport M, De Ville de Goyet J, Stringer MD, et al. Seamless management of biliary atresia in england and wales (1999-2002). Lancet. 2004;363(9418):1354-1357.
74. Lampela H, Ritvanen A, Kosola S, et al. National centralization of biliary atresia care to an assigned multidisciplinary team provides high-quality outcomes. Scand J Gastroenterol. 2012;47(1):99-107.
75. Leonhardt J, Kuebler JF, Leute PJ, et al. Biliary atresia: Lessons learned from the voluntary german registry. Eur J Pediatr Surg. 2011;21(2):82-87.
76. Tseng JJ, Lai MS, Lin MC, Fu YC. Stool colour card screening for biliary atresia. Pediatrics. 2011.
77. Chang MH. Screening for biliary atresia. Chang Gung Med J. 2006;29(3):231-233. 78. Schreiber RA, Masucci L, Kaczorowski J, et al. Home-based screening for biliary
atresia using infant stool colour cards: A large-scale prospective cohort study and cost-effectiveness analysis. J Med Screen. 2014;21(3):126-132.
79. Morinville V, Ahmed N, Ibberson C, et al. Home-based screening for biliary atresia using infant stool colour cards in canada: Quebec feasibility study. J Pediatr Gastroenterol Nutr. 2016;62(4):536-541.
80. Santos JL, Carvalho E, Bezerra JA. Advances in biliary atresia: From patient care to research. Braz J Med Biol Res. 2010;43(6):522-527.
81. Wildhaber BE. Screening for biliary atresia: Swiss stool colour card. Hepatology. 2011;54(1):367-8; author reply 369.
82. Gu YH, Yokoyama K, Mizuta K, et al. Stool colour card screening for early detection of biliary atresia and long-term native liver survival: A 19-year cohort study in japan. J Pediatr. 2015;166(4):897-902.e1.
83. von Kries R, Shearer M, McCarthy PT, Haug M, Harzer G, Gobel U. Vitamin K1 content of maternal milk: Influence of the stage of lactation, lipid composition, and vitamin K1 supplements given to the mother. Pediatr Res. 1987;22(5):513-517.
84. Shearer MJ. Vitamin K deficiency bleeding (VKDB) in early infancy. Blood Rev. 2009;23(2):49-59.
85. Sutor AH, von Kries R, Cornelissen EA, McNinch AW, Andrew M. Vitamin K deficiency bleeding (VKDB) in infancy. ISTH pediatric/perinatal subcommittee. international society on thrombosis and haemostasis. Thromb Haemost. 1999;81(3):456-461. 86. van Hasselt PM, de Koning TJ, Kvist N, et al. Prevention of vitamin K deficiency
bleeding in breastfed infants: Lessons from the dutch and danish biliary atresia registries. Pediatrics. 2008;121(4):e857-63.
87. Loughnan PM, McDougall PN. Epidemiology of late onset haemorrhagic disease: A pooled data analysis. J Paediatr Child Health. 1993;29(3):177-181.
88. von Kries R. Oral versus intramuscular phytomenadione: Safety and efficacy compared. Drug Saf. 1999;21(1):1-6.
89. Sutor AH, Dagres N, Niederhoff H. Late form of vitamin K deficiency bleeding in germany. Klin Padiatr. 1995;207(3):89-97.
90. de Winter JP, Joosten KF, Ijland MM, et al. New dutch practice guideline for administration of vitamin K to full-term newborns. Ned Tijdschr Geneeskd. 2011;155(18):A936.
91. de Vries W, de Langen ZJ, Groen H, et al. Biliary atresia in the netherlands: Outcome of patients diagnosed between 1987 and 2008. J Pediatr. 2012;160(4):638-644.e2.
92. 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(1):75-84. 93. Schreiber RA, Barker CC, Roberts EA, Martin SR, Canadian Pediatric Hepatology
Research Group. Biliary atresia in canada: The effect of centre caseload experience on outcome. J Pediatr Gastroenterol Nutr. 2010;51(1):61-65.
94. Wildhaber BE, Majno P, Mayr J, et al. Biliary atresia: Swiss national study, 1994-2004. J Pediatr Gastroenterol Nutr. 2008;46(3):299-307.
95. Davenport M, Tizzard SA, Underhill J, Mieli-Vergani G, Portmann B, Hadzic N. The biliary atresia splenic malformation syndrome: A 28-year single-center retrospective study. J Pediatr. 2006;149(3):393-400.
96. Davenport M. Biliary atresia: Clinical aspects. Semin Pediatr Surg. 2012;21(3):175-184. 97. Nizery L, Chardot C, Sissaoui S, et al. Biliary atresia: Clinical advances and perspectives.
Clin Res Hepatol Gastroenterol. 2016;40(3):281-287.
98. Caponcelli E, Knisely AS, Davenport M. Cystic biliary atresia: An etiologic and prognostic subgroup. J Pediatr Surg. 2008;43(9):1619-1624.
99. Chung PH, Wong KK, Tam PK. Predictors for failure after kasai operation. J Pediatr Surg. 2015;50(2):293-296.
100. Decharun K, Leys CM, West KW, Finnell SM. Prophylactic antibiotics for prevention of cholangitis in patients with biliary atresia status post-kasai portoenterostomy: A systematic review. Clin Pediatr (Phila). 2016;55(1):66-72.
101. Stringer MD, Davison SM, Rajwal SR, McClean P. Kasai portoenterostomy: 12-year experience with a novel adjuvant therapy regimen. J Pediatr Surg. 2007;42(8):1324-1328.
102. Meyers RL, Book LS, O’Gorman MA, et al. High-dose steroids, ursodeoxycholic acid, and chronic intravenous antibiotics improve bile flow after kasai procedure in infants with biliary atresia. J Pediatr Surg. 2003;38(3):406-411.
103. Shneider BL, Brown MB, Haber B, et al. A multicenter study of the outcome of biliary atresia in the united states, 1997 to 2000. J Pediatr. 2006;148(4):467-474.
104. van der Doef HPJ, van Rheenen PF, van Rosmalen M, Rogiers X, Verkade HJ, pediatric liver transplantation centers of Eurotransplant. Waiting list mortality of young patients with biliary atresia: Competing risk analysis of an eurotransplant
registry-1
105. Duche M, Habes D, Roulleau P, Haas V, Jacquemin E, Bernard O. Prophylactic endoscopic sclerotherapy of large esophagogastric varices in infants with biliary atresia. Gastrointest Endosc. 2008;67(4):732-737.
106. Kobayashi H, Stringer MD. Biliary atresia. Semin Neonatol. 2003;8(5):383-391.
107. Shneider BL, de Ville de Goyet J, Leung DH, et al. Primary prophylaxis of variceal bleeding in children and the role of MesoRex bypass: Summary of the baveno VI pediatric satellite symposium. Hepatology. 2016;63(4):1368-1380.
Early detection of neonatal cholestasis:
inadequate assessment of stool colour by parents
and youth healthcare doctors
Mauri Witt, Jeanet Lindeboom, Corry Wijnja, Anneke Kesler,
Claudia M. G. Keyzer-Dekker, Henkjan J. Verkade, Jan B. F. Hulscher Eur J Pediatr Surg 2016;26:67–73. doi: 10.1055/s-0035-1566101.
ABSTRACT
Introduction
Early diagnosis and surgery (< 60 days of age) improve outcomes in children with biliary atresia. Only 56% of patients undergo timely surgery in the Netherlands. Lack of acquaintance with symptoms such as discoloured stools might underlie this delay. We analysed whether Dutch parents, youth healthcare doctors, or general practitioners recognised discoloured stools and evaluated the effect of the Infant Stool Colour Card (ISCC) on recognising discoloured stools.
Material and Methods
We asked 100 parents, 33 youth healthcare doctors, and 50 general practitioners to classify photographs of stools as “normal” or “abnormal.” Subsequently, we asked whether parents would seek medical help and doctors would refer the patient for medical investigation. Finally, parents scored stools using the ISCC.
Results
Two-third of both parents and youth healthcare doctors recognised all discoloured stools. Only half of them would seek medical help for all discoloured stools resp. refer patient for medical investigation. Only one-third of the general practitioners recognised all discoloured stools and would refer for medical investigation for all discoloured stools. Using the ISCC, the percentage of parents recognising all discoloured stool increased from 66 to 87% (p < 0.01).
Conclusion
Neither parents nor youth healthcare doctors nor general practitioners reliably recognise discoloured stool. The ISCC is an effective screening method for discoloured stool. Our data indicate that the ISCC should be accompanied by unequivocal advices regarding referral for medical investigation upon detection of discoloured stools.
2
INTRODUCTION
Biliary atresia (BA) is a rare but life-threatening disease presenting in early infancy. The aetiology of this disease is still unknown.1 Progressive fibro-obliteration of all or part of the extrahepatic biliary tree leads to cholestasis and liver cirrhosis and if left untreated, to death within 2 to 3 years.1,2 The incidence of BA varies from 1:5,000 to 6,600 live births in Taiwan to 1:17,000 to 19,000 live births in Western Europe.3–7 The “Kasai (hepato) portoenterostomy” is considered the gold standard of treatment for BA.1,2 Restoration of bile flow from the liver to the proximal small bowel is attempted by creating a Roux-en-Y loop of bowel that is directly anastomosed to the hilum of the liver, following excision of the biliary remnant and portal fibrous plate.2 If the Kasai procedure fails to restore bile flow, or if cirrhosis progresses, liver transplantation may be needed. BA is the most common indication for liver transplantation in children worldwide, accounting for 74% of transplantations in children younger than 2 years.8 However, successful Kasai
surgery can postpone and even prevent the need for liver transplantation.9
A timely Kasai portoenterostomy (e.g., < 60 postnatal days) results in higher rates of sufficient bile drainage and longer transplant-free survival.2–4,10,11 To allow timely surgery, early identification and diagnosis of children with BA is crucial. Unfortunately, only 56% of all children with BA in the Netherlands undergo surgery before the age of 60 days.5 Insufficient recognition of the early symptoms of neonatal cholestasis might underlie this delay. Most parents might not be alarmed by prolonged jaundice, which is usually mild, and might not recognise
pale-coloured stools; two of the most important symptoms of the disease.1 This
might also hold true for youth healthcare physicians and/or general practitioners. To establish early recognition and diagnosis of the disease, the Infant Stool Colour Card (ISCC) was developed and launched in Taiwan in 2004.3,9 It has been described as a simple, cost-effective, and convenient screening method for BA and appears to be a sensitive and specific screening method for BA in infants.3,9,12,13 The percentage of children who underwent Kasai surgery before 60 days of age significantly increased in Taiwan during the stool card screening era and more importantly, the 3- and 5 year survival rates with native liver improved significantly.9
In this study, we analysed the following:
1. Whether Dutch parents, youth healthcare doctors, or general practitioners recognise discoloured stools.
2. Whether parents would seek medical help for discoloured stool and whether
youth healthcare doctors or general practitioners would refer patients with discoloured stool for further medical investigation.
3. Whether the use of the ISCC could improve the recognition of discoloured stool by Dutch parents.
MATERIAL AND METHODS
Research design
The Medical Ethics Committee of the University Medical Center Groningen approved the study. A regional pilot study was conducted under Dutch parents and caretakers of infants aged 3 to 6 weeks. Between April and June 2014, all parents who visited one of two youth health clinics in Groningen for the routine 1-month health check were invited to participate. Information about the purpose of our research was limited to “research on recognition of abnormal and normal stools by parents.” Exclusion criteria were colour blindness, blindness or having very poor eyesight, and mental retardation of the parent. Subsequently, we performed an electronic survey among youth healthcare doctors and general practitioners. All Dutch youth healthcare doctors who attended a national convention in November 2014 were asked to participate in an online questionnaire on the recognition of neonatal cholestasis. General practitioners were recruited per mail using the senior authors’ professional network.
Parents were shown a total of 10 colour photographs of different coloured stool samples from Dutch infants: 6 with normal stool colours and 4 showing abnormal, discoloured stools, varying from almost white stools to pale beige (Figure 1). First, we showed the photographs successively and parents classified the stool on the photograph as “normal” or “abnormal.” Second, parents were asked whether similar stools would be a reason for them to seek medical advice. Third, they scored the same photographs using the ISCC. Participants were asked which number on the stool card was most similar to the stools on the photograph. All participants were asked to fill in a short questionnaire, to define participant characteristics, such as gender, age, level of education, and number of children.
2
For the second part of the study, we sent an online questionnaire to youth healthcare doctors and general practitioners across the Netherlands. The questionnaire included eight questions on neonatal jaundice and discoloured stools. Subsequently, the same 10 stool photographs as mentioned earlier were shown. We asked participants to classify the stool on the photograph as “normal’ or “abnormal” and whether they would refer an infant with similar stools for further medical investigation.
STUDY INSTRUMENTS
Photographs
All of the stool photographs were taken in the University Medical Center Groningen, using either an Apple iPhone 4S or Apple iPhone 5S iSight camera (both 8 MP, Apple Inc. Cupertino, California, United States). All photographs were taken without flash. All diapers were from children aged 2 to 12 weeks. The photographs of the discoloured stools were from infants with surgically confirmed BA, or neonatal cholestasis by another cause, such as total parenteral nutrition (TPN)- associated cholestasis. For this study, 10 photographs of high quality were carefully selected, so that every stool colour of the ISCC would be represented at least once (Figure 1). We used PiCasa (image organizer and image viewer, version 3.8. Google) for cropping and reduction of colour alteration due to indoor lights. Size of the photographs was A6 (105x48 mm/4.1x5.8 in); roughly the size of (the inside of) a diaper.
*Discoloured stool
Figure 1: Photographs of stools used in study.
Infant Stool Colour Card (“Taiwan Stool Colour Card”)
The ISCC consists of seven photographs of different coloured stool samples from infants. Three colours (1–3) on this card can be considered abnormal (clay-coloured, pale yellowish, and light-yellowish), whereas the other four are considered normal (yellowish, dark-yellowish, brown, and greenish). We used the ISCC without the usual information that is provided on the card and without any text, so that only the seven images of different coloured stool samples and their numbers were visible (Figure 2).
Figure 2: Infant Stool Colour Card/Taiwan Stool Colour Card.
Statistical Procedures
Statistical analyses were performed using SPSS (IBM Corp. Released 2013. IBM-SPSS Statistics for Windows, Version 22.0. Armonk, NY: IBMCorp). Descriptive analyses were performed to describe sociodemographic characteristics. We divided ISCC numbers 1 to 7 into two separate groups: “discoloured stools” (numbers 1–3) and “normal coloured stools” (numbers 4–7). To compare recognition of abnormal stools before and with using the ISCC, we used McNemar test. Sensitivity and specificity of the ISCC used by parents were calculated. In this study, a p-value < 0.05 was considered statistically significant.
RESULTS
In the first pilot study, 100 parents participated. The median age of participants was 32 years (range 22–55). The study population included 32 male (32%) and 68 female (68%) participants. Of the participants, 92% were Caucasian and 66% received higher professional education or scientific education (Table 1). For the second study, 33 youth healthcare doctors completed all questions concerning the stool photographs. The median age was 48 years (range 31–64). The study sample included 1 male (3%) and 30 female (91%) participants; of 2 (6%) participants, the gender was unknown. We included 50 general practitioners. The median age was 36 years (range 28–65). The study sample included 9 (18%) male and 40 (80%) female participants; 1 (2%) participant did not list his or her gender.
Recognition of discoloured stools
Of all parents, 66% classified all discoloured stools correctly as “abnormal” and 8% of them also classified all coloured stools correctly as “normal”. Sixty-one per cent of all youth healthcare doctors classified all discoloured stools correctly as “abnormal,” and 18% of them also classified all coloured stools correctly as “normal.” Thirty-six per cent of all general practitioners classified all discoloured stools correctly as “abnormal,” and 22% of them classified all 10 photographs correctly. Another 26% of parents, 27% of youth healthcare doctors, and 22% of general practitioners recognised three out of the four discoloured samples correctly and 8, 12, and 42%, respectively, recognised two or less. Forty-nine per cent of all parents would seek medical help for all discoloured stools, 26% for three
2
Fifty-five per cent of the youth healthcare doctors would refer a child for all discoloured stools, 27% for three out of four, and 18% for two or less. Thirty-two per cent of the general practitioners would refer a child for all discoloured stools, 18% for three out of four, and 50% for two or less (Figure 3).
The photographs of discoloured stools numbers 6 and 10 (Figure 1) were the most difficult for parents to classify correctly (Figure 4). For youth healthcare doctors and general practitioners photograph numbers 4 and 6 were the most difficult to correctly recognise as abnormal (Figures 5 and 6). Photographs of normal coloured stools were classified abnormal by parents in 44%, by youth healthcare doctors in 21%, and by general practitioners in 19% of cases. Especially, number 7 and number 9 (Figure 1) were often wrongly classified (Figures 4–6).
Infant Stool Colour Card (“Taiwan Stool Colour Card”)
Using the ISCC, correct recognition of all discoloured stools by parents improved from 66 to 87% (p=0.001, Figure 3). Sensitivity and specificity of the ISCC for recognition of discoloured stools were 97 and 99%, respectively (Figure 4).
Table 1: Parent characteristics
N = 100
Gender Female 68
Male 32
Median age (years) 32 (22-55)
Ethnicity Dutch 83 European other 9
Asian 4
Antillean 2
Other 2
Level of education Primary/High school 9 Intermediate professional education 25 Higher professional education 30 Scientific education (University) 36
Number of children One 59
Two 32
Figure 3: Recognition of all four photographs of discoloured stools by parents and primary healthcare doctors.
2
*Discoloured stool Figure 4:
The assessment of different stool colours by parents.
*Discoloured stool Figure 5:
The assessment of different stool colours by youth healthcare doctors.
*Discoloured stool Figure 6:
DISCUSSION
BA is a leading cause of paediatric liver failure and liver transplantation. Poor outcomes due to delayed diagnosis are a problem worldwide.10,14 In the Netherlands, only half of all BA patients are operated before the recommended age of 60 days.5 An important part of this delay could be insufficient recognition of
the symptomsof neonatal cholestasis by parents and primary healthcare doctors.
Discoloured stool is an important symptom of BA.15 This pilot study was one of the first studies on the recognition of discoloured stools by parents, youth healthcare doctors, and general practitioners.
We found that neither parents nor youth healthcare doctors nor general practitioners were able to recognise discoloured stools reliably. Two-third of all parents and youth healthcare doctors and only one-third of the general practitioners recognised all discoloured stool samples. Our data are in line with the study of Bakshi et al., which shows how reliably paediatric professionals could identify pale stools from cholestatic newborns.16 They reported that 37.2% of doctors and nurses failed to identify a suspect stool. Our data support the hypothesis that insufficient recognition of discoloured stool by parents and primary healthcare doctors could contribute to the delay in the diagnosis of BA in the Netherlands. Therefore, a screening tool for discoloured stool is desirable. Furthermore, parents and primary healthcare doctors were not as alarmed as they should be by discoloured stools. Only half of the parents and youth healthcare doctors and only one-third of the general practitioners would seek medical help or refer the child for further medical investigation, respectively. Implementation of a screening tool should be accompanied by unequivocal advices with respect to referral for medical investigation upon the detection of discoloured stools.
In several countries, the “ISCC” (Taiwan Stool Colour Card) has proven to be a simple, very effective screening tool for discoloured stools.3, ,9,12,14 After implementation of the ISCC in Taiwan, the percentage of patients being operated within 60 days of age increased from 49 to 74% and 5-year transplant-free survival rates are more than doubled.3,9 Our study confirms that the ISCC is both sensitive and specific screening tools for discoloured stools and significantly improves parents’ recognition of discoloured stools from 66 to 87% (p = 0.001). Sensitivity and specificity of the ISCC as calculated in our study, 97 and 99%, respectively, are identical to those found in Taiwanese studies.3,17 Our findings support the concept that a simple screening tool such as the ISCC could help parents identify pale-pigmented stools from normal coloured stools. Besides helping parents in identifying abnormal, pale stools, we noticed during our pilot study that a stool colour card could also aid parents in identifying normal coloured stools.
2
In the Netherlands, all parents receive a “child health booklet” when their child is born, which is discussed at the first visit to the youth healthcare doctor at the age of 4 weeks. Since the routine 1-month health check would be an optimal time for identification of BA, we suggest adding the ISCC to the health booklet. Implementation of this screening method in the Netherlands might lead to earlier diagnosis, referral and treatment of BA, and thereby to significantly improved outcome.
We do realise that our study is based on a relatively small sample size. The vast majority of our sample consisted of highly educated Caucasian parents, which is not representative for the whole population and may have led to different results than in a larger, more representative sample. In this study, we asked parents to classify the stools as normal or abnormal. They were not informed that they had to judge the colour of the stools. It is possible that some parents have focused on consistency.
As only youth healthcare doctors who attended a national convention were included, there might be a selection bias in this sample. The results of these doctors might differ from doctors who are less interested in the subject, and therefore did not visit the convention.
In this study, we did not evaluate the effect of the ISCC when used in practice. Further research to the effect of implementation of the ISCC in the Netherlands is needed. The ISCC might also be a useful adjunct for youth healthcare doctors and general practitioners.
CONCLUSION
Our study shows that parents and primary healthcare doctors do not always recognise discoloured stools and do not always contact a doctor resp. refer a patient for further investigation. This might contribute to the late diagnosis of BA in the Netherlands. Implementation of a screening tool for discoloured stool could possibly significantly improve the time of diagnosis. Our data confirm that the ISCC is a simple and effective screening tool for discoloured stool, even when used by non-professionals. The 4-week check at the youth health clinic would be an ideal opportunity to test the colour of the stools. In this way, timely referral and treatment in case of suspected BA could be realised, which could significantly improve the outcome of children with BA.
Our data also indicate that the use of the ISCC should be accompanied by unequivocal advices with respect to referral for medical investigation upon the detection of discoloured stools.
Acknowledgment
The authors thank the staff at the youth health centres for their help in recruiting participants and also thank the nursing staff at the paediatric wards of the Beatrix Children’s Hospital (University Medical Center Groningen) for collecting all the diapers to photograph. They also thank the participants of this study. Also, the authors thank Professor Mei-Hwei Chang (College of Medicine, National Taiwan University and the Health Promotion Administration, Ministry of Health and Welfare, Taiwan) for agreeing us to use the Taiwan stool colour card.
2
REFERENCES
1. Hartley JL, Davenport M, Kelly DA. Biliary atresia. Lancet. 2009;374(9702):1704-1713. 2. Ohi R. Surgery for biliary atresia. Liver. 2001;21(3):175-182.
3. Hsiao CH, Chang MH, Chen HL, et al. Universal screening for biliary atresia using an infant stool color card in taiwan. Hepatology. 2008;47(4):1233-1240.
4. Lin YC, Chang MH, Liao SF, et al. Decreasing rate of biliary atresia in taiwan: A survey, 2004-2009. Pediatrics. 2011.
5. De Vries W, de Langen ZJ, Groen H, et al. Biliary atresia in the netherlands: Outcome of patients diagnosed between 1987 and 2008. J Pediatr. 2012;160(4):638-644.e2.
6. McKiernan PJ, Baker AJ, Kelly DA. The frequency and outcome of biliary atresia in the UK and ireland. Lancet. 2000;355(9197):25-29.
7. Chardot C, Carton M, Spire-Bendelac N, Le Pommelet C, Golmard JL, Auvert B. Epidemiology of biliary atresia in france: A national study 1986-96. J Hepatol. 1999;31(6):1006-1013.
8. European Liver Transplant Registry.http://www.eltr.org/spip.php?article178. Accessed January/22, 2012.
9. Lien TH, Chang MH, Wu JF, et al. Effects of the infant stool color card screening program on 5-year outcome of biliary atresia in taiwan. Hepatology. 2011;53(1):202-208.
10. Schreiber RA, Barker CC, Roberts EA, et al. Biliary atresia: The canadian experience. J
Pediatr. 2007;151(6):659-65, 665.e1.
11. Serinet MO, Wildhaber BE, Broue P, et al. Impact of age at kasai operation on its results in late childhood and adolescence: A rational basis for biliary atresia screening. Pediatrics. 2009;123(5):1280-1286
12. Tseng JJ, Lai MS, Lin MC, Fu YC. Stool color card screening for biliary atresia. Pediatrics. 2011.
13. Chang MH. Screening for biliary atresia. Chang Gung Med J. 2006;29(3):231-233. 14. Schreiber RA, Masucci L, Kaczorowski J, et al. Home-based screening for biliary
atresia using infant stool colour cards: A large-scale prospective cohort study and cost-effectiveness analysis. J Med Screen. 2014;21(3):126-132.
15. Lai MW, Chang MH, Hsu SC, et al. Differential diagnosis of extrahepatic biliary atresia from neonatal hepatitis: A prospective study. J Pediatr Gastroenterol Nutr. 1994;18(2):121-127.
16. Bakshi B, Sutcliffe A, Akindolie M, et al. How reliably can paediatric professionals identify pale stool from cholestatic newborns? Arch Dis Child Fetal Neonatal Ed. 2011. 17. Chen SM, Chang MH, Du JC, et al. Screening for biliary atresia by infant stool color
Prophylactic Dosing of Vitamin K
to Prevent Bleeding
Mauri Witt, Nina Kvist, Marianne Hørby Jørgensen, Jan B.F. Hulscher,
Henkjan J. Verkade, Also, on behalf of the Netherlands Study group of Biliary Atresia Registry (NeSBAR) Pediatrics 2016 May;137(5):10.1542/peds.2015-4222. (Adapted version) doi: 10.1542/peds.2015-4222.
ABSTRACT
Background and objectives
Based on a high incidence of Vitamin K deficiency bleeding (VKDB) in breastfed infants with thus far unrecognised cholestasis, such as biliary atresia (BA), the Dutch regimen to prevent VKDB in breastfed infants was changed from a daily oral dosage of 25 μg to 150 μg vitamin K. Infants continued to receive 1 mg of vitamin K orally at birth. We compared the efficacy of the 150-μg regimen with the 25-μg regimen and with the Danish regimen of a single intramuscular (IM) dose of 1 mg vitamin K at birth.
Methods
Data were retrieved from the national BA registries: 25 μg group (Netherlands, January 1991 to February 2011); 150 μg group (Netherlands, March 2011 to January 2015); and IM 1 mg group (Denmark, July 2000 to November 2014). We compared the incidence of VKDB in the groups.
Results
VKDB occurred in 45 of 55 (82%) infants of the 25 μg group, in 9 of 11 (82%) of the 150 μg group, but in only 1 of 25 (4%) of the IM 1 mg group (P < .001). Forty per cent of all infants of the 25 μg group had an intracranial haemorrhage as presenting symptom, compared with 27% of the infants of the 150 μg group (P = .43).
Intracranial haemorrhage was not observed in the IM 1 mg group (0%; P < .001).
Conclusions
A vitamin K prophylactic regimen of 1 mg of vitamin K orally at birth followed by a daily oral dosage of either 25 or 150 μg fails to prevent VKDB in breastfed infants with still unrecognised BA. The data support 1 mg vitamin K IM at birth as prophylaxis against VKDB.
3
INTRODUCTION
Vitamin K deficiency can cause severe bleeding in breastfed infants owing to insufficient amounts of vitamin K in breastmilk.1 This bleeding, known as vitamin K deficiency bleeding (VKDB), can be classified according to the time of presentation: early (<24 hours of age), classic (first week after birth), and late (between 1 week
and 6 months of age).2 In 50% of patients with late VKDB, the bleeding location
involves an intracranial haemorrhage, which is associated with high mortality and morbidity.3–5 The absorption of vitamin K is strongly dependent on the intestinal availability of bile acids. Diminished or absent intestinal delivery of bile, which occurs during cholestasis, puts infants especially at risk for malabsorption of vitamin K and other fat-soluble vitamins.6,7 Infants who have been breastfed exclusively are at the highest risk for late VKDB, particularly if the cholestasis has not yet been diagnosed.
Many countries have introduced prophylactic regimens of vitamin K supplementation to prevent VKDB (Table 1).8 The optimal dose, route, and frequency of administration of vitamin K, however, are still unclear. Oral and intramuscular (IM) regimens of vitamin K administration at birth have been proven effective in the prevention of classic VKBD.9 A single dose of IM vitamin K at birth
can also prevent late VKDB.10 Between 1990 and February 2011, all infants in the
Netherlands received a single oral dose of 1 mg vitamin K at birth, followed by a recommended daily oral supplementation of 25 μg vitamin K between week 2 and 13 in breastfed infants.11 This regimen significantly decreased the incidence of
late VKDB.12 Previously, however, we and others reported several cases of VKDB
based on surveillance studies and studies in high-risk populations, despite strong indications of adherence to the recommendations. In fact, in >80% of infants with biliary atresia (BA), severe late VKDB was the presenting symptom.13 This observation was in sharp contrast to a very low incidence of VKDB as presenting symptom in BA patients in Denmark, where other prophylactic vitamin K regimens
are used.14–17 The risk of VKDB in Dutch breastfed BA patients was 8 to 10 times
higher than that of Danish BA patients, on either a weekly oral dose of 1 mg vitamin K or a single IM dose of 1 mg vitamin K at birth. Since March 2011, the prophylactic regimen was changed in the Netherlands; the recommended daily oral dose of 25 μg vitamin K was increased to 150 μg daily for all breastfed infants from week 2 to 13 of life. The single oral dose of 1 mg vitamin K at birth was maintained.
In the current study, we evaluated the preventive effect of the adapted Dutch guideline with respect to the incidence and severity of VKDB as the presenting symptom in breastfed children with BA. We compared the incidence and severity of VKDB with the repeated oral 25 μg, repeated oral 150 μg, and single 1 mg IM regimens.
