Review
Biliary atresia and other cholestatic childhood diseases: Advances and future challenges
⇑ Henkjan J. Verkade1, , Jorge A. Bezerra2, Mark Davenport3, Richard A. Schreiber4, Georgina Mieli-Vergani5, Jan B. Hulscher6, Ronald J. Sokol7, Deirdre A. Kelly8, Benno Ure9, Peter F. Whitington10, Marianne Samyn5, Claus Petersen9
Summary Keywords: Biliary atresia; Alagille syndrome; Biliary diversion; Choledochal cyst; Choledochal Biliary Atresia and other cholestatic childhood diseases are rare conditions affecting the malformation; Liver transplantation; function and/or anatomy along the canalicular-bile duct continuum, characterised Progressive familial intrahepatic by onset of persistent cholestatic jaundice during the neonatal period. Biliary atresia cholestasis. (BA) is the most common among these, but still has an incidence of only 1 in Received 8 February 2016; received in 10–19,000 in Europe and North America. Other diseases such as the genetic conditions, revised form 26 April 2016; accepted 28 Alagille syndrome (ALGS) and Progressive Familial Intrahepatic Cholestasis (PFIC), are less April 2016 common. Choledochal malformations are amenable to surgical correction and require a high index of suspicion. The low incidence of such diseases hinder patient-based studies that include large cohorts, while the limited numbers of animal models of disease that recapitulate the spectrum of disease phenotypes hinders both basic research and the development of new treatments. Despite their individual rarity, collectively BA and other cholestatic childhood diseases are the commonest indications for liver transplantation during childhood. Here, we review the recent advances in basic research and clinical pro- gress in these diseases, as well as the research needs. For the various diseases, we formu- 1Department of Paediatrics, University of late current key questions and controversies and identify top priorities to guide future Groningen, Beatrix Children’s Hospital/ University Medical Center, Groningen, The research. Netherlands; Ó 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All 2Cincinnati Children’s Hospital Medical rights reserved. Center, Cincinnati, OH, USA; 3Department of Paediatric Surgery, King’s College Hospital, Denmark Hill, London, UK; Diagnostic developments for neonatal cholestasis 4Department of Paediatrics, University of British Columbia, Vancouver, Canada; 5Paediatric Liver, GI & Nutrition Centre, Key questions Benign physiological or breast-milk associated King’s College London School of Medicine unconjugated hyperbilirubinemia with normal at King’s College Hospital, London, UK; Which strategies can enhance earlier color stools and urine is frequent, so the presence 6Department of Paediatric Surgery, recognition of neonatal cholestasis, of acholic stools and pigmented urine should University of Groningen, Beatrix Children’s including biliary atresia (BA)? raise suspicion of liver disease in all jaundiced Hospital-University Medical Center, Groningen, The Netherlands; What is the value of abdominal ultra- babies. Unfortunately, however, these symptoms 7Section of Paediatric Gastroenterology, sound, nuclear isotope excretion scan, can appear relatively late in biliary atresia (BA) Hepatology, and Nutrition, Department of liver biopsy and endoscopic retrograde and may go unrecognised. Thus, it has been Paediatrics, University of Colorado School Review cholangiopancreatography (ERCP) in the recommended by the American Academy of of Medicine, Digestive Health Institute, diagnostic work up? Children’s Hospital Colorado, Aurora, CO, Pediatris that all infants with jaundice persisting USA; beyond 2–3 weeks of age should have conju- 8Liver Unit, Birmingham Children’s BA prognosis relates to timely surgical correc- gated/direct bilirubin measured to identify those Hospital NHS Trust, Birmingham, UK; tion and therefore early diagnosis is mandatory infants with cholestasis who require further 9Department of Paediatric Surgery, (ideally before 30 days of age). Various diagnostic evaluation in a referral unit [4], which should Hannover Medical School, Hannover, Germany; algorithms have been proposed [1–3]. A prompt have the capacity to perform radiological imag- 10Department of Paediatrics, Ann & Robert diagnosis relies on the basic recognition that ing, liver biopsy interpretation and exclusion of H. Lurie Children’s Hospital of Chicago, the infant has conjugated hyperbilirubinemia. genetic conditions mimicking BA within a few Chicago, IL, USA
Journal of Hepatology 2016 vol. 65 j 631–642 Review days. Despite these recommendations, the inherited cholestasis may take several weeks, Key point average age at diagnosis and treatment of BA they are not included in the typical diagnostic ( 60 days) has not changed over the past algorithm for BA. Novel mechanisms have been identified in the pathophysiol- 20 years in the United States and many other ogy of these diseases, including countries [5,6], and only decreased to some Top priorities for enhancing early diagnosis of the roles of viral infections, extent in the United Kingdom [7]. neonatal cholestasis immune dysregulation, gene New strategies to screen for neonatal polymorphisms and toxins. cholestasis are clearly needed to enhance early We recommend a broader implementa- diagnosis of BA. One such method is the provi- tion of screening strategies, in particular sion of stool color cards to parents of newborns the stool color card, with implementation for identification of acholic stools. Routine that is tailored to country-specific infant screening for BA with stool color cards started care models. Educating parents of new- in Japan in the 1990s [8], and was later intro- borns is essential to the success of the duced nationwide in Taiwan [9] and in Switzer- stool color card program. To minimise land [10]. In Taiwan, five years after starting diagnostic delay, patients with neonatal the stool color card screening, the rate of Kasai cholestasis should be evaluated in (or hepatoportoenterostomy (KPE) at <60 days under guidance of) an experienced center increased from 49% to 66%; the jaundice free rate that can complete the evaluation rapidly at 3 months after surgery from 35% to 61%, and and, if indicated, can perform an intraop- the 5-year survival with native liver from 27% erative cholangiogram and KPE without to 64% [9]. As reported by Matsui, a program delay. involving 313,230 infants in Japan’s Tochigi Pre- fecture between 1994 and 2011 – with an 84% card return rate – demonstrated a sensitivity, Advancing the prognosis of biliary atresia specificity, positive predictive value, and nega- tive predictive value for BA of 77%, 99.9%, 13%, Key questions and 99.9% respectively, with a native liver sur- vival of BA children at 5, 10 and 15 years of To what extent has the prognosis of BA 88%, 77% and 49% [11]. Recently, a large-scale been characterised among different cen- prospective study demonstrated the practicality ters and countries? How has this evolved and cost effectiveness of the stool color card over time? [12]. However, the success of a stool color card What are the major causes and predictors program may be more limited in countries with- of morbidity and mortality of patients out routine 30-day old well-child visits for with BA? review of the stool color card. Finally, the possi- Is centralized care essential for improv- bility of using direct/conjugated serum bilirubin ing prognosis? measurements in newborns to screen for BA has recently been proposed [13] and is being pur- Paediatric registries have proven useful for sued in different centers. detailing epidemiology of BA and for benchmark- The diagnostic role of endoscopic retrograde ing both their short and long-term outcomes Abbreviations: ALGS, Alagille syndrome; cholangiopancreatography (ERCP) remains con- [7,19–23]. The UK registry was the basis for the BARD, Biliary Atresia and Related troversial. In some centers with particular exper- Diseases; PFIC, Progressive Familial first report of a significantly higher post-KPE Intrahepatic Cholestasis; KPE, Kasai tise, ERCP is used as a first-line diagnostic tool jaundice free survival rate in high (>5 cases/year) hepatoportoenterostomy; NeSBAR, [14,15], while in others it is limited to cases vs. low surgical volume centers resulting in cen- Netherlands Study group for Biliary where the diagnosis remains doubtful after stan- tralization of KPE surgery to only 3 high volume Atresia Registry; ChiLDReN, Childhood dard diagnostic tests (typically liver biopsy) [16]. centers [20,24]. In contrast, France has a decen- Liver Disease Research Network; ERCP, Some centers rely heavily on ultrasound findings endoscopic retrograde tralised policy for the care of BA [6]. The national Review cholangiopancreatography; START, for the diagnosis of BA, including the ‘‘triangular institutes of health sponsored childhood liver Steroids in Biliary Atresia Randomised cord” sign [17]. Most centers, however, consider disease research network (ChiLDReN) is a consor- Trial; BASM, Biliary Atresia Splenic ultrasound a complementary investigation, rely- tium of 16 specialised centers in North America Malformation syndrome; ASBT, apical ing mostly on histological findings (liver biopsy) sodium dependent bile acid transporter; (www.childrennetwork.org), using similar clini- CM, choledochal malformation; GGT, and exclusion of genetic disorders mimicking BA cal care protocols (without centralizing care) gamma glutamyltransferase. [18] in decision making for exploratory surgery. within prospective longitudinal study of 8 rare Nuclear isotope excretion scans are no longer fre- ⇑ Corresponding author. Address: liver diseases, evaluating and tracking BA out- Department of Paediatrics, University of quently used: the absence of excretion into the comes and their predictors [25]. Table 1 Groningen, Beatrix Children’s Hospital/ intestines does not confirm BA. After the identifi- describes outcomes in several other disease reg- University Medical Center, P.O. cation of cholestasis in an infant, diagnostic eval- istries, national or otherwise. Box 30.001, 9700 RB Groningen, The uation that would yield the diagnosis of BA The French registry reported a BA incidence of Netherlands. Tel.: +31 50 361 4147; fax: +31 50 3611704 should be completed within one week in order 1:19,400 live births [26], similar to other reports E-mail address: [email protected] to expedite early surgery (before 35 days). Rec- from western Europe and Canada, and somewhat (H.J. Verkade). ognizing that genetic tests for syndromes of lower than the incidence in USA [19,21,22,25,27].
632 Journal of Hepatology 2016 vol. 65 j 631–642 JOURNAL OF HEPATOLOGY
Table 1. Overview of national or multicenter registries on biliary atresia, based on published reports. Biliary atresia registries, national or otherwise.
Country, period, and No. of centers No. of No. of Age at KPE days Primary Survival Survival with Jaundice free Reference Follow-up (median, range) patients KPE (in average) LTx overall native liver after KPE* Canada, 1992-2002, 3 centers 230 207 64 10% 83% (1) 39% (1) n.a. [23] Follow-up 5.5 years (0.4-14.2 years) France, 1986-2009, 45 centers 1107 1044 59 4% 79% (2) 40% (3) 38% (4) [6] Follow-up 9.5 years (0.3-24.6 years) Germany, 2001-2015, 29 centers 183 159 57 11% 83% (5) 20% (5) 18% (5) [111] Follow-up 3.3 years (2.1-7.1) Japan, 1989-1999, 93 centers 1381 1181 n.a. 0.1% 75% (3) 60% (3) 57%** (4) [28] Follow-up 5 resp. 10 years# Netherlands, 1987-2008, 6 centers 231 214 59 3% 73% (1) 46% (1) 36% (1) [21] Follow-up 6.9 years (0.1-21.9 years) Switzerland, 1994-2004, 7 centers 48 43 68 10% 92% (3) 37% (3) 37% (3) [112] Follow-up 4 years#* UK&, 1999-2009, 3 centers 443 424 54 3% 89% (6) 46% (1) 55% (7) [7] Follow-up 4 years USA/Biliary Atresia Research Consortium, 104 104 61 n.a.## 87% (5) 56% (5) 38% (7) [25] 1997-2000; 9 centers (not a national registry) Follow-up 2 years#
&United Kingdom (England and Wales); ⁄jaundice free defined as bilirubin <20 lmol/l; ⁄⁄jaundice free defined as bilirubin <34.2 lmol/l; #length of total follow-up not available; ##patients not undergoing KPE had been excluded; (1)4 years; (2)at last follow-up; (3)5 years; (4)undefined period; (5)2 years; (6)10 years; (7)6 months. KPE, Kasai hepatic portoenterostomy; LTx, liver transplantation; n.a., not available.
However, these rates are much lower than those What can be learned from variance in reported from Asia (e.g., Japan, 1:9,640) [28] and outcome of BA and KPE among different in the smaller populations of French Polynesia centers and countries? (1:3,401) [29] and the Maoris of New Zealand (1:3,124) [30]. The reasons for this remain The most important advances for the long- obscure. term prognosis of BA have been the development of KPE [32] and of paediatric liver transplanta- Top priorities for advancing the prognosis of biliary tion. The development of effective medical atresia treatments following KPE to delay need for liver transplantation has been limited. Davenport To study the relationships between clini- et al. reported a randomised, double-blind cal and therapeutic interventions and placebo-controlled trial of oral prednisolone outcomes through expanding the reach treatment vs. placebo in BA patients post-KPE and depth of data in databases. Expanded [33]. The steroid regime did not reduce the need databases in BA will also facilitate collab- for liver transplantation within 1 year, but sub- orative studies to ‘‘enable better assess- group analysis suggested beneficial effects on ment of disease risk, understanding of serum bilirubin in infants aged less than 70 days disease mechanisms, and prediction of at KPE. In a follow-up open-labeled study in optimal therapy” – as proposed by the young BA patients (<70 days at KPE), this obser- National Institute of Health of the USA vation was confirmed together with a statisti- [31]. The recently launched online reg- cally significant increase in the proportion able istry ‘‘bard-online” (www.bard-online.- to clear their jaundice. Despite this, there was com) might aid in the collection of no statistical difference in either 4-year patient
multinational data, including from coun- survival or native liver survival [34]. Review tries without registries. In the largest randomised controlled double- blind clinical trial in BA thus far, Bezerra et al. studied the effects of a 13 week course of steroids on clearance of jaundice with native liver Treatment of biliary atresia after Kasai at 6 months after KPE. This began with 4 weeks portoenterostomy of high dose intravenous or oral methylpred- nisolone vs. placebo [35]. The clearance of jaun- Key questions dice was not statistically different between the two groups, but a small clinical benefit could not Which strategies following the Kasai por- be excluded. Survival with native liver at 2 years toenterostomy (KPE) may delay or pre- was virtually identical between the treatment vent the need for liver transplantation? and control groups. Earlier onset of serious What are accepted prognostic parame- adverse events occurred during treatment in the ters for long-term success of KPE? steroid group compared to the placebo group,
Journal of Hepatology 2016 vol. 65 j 631–642 633 Review raising concerns for high dose steroid therapy in Developments in understanding of the the face of no demonstrable benefit. pathogenesis of biliary atresia Some other drugs have been hypothesised to modify the prognosis of BA including antibiotics Key questions/controversies (administered in the immediate post-operative period after KPE or as prolonged prophylaxis What are the genetic susceptibility fac- against cholangitis) and choleretic agents, such tors for BA? as ursodeoxycholic acid. However, there are no Which viruses may trigger BA and does published randomised controlled or pragmatic viral infection occur prenatally? clinical trials post-KPE that are statistically pow- Does immune dysregulation or autoim- ered to firmly support either antibiotic treatment munity play a role in the progressive bile or choleretic agents. Current use of these agents duct injury after KPE? is therefore opinion- and center-based rather Do the intestinal microbiome and innate than evidence-based. immunity play a role in BA pathogenesis The available trials indicate that age at sur- and the rapid progression of fibrosis, gery may influence the responsiveness to treat- even after successful KPE? ment. It has recently been proposed that the Is there evidence that a toxin or vascular presence of cytomegalovirus IgM-positivity insult causes human BA? defines a phenotype of BA with inferior out- comes [36]. Thus, age at KPE and evidence of There are several phenotypes of BA, each cytomegalovirus infection should be considered likely with its own etiology and mechanistic when establishing inclusion and exclusion crite- underpinning. Genetic expression studies com- ria of future study designs. Another factor that bined with histologic examination of hepatobil- may influence the (lack of) therapeutic response iary tissues at diagnosis suggest that there may to steroids in BA is the stage of disease, such as be inflammatory and fibrosing subtypes of BA, advanced fibrosis in patients older than 70 days each with its own pattern of progression. There of age at KPE. Recently, an unprecedented high are subtypes of BA associated with congenital success rate has been reported with respect to malformations (fetal or embryonic BA) suggest- long-term native liver survival in Japan after ing abnormal bile duct morphogenesis in the portoenterostomy: 88%, 77% and 49% at 5, 10 etiology of BA. Biliary atresia splenic malforma- and 15 years, respectively [11]. It is still unclear tion syndrome (BASM; about 4–14% of cases) is whether existing practices and techniques in associated with laterality defects, which sug- Japan could be helpful in improving global out- gest a genetic or epigenetic etiology [37,38]. comes of patients with BA. It cannot be Other subtypes include the presence of major excluded that differences in genetic background congenital malformations without laterality or environmental factors account for the defects (<5% of cases), or those with laterality improved prognosis. defects but without splenic malformation (<5% of cases) [39,40]. Finally, a so called cystic bil- iary atresia has recently been described in up Top priorities for improving the treatment success to 8% of BA [41], which includes the presence of biliary atresia after Kasai portoenterostomy of a cyst within an otherwise obliterated biliary tree. The high success rates recently reported in The majority of BA infants do not have con- Japan suggest that the prognosis of BA can be genital malformations (‘‘isolated BA”, formerly further improved. Top priorities for improving known as perinatal or acquired BA). Almost all the treatment success are: BA infants in fact have elevated serum direct bilirubin within the first 5 days of life [13], call- Review Identification of predictors of the respon- ing into question if perinatal cases are not indeed siveness to medical treatments after KPE, all prenatal in onset. Several susceptibility genes through analysis of clinical, laboratory, have been described based on GWAS and target- genetic and radiological characteristics. ing sequencing approaches [42–46]. There are at Studies of environmental, medical, and least two theories regarding pathogenesis of iso- surgical approaches that may be linked to lated BA, based on human observations and the variance in outcomes in different mouse models. A viral-induced, immune or centers and countries. autoimmune mediated inflammatory obstruction Exploration of new therapeutic strategies of the biliary tree is the most commonly accepted (e.g., anti-fibrotic drugs or farnesoid theory based on strong experimental evidence X-receptor agonists) that presently are in from the rhesus rotavirus (RRV) Balb/C newborn development, particularly in adult chole- mouse model [47–49]. Both T-cell [50,51] and B- static diseases, to assess their ability to cell-mediated autoimmunity [49,52] have been improve native liver survival. implicated as well as dysfunction of regulatory
634 Journal of Hepatology 2016 vol. 65 j 631–642 JOURNAL OF HEPATOLOGY
T-cells [53,54], activation of innate immunity Choledochal malformation and NK cells [55] and dendritic cells [56], activa- tion of a pro-inflammatory gene footprint in liver Key questions tissue [57] and the loss of cholangiocyte primary cilia [58]. Recently, the contribution of Does prenatally discovered choledochal interleukin-17 to the inflammation and destruc- malformation (CM) require a different tion of the biliary system has been demonstrated, treatment strategy than postnatally diag- both in infants with BA and in the RRV newborn nosed CM? mouse model [59,60]. What is the right timing of surgery in A more recent provocative toxin theory for BA patients with asymptomatic CM? pathogenesis is centered on a plant toxin (bilia- What is the life-long risk of bile duct tresone). It is proposed to be responsible for both malignancy in CM patients? the BA that occurs naturally in Australian live- stock, and for a BA-like lesion in zebrafish The diagnosis and treatment of CM has been [61,62]. Biliatresone appears to act by interfering rather controversial, probably due to the very with cholangiocyte polarity involving both Sox low incidence and the large variability in clinical and Notch pathways. Ongoing investigations will and anatomical presentation. CM can be diag- need to determine the mechanisms of bile duct nosed pre- or postnatally. The optimal mode of injury and obstruction by biliatresone and diagnostic imaging and time of surgical resection whether it is involved in human BA. remain unclear. Preliminary data from a recent Finally, a vascular hypothesis for biliary atre- Dutch survey highlight that magnetic resonance sia is based on the findings of anatomic variants cholangiopancreatography (MRCP) was routinely of hepatic artery and arterial hyperplasia in liver used in 71% and the more invasive ERCP in 29% of of some cases of human BA [63]. It is currently departments [65]. unclear however, whether vascular changes are The introduction of minimally invasive sur- causative, the result of injury or part of the gery has certainly changed the approach to CM. remodeling process [64]. Liem et al. confirmed the potential for excellent In summary, the available data point to roles results in 400 Vietnamese children using a of single nucleotide polymorphisms (e.g., CFC1 laparoscopic approach [66]. In a meta-analysis and ADD3 genes) and extrinsic factors (e.g., on 679 patients, Narayanan et al. reported no viruses and toxins) as susceptibility and/or trig- differences in the rates of bile leak, cholangitis, gering factors that target bile ducts. An initial operative time, hospital stay and reoperation injury may be accompanied by a dysregulated after laparoscopic hepaticoduodenostomy vs. or immature immune response that produces the fibrosing and obstructing phenotype of BA (Fig. 1). Potentially predisposing conditions
Top priorities to understand the pathogenesis of Intrauterine factors e.g. maternal diabetes biliary atresia Single-nucleotide Single-nucleotide polymorphism e.g. GPC1, ADD3, ARF6 Top priorities to increase the understanding of polymorphism CFC1 the pathogenesis are: e.g.