Atresia biliar no Brasil: onde estamos e para onde vamos

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Editorials
89
0021-7557/10/86-06/445
Jornal de Pediatria
Copyright © 2010 by Sociedade Brasileira de Pediatria
445
Caring for children brings many joys to the day of a
pediatrician: sound nutritional guidance to foster growth,
immunization to prevent infectious disease, timely use
of antibiotics for an acute illness. But the encounter with
an infant with jaundice and pale stools breaks a smooth
day and heightens the fear of danger: does the infant
have biliary atresia? Often, these
clinical signs develop in otherwise
asymptomatic infants and during a
time when parents are enjoying the
new family member. Yet, they may
represent the hallmarks of a disease
of devastating consequences to the
infant if untreated. And even when
treated, the diagnosis of biliary atresia
brings challenging times for the infant, for the family, and
for the pediatrician.
As the most common cause of pathologic jaundice in
infants, biliary atresia is an inammatory cholangiopathy
that destroys the epithelial lining of bile ducts, disrupts bile
ow, and promotes a brosing obstruction of extrahepatic
bile ducts. The etiology of biliary atresia is yet to be dened,
but the pathogenic mechanisms of the disease are tightly
linked to a robust response of the immune system that
targets the bile ducts.1,2 Among the elements of the system,
CD8+ and natural killer (NK) lymphocytes have been shown
to be key regulators of the biliary atresia phenotype in a
mouse model of disease.3,4
The clinical and laboratory hallmarks of the disease are
jaundice secondary to direct (conjugated) hyperbilirubinemia,
pale stools, variable hepatosplenomegaly, high gamma-
glutamyl transpeptidase, and a liver histopathology
suggestive of biliary obstruction. The nal diagnosis is
obtained at the time of exploratory cholangiography, which
demonstrates obstruction of the extrahepatic bile duct.
The only hope to restore bile ow is the resection of biliary
remnants and the creation of an intestinal conduit that is
anastomosed to the hilum in a roux-en-Y
fashion as originally designed by Kasai
& Suzuki.5 Clinical course and treatment
response obey the basic principles of
illnesses: earlier diagnosis is associated
with better response and outcome.
The reproducibility of this paradigm
across patient populations suggests
that the biological basis of clinical
phenotype and response to treatment are less inuenced
by geographical boundaries. If this statement is correct,
is it worth studying biliary atresia in individual countries?
The article by Carvalho et al.6 in this issue of Jornal de
Pediatria shows that the answer is yes. The article reports
the current state of diagnosis and treatment of infants with
biliary atresia in Brazil and identies goals for the future
that are tailored to the national clinical practice.
Carvalho et al. reviewed the clinical presentation,
treatment, and outcome of 513 children with biliary
atresia. The data were obtained from large clinical centers
in different geographical regions of Brazil. In general, the
clinical presentation with direct hyperbilirubinemia, high
gamma-glutamyl transpeptidase, and a histopathology with
ductal proliferation and plugs was typical in the cohort. The
mean age at diagnosis and portoenterostomy was 82.6±32.8
See related article
on page 473
Biliary atresia in Brazil:
where we are and where we are going
Jorge A. Bezerra*
* MD. The Pediatric Liver Care Center, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Department
of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
No conflicts of interest declared concerning the publication of this editorial.
Financial support: this work was supported by NIH grant DK83781.
Suggested citation: Bezerra JA. Biliar y atresia in Brazil: where we are and where we are going. J Pediatr (Rio J). 2010;86(6):445-447.
doi:10.2223/JPED.2057

446 Jornal de Pediatria - Vol. 86, No. 6, 2010
Figure 1 - Natural history of onset of symptoms, surgical intervention, and outcome with the native liver in children
with biliary atresia. The gure depicts the average age at onset of symptoms, the percentage of infants
undergoing hepatoportoenterostomy (HPE), and survival with the native liver by 4 years of age (overall and
according to age groups at diagnosis). In gray is the percentage of infants undergoing HPE according to age
groups and the survival (HPE + liver transplantation) in the last decade (2000s)
d = days; Dx = diagnosis; HPE = hepatoportoenterostomy; LTx = liver transplantation; yr = year.
Biliary atresia in Brazil - Bezerra JA
days, with surgery performed in 76.4% of the infants. In
those infants treated with portoenterostomy, the 4-year
survival with the native liver was 36.8%, with higher survival
at 54% if the portoenterostomy was performed in infants
≤ 60 days of age. The combination of portoenterostomy
and liver transplantation increased the overall survival to
73.4%. However, only 46.6% of all patients underwent
transplantation – a low rate compared to other countries,
in which access to transplantation increases to ≥ 60% of
children.7,8
How do the ndings help understand the continuum of
care (diagnosis, treatment options, outcome) for infants with
biliary atresia in Brazil? First, it is true that the mean age at
portoenterostomy at 82.6±32.8 days exceeds the practice
in other nations, which is around 60 days.7,9-11 However,
an analysis of the data for the most recent decade (2000
to 2010) in Brazil shows a shift of diagnosis to younger
ages, with a greater percentage of infants diagnosed
between 61-90 days (48.5 vs. 35% in the 80s) and a lower
percentage of diagnosis beyond 120 days (4.8 vs. 20% in
the 80s). In agreement with this concept, although a 4-year
survival with the native liver for those infants treated with
portoenterostomy was reported at 36.8%, survival improved
to a robust 54% if the infants were ≤ 60 days at the time
of surgery. Thus, there is a real trend to earlier diagnosis
during the current decade, which is already translated into
a greater number of children surviving with the native liver
beyond 4 years.
The study also ide nt if ie s two a re as f or f ut ur e
improvement. First, there is almost 2 weeks separating
the age at onset of symptoms (12.3±17 days) and the age
at portoenterostomy (82.6±32.8 days). While the reasons
for such delay in diagnosis and surgical intervention were
not obvious, they may have been related to community
awareness of the disease, recognition by primary care
physicians, and access to specialized care. Pediatric
hepatologists have partnered with the Brazilian Society
of Pediatrics and the Brazilian Health Ministry to increase
community awareness by the incorporation of a stool color
card in the Childhealth Booklet distributed by the Ministry
to the parents of every neonate. The goal is to aid parents
realize that acholic stools (pale, clay-colored stools) is
abnormal and seek medical help as soon as the abnormal
color is noted – hopefully at early stages of the disease.
These are the infants that are presumed to benet the most
from current treatment modalities.
The second area for improvement relates to the use
of liver transplantation to improve survival when the
child develops advanced liver disease. In the centers
participating in the study, survival of children treated
with portoenterostomy and later with liver transplantation
increased in the 2000s to 77.6%. Despite this success, only
46.6% of the patients underwent liver transplantation. The
simple answer is to increase the access of children with
progressive liver disease to liver transplant centers. While
simple, this solution is largely dependent on an expansion
in the number of accredited transplant centers, support for
transplant-related cost, and appropriate follow-up care. To
become a reality, these factors must become priorities for
the eld of pediatrics and for the society as a whole.
The data reported by Carvalho et al. portrait the current
state of diagnosis, treatment and outcome of children with
biliary atresia – or “where were are” today (Figure 1). They
also identify potential areas for improvement – or “where we

Jornal de Pediatria - Vol. 86, No. 6, 2010 447
References
1. Santos JL, Carvalho E, Bezerra JA. Advances in biliary atresia: from
patient care to research. Braz J Med Biol Res. 2010;43:522-7.
2. Sokol RJ, Shepherd RW, Superina R, Bezerra JA, Robuck P,
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Gastroenterology. 2007;133:268-77.
4. Shivakumar P, Sabla GE, Whitington P, Chougnet CA, Bezerra JA.
Neonatal NK cells target the mouse duct epithelium via Nkg2d
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Smith L, et al. Biliary atresia: the Canadian experience. J Pediatr.
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8. Wildhaber BE, Majno P, Mayr J, Zachariou Z, Hohlfeld J, Schwoebel
M, et al. Biliary atresia: Swiss national study, 1994-2004. J Pediatr
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Universal screening for biliary atresia using an infant stool color
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10. Serinet MO, Broue P, Jacquemin E, Lachaux A, Sarles J, Gottrand F, et
al. Management of patients with biliary atresia in France: results of
a decentralized policy 1986-2002. Hepatology. 2006;44:75-84.
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Correspondence:
Jorge A. Bezerra
Division of Pediatric Gastroenterology, Hepatology, and Nutrition
Cincinnati Children’s Hospital Medical Center
3333 Burnet Ave
45229-3031 - Cincinnati, OH - USA
Tel.: +1 (513) 636.3008
Fax: +1 (513) 636.5581
E-mail: Jorge.bezerra@cchmc.org
are going.” It will be important for pediatric hepatologists
to broaden their investigative network to include greater
representation of the geographical and cultural differences
in Brazil, for they are likely to inuence the natural history
of disease and the quality of care. It will also be important
for them to continue to collect clinical data prospectively,
store tissues to study the pathogenesis of the disease,
and to pursue clinical trials. To be successful, their effort
must be matched by an investment by the society, perhaps
through funds from federal research agencies, to create a
sound research infrastructure. Only then will we diagnose
early and nd new therapies to block disease progression
and save children with their own livers.
Biliary atresia in Brazil - Bezerra JA