Download Biliary atresia

BILIARY ATRESIA
aetiopathology
INTRODUCTION
Little is understood
HPE
LIVER TRANSPLANTION
CONT.
a better understanding of the pathogenesis
to identify new targets for therapeutic
intervention
BA is a phenotype characterized by an
obliterated (or absent) biliary tree
presenting in the first few weeks after birth
CLINICAL VARIENTS
BA & CONGENITAL LATERALITY MALFORMATION
Splenic malformation (BASM)
Situs inversus
Intraabdominal veins
usually girls, NO racial differences
abnormal intrauterine environment (e.g. maternal diabetes, maternal thyrotoxicosis)
genetic basis CFC-1 mutations have been have identified in 50% of a French series
of infants with BASM
2)BA, WITH DISTINCT SYNDROMES
cat-eye syndrome
coloboma
ano-rectal atresia etc.)
chromosomal aneuploidy (Ch 22) has been
shown
3)NON-SYNDROMIC
congenital anomalies such as
oesophageal atresia,
jejunal atresia,
ano-rectal atresia etc.
no convincing genetic explanation
CYSTIC BA 10%
The extrahepatic component is atrophic or absence or by inflammatory obliteration
of an intact tree, in about 10% of cases, cyst formation (bile or mucus) can occur,
and may lead to diagnostic confusion with early obstructed cystic choledochal
malformation.
Cholangiography intrahepatic ducts are grossly abnormal with irregularity (a treelike pattern )caused by multiple interconnections of filamentous intrahepatic biliary
ductules
NO racial, genetic or epidemiological peculiarities
They also have a better outcome following surgery
ISOLATED BILIARY ATRESIA(80%)
wide geographical (and presumed racial) variation across the world with no overt
seasonal variation
equal gender split
A- 1st trimester arrested development–for whatever reason ), The timing of onset
must be later than the syndromic groups
B-The alternate hypothesis a completely formed intact biliary tree but obliteration
occurs as a secondary perinatal phenomenon. The clinical evidence supporting a
patent bile duct system and then obliteration is difficult to obtain
CONT.
reports of an initial “neonatal hepatitis” picture on
investigation but evolving into biliary atresia later have
been suggested.
intrahepatic and extrahepatic bile ducts. Both elements
have different origins, develop along separate lines from
different structures and biliary continuity is only
established by 10-12 weeks gestation.
CONT.
prenatal onset
Amniotic fluid assayed for the enzyme γ-glutamyl transpeptidase in one large
screening study. low IN BA
bile acids in the blood (taken in first few days of life) has also been measured
and showed that 77%) of infants who later proved to have BA had elevated total
bile acids.
This suggests that cholestasis is already obvious (if looked for) during the first
post-natal week in at least three-quarters of those who prove to have isolated BA
PATHOGENESIS
viral infection
Immune dysfunction
Autoimmunity
genetic predisposition
Epigenetic factors
 exposure to environmental toxins
vascular abnormalities
,
INFECTIOUS PROCESSES
seasonal oscillation?? environmental factors? probably by a virus?
perinatal
isolation of hepatotropic viruses from children with biliary atresia.
the presence on liver biopsy of a portal tract mononuclear cell
infiltrate suggesting an inflammatory process leading to bile duct
obstruction.
the development of a virally induced mouse model of BA
the observation that the immune response in BA is similar to that seen
with viral infection
VIRUSES
CMV Some studies (25%) CMV-positive(serology &histology) patients.
&positive IgM for CMV in 28.5% of patients
CMV DNA IN the liver of 50% of patients
 ROEVIRUS
high prevalence of positive serologic results for reovirus in one study
The presence of reovirus in liver tissue and bile ducts, detected by
(PCR),
potential role
ROTAVIRUS . rotavirus inoculation was found to induce EHBA in newborn
mice
CONTIN.
Thus, no study so far definitively proved the role of a specific virus
as etiologic agent, or to
explain why some viruses, which affect millions of children,cause
bile duct injury in only a small percentage of them?
One alternate :virus-induced injury to the biliary system in the
pathogenesis of biliary atresia is immune dysfunction.
IMMUNE DYSFUNCTION
assumption that the biliary epithelium may express inappropriate
antigens on its surface that can be recognized by lymphocytes after
viral or toxic damage , There could be an immune cascade, which
could produce inflammation and biliary fibrosis
viral antigens may cross-react with biliary antigens, triggering an
immune response against the virus, and also against biliary antigens
Therefore, persistence of immune injury to bile duct cells may lead to
disease progression.
The abnormal expression of the (HLA) in the biliary epithelium is
another evidence of participation of the immune process
CONT.
Increased expression OF integrin β2 ( an intercellular adhesion molecule) in the
cells of the inflammatory infiltrate of the portal space
increased expression of LFA-1 ligand, ICAM-1, in the endothelium of patients
with atresia.
Elevated ICAM-1 and VCAM-1 levels are associated with advanced liver
disease
evidence suggests that adhesion molecules may play a remarkable role in the
inflammatory reaction in biliary atresia, possibly by the retention and
activation of circulating leukocytes
CONT.
activation of proinflammatory genes
an increase in interferon (IFN)-gamma and osteopontin, which
indicates TH1 response,
low levels of expression of immunoglobulin-related genes, pointing
to an inhibition of the TH2 response.
periductular lymphocyte infiltration, with predominance of TH1 and
cytotoxic T lymphocytes.
CONT.
the role of IFN-gamma in knockout mice and observed, in the
first stage of the study, that the mice did not develop biliary
atresia after rhesus rotavirus (RRV) inoculation. Interestingly,
the administration of recombinant IFN-gamma into the knockout mice resulted in the development of bile duct obstruction
due to the accumulation of inflammatory cells
Thus, the immune dysfunction hypothesis suggests that a perinatal or postnatal event,
probably a viral infection,may trigger an immunopathological process, which results in
fibrosing obstruction of extrahepatic bile ducts,which had been well-formed in the
embryonic period. In this case, EHBA would be the final stage of this
inflammatoryprocess.
AUTOIMMUNITY
The progressive nature of liver injury in patients with atresia,
the presence of lymphocytes in the liver
the association with certain types of HLA suggest a possibly autoimmune,
persistent attack against the bile ducts.
autoimmune hepatitis in the post-transplant period, which could translate into
susceptibility to autoimmune diseases.
Genetics and hepatic morphogenesis

genetic factors might be involved in its pathogenesis

The most widely investigated genes are those related to laterality (inversin)
and to the development of bile ducts.

In the mice, a spontaneous mutation in the inversin gene, resulted in total
abdominal situs inversus, obstructive jaundice and death in the first week of
life

Nevertheless, the lack of inflammation or necrosis in the liver
parenchyma of these mice is not compatible with the histological
characteristics observed in infants with biliary atresia

the human inversin gene was mapped and no mutation in this gene was
detected in a case series of patients with biliary atresia and laterality defects
CONT.

Another gene that may play a role in EHBA is Jag-1

The genetic inactivation of hepatocyte nuclear factors (HNF), such as
HNF-1β: was associated with paucity of intrahepatic bile ducts
HNF6 :was related to ductal plate malformation and to the
presence of intrahepatic cysts

Altogether, these data suggest that mutations in the genes that
regulate hepatobiliary development may play a role in extrahepatic
biliary atresia, but the implication of these specific genes in the
pathogenesis of atresia in humans remains unclear.
EPIGENETIC FACTORS
increased expression of genes related to chromatin regulatory factors (SMARCA-1,
HDAC3 and RYBP).57 Because these genes influence epigenetic processes, it was
speculated a potential role for epigenetic factors on the pathogenesis of bile duct
obstruction.
TOXIC ETIOLOGIES
— The clustering of cases of BA is also consistent with the possibility of a toxinmediated inflammatory response.
three reported outbreaks of BA in lambs in Australia ewes that gave birth to affected
lambs were thin, jaundiced, had acholic stools, and eventually died, and autopsy
revealed a diagnosis of BA. The hypothesized mechanism is that the pregnant ewes
ingested a A novel isoflavonoid toxin was isolated from the Dysphania plant, This
toxin caused severe damage to the extrahepatic biliary tree in a zebrafish model
This evidence suggests that an environmental toxin may be implicated in some cases
of BA
Decrease in arterial blood supply to the
liver

Association between EHBA and occlusion of portal vein and hepatic artery
suggests that an intrauterine ischemic event may exert some influence upon
the development of bile ducts, and may play a role in the pathogenesis of
atresia.
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