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ALAGILLE SYNDROME
ByAdetunji A.E
Department ofPaediatrics
ISTH
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Outline Introduction
Epidemiology Genetics
Pathophysiology
Clinical features
Natural history
Investigation
Differential
Treatment
Prognosis
Conclusion
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Introduction
Alagille syndrome (AGS) is a genetic and
complex disorder that affects the liver, heart,
kidney, and other systems of the body.
First described in 1969 by Dr. Daniel Alagille, a
French Pediatric Gastroenterologist
It is an inherited disorder characterized by
hepatic bile ducts paucity.
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Introduction
Bile duct paucity is defined as a ratio of bileducts to portal tracts of < 0.5 in a liver biopsywith an adequate (10) number of portal
tracts present . The ratio increases throughout the first years
of life, reaching a normal ratio of nearly 2 by
adolescence. The normal ratio in premature infants is less
than 1.
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Normal liver & Biliary System
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Introduction
Bile is produced in the liver and serves two
main functions:
carrying toxins and waste products out of thebody .
helping the digestion of fats and the fat-
soluble vitamins A, D, E, and K.
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Epidemiology
Incidence: United States it is approximately 1case in every 100,000 live births.
Sex : No difference in penetrance is reported.
Age:Most children are evaluated when < 6months for either NNJ (70%), or cardiac
murmurs/symptoms (17%).
Mortality/Morbidity: Depends on bile ductpaucity or cholestatic liver disease, underlying
cardiac disease, CNS vasculopathy, and renal
disease.
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Genetics
Mutations in Notch2(
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Genetics
During embryogenesis JAG1 is expressed
mainly in the CVS; the liver & associated blood
vessels. Also expressed in other structures of
mesenchymal origin.
There is extreme variability of phenotype,
even within families, suggesting other
modifying genes or environmental factors .
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Pathophysiology
Mutations in JAG1 disrupt the signaling
pathway, causing errors in development,especially of the heart, bile ducts in the liver,
spinal column, and certain facial features.
The majority of the mutations detected result
in protein truncation.
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Pathophysiology
NOTCH2 signaling has been found to regulateformation of 3-dimensional intrahepaticbiliary architecture in murine models.[
Bile is produced in the liver and movesthrough the bile ducts into the small intestine,where it helps to digest fat.
In AGS, the bile builds up in the liver andcauses scarring that prevents elimination ofwaste products
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Clinical Features
FACIAL FEATURES
Prominent, wide forehead,
deep-set eyes with moderate hypertelorism,
a small, pointed chin
saddle or straight nose with a bulbous tip.
These features give the face the appearance of an
inverted triangle. These features are not usually recognized until after
infancy. The face typically changes with age, and by
adulthood the chin is more prominent
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Deep-set eyes with moderate
hypertelorism
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Small, pointed chin
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Straight nose with a bulbous tip
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Facial features
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Clinical Features
LIVER SYMPTOMS
Jaundice. High levels of bilirubin in the blood can
darken the urine, while stools may become pale,
gray, or white from a lack of bilirubin in theintestines.
Pruritus. The buildup of bile acids in the blood may
cause itching. Pruritus usually starts after 3 months
of age and can be severe
Hepatosplenomegaly is common
Fat-soluble vitamin deficiencies, including
coagulopathies and rickets, are frequent.
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Right pulmonary
arteriogramdemonstrating
multiple stenoses
(black arrows) in n
Alagille syndromepatient with prior
surgery for tetralog
of Fallot, peripheral
pulmonic stenoses,and a butterfly
vertebrae (white
arrow).
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Clinical Features
BLOOD VESSELS.
People with AGS may have abnormalities of
the carotid arteries which can lead to internalbleeding or stroke(15%).
Prompt evaluation with MRI or a CT scan of
the brain are needed following head injury.
AGS can also cause narrowing or bulging of
other blood vessels in the body.
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Aneurysmof the
external
carotid
artery in
an
adolescen
t withAlagille
syndrome
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Clinical Features
NEUROLOGIC
mild developmental delay
mental retardation are reported in some children
with AGS
Diminished deep tendon reflexes (exclude vitamin E
deficiency)
SPLEEN Portal hypertension may occur in advanced liver
disease, with spleen enlargement. There is risk of
injury contact sports.
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Clinical Features
SKELETAL
Abnormalities include rib anomalies and
shortening of the radius, ulna, andphalanges
Butterfly hemivertebrae found in about
33 87% of the patients with AGS on X- ray
rarely causes spine problem
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Butterfly
vertebraeof T5 and
T6, with
vertebral
anomalies
at T4, T7,
T8 and T9
in aninfant with
AGS.
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Clinical Features
OPHTHALMOLOGIC
The most frequent ophthalmologic finding
is a posterior embryotoxon (an extracircular line on the surface of the eye -
prominent Schwalbe's ring & usually
doesnt affect vision),seen > 75%.
Reported to occur in 20% of normal eyes.
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Posterior
embryotox
on and
prominent
Schwalbes
line
(arrows).
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Clinical Features
Some may have Axenfeld anomaly (iris
attachment to inner membrane), seen in
13% of AGS patients.
Other findings reported include
retinitis pigmentosa
pupillary abnormalities
anomalies of the optic disc
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Clinical Features
RENAL
dysplastic or cystic kidneys.
solitary kidney, and duplicated ureters .decreased function
occult renal artery stenosis, lipoid nephrosis,
or glomerulosclerosis causing chronichypertension
tubular disease, including renal tubular
acidosis, tubulointerstitial nephropathy
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Diffuse renal cystic dysplasia in a patient
with AGS
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Natural history
The 20 year life expectancy is 80 %(without
liver transplantation) & 60% for those
requiring transplantation.
factors contributing to mortality are complex
congenital heart disease (15 %)
intracranial bleeding (25 %)
hepatic disease potentially leading to hepatic
transplantation.
In smaller series, the likelihood to reach
adulthood without transplantation was only
50 %
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Investigations
Liver biopsy
The typical feature is paucity of bile ducts; this
can be difficult to recognize in biopsiesobtained in infancy. Paucity can be progressive
with time .
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Investigations
Cholangiography, direct visualization of the
intrahepatic and extra hepatic biliary treeafter injection of opaque material.
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Endoscopic retrograde
cholangiopancreatography (ERCP)
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Investigations
Evaluate patients with AGS for chronic liver disease:
Assay for adequacy of fat-soluble vitamin
deficiencies(especially Vitamins A & D) .
Serum albumin
Prolongation of prothrombin time (PT) or activated
partial thromboplastin time (APTT)
Hypercholesterolemia (>200 mg/ dL) and
hypertriglyceridemia (500-2000 mg/ dL)
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Investigations
Hyperbilirubinemia with SB = 4 -14mg/dlusually in infancy, direct fraction generally
30%
Serum bile acids are significantly elevated withincreased amounts of cholic &chenodeoxycholic acids.
Alanine aminotransferase (ALT- is liver specific)aspartate aminotransferase (AST) areelevated.
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Investigations
ECG & echocardiogram.
An ophthalmologic assessment
Ultrasonography (US) provides informationabout the size, composition, and blood flow of
the liver.
An x ray of the spine
Examinations of the blood vessels and kidneys
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Investigations
Chromosomal analysis for mutations within
the JAG1 gene (20p12) confirms diagnosis of
AGS
Prenatal testing is available at specialized
centers
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Diff i l
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Differential Biliary atresia
Idiopathic neonatal hepatitis
Cystic fibrosis (sweat chlorine or cystic fibrosis
DNA testing)
Hypothyroidism (thyroid functions) Galactosemia (urine-reducing substance)
Sepsis or infection (urinary tract infection or
cytomegalovirus) Alpha-1 antitrypsin deficiency (serum alpha-1
antitrypsin level with PI typing)
Polycystic Kidney Disease
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Treatment
Multidisciplinary approach is required
Medical
Surgical
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SSuggested Medical Management
CLINICAL IMPAIRMENT MANAGEMENT
Malnutrition resulting from
malabsorption of dietary long-
chain triglycerides
Replace with dietary formula or
supplements containing medium-
chain triglycerides
Fat-soluble vitaminmalabsorption:
Vitamin A deficiency (night
blindness, thick skin)
Replace with 10,00015,000
IU/day as Aquasol A
Vitamin E deficiency(neuromuscular degeneration)
Replace with 50400 IU/day asoral - tocopherol
Vitamin D deficiency (metabolic
bone disease)
Replace with 5,0008,000 IU/day
of D2 or 35 g /kg/day of 25-
hydroxycholecalciferol
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Vitamin K deficiency
(hypoprothrombinemia)
Replace with 2.55.0 mg every
other day as water-soluble
derivative of menadioneMicronutrient deficiency Calcium, phosphate, or zinc
supplementation
Deficiency of water-soluble
vitamins
Supplement with twice the
recommended daily allowance
Retention of biliary constituents
such as cholesterol (itch or
xanthomas)
Administer choleretic bile acids
and ursodeoxycholic acid, 1520
mg/kg/day
Progressive liver disease; portalhypertension (variceal bleeding,
ascites, hypersplenism)
Interim management (controlbleeding; salt restriction;
spironolactone)
End-stage liver disease (liver
failure)
Transplantation
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Cholestyramine Forms a nonabsorbable
complex with bile acids in the intestine
ursodeoxycholic acid may increase bile flow
or interrupt the enterohepatic circulation of
bile acids.
Antihistamine agents, e.g. hydroxyzine anddiphenhydramine
Rifampin mechanism of action is unclear. May
involve inhibition of bile acid uptake intohepatocytes
Hydrating the skin
keeping fingernails trimmed
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Surgical Care
Liver transplantation
Indications for consideration of liver
transplantation include the following:Progressive hepatic dysfunction
Severe portal hypertension
Failure to thrive
Intractable pruritus and osteodystroph
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Surgical Care
Partial external biliary diversion (PEBD) has
been used when Pruritus is recalcitrant to
medical therapy.
Cardiac surgery- in serious cardiac defect.
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Prognosis
Depends on degree of cardiac, hepatic andcentral nervous system involvement.
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Conclusion
AGS is a rare genetic condition which can be
confused with other causes of cholestasis. A high index of suspicion is needed
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THANK YOU
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References
Nelson Textbook Of Paediatrics 18th Edition
Childhood Liver Disease Research & Education
Network