Alagille Syndrome Final

8/6/2019 Alagille Syndrome Final

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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

Alagille Syndrome Final

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