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ALAGILLE SYNDROME

By Adetunji A.E Department of Paediatrics ISTH

Outline
Introduction Epidemiology Genetics Pathophysiology Clinical features Natural history Investigation Differential Treatment Prognosis Conclusion

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.

Introduction
Bile duct paucity is defined as a ratio of bile ducts to portal tracts of < 0.5 in a liver biopsy with 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.

Normal liver & Biliary System

Introduction
Bile is produced in the liver and serves two main functions:  carrying toxins and waste products out of the body .  helping the digestion of fats and the fatsoluble vitamins A, D, E, and K.

Epidemiology
Incidence: United States it is approximately 1 case in every 100,000 live births. Sex : No difference in penetrance is reported. Age: Most children are evaluated when < 6 months for either NNJ (70%), or cardiac murmurs/symptoms (17%). Mortality/Morbidity: Depends on bile duct paucity or cholestatic liver disease, underlying cardiac disease, CNS vasculopathy, and renal disease.

Genetics
AG is an autosomal dominant disorder with variable expression. Approximately 50-60% of cases result from a de novo mutation. If the parents of a proband do not have clinical features of AGS, siblings of the proband are at low risk. It is primarily caused by mutations in Jagged1 (JAG1) gene on chromosome 20p12 , a ligand in the Notch signaling pathway.

Genetics
Mutations in Notch2(<1%) on chromosome 1p13-p11 , a receptor in the Notch signaling pathway. Notch genes control cell fate determination , cell-cell interactions and in development , and are active during (and sometimes after) fetal development.

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 .

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.

Pathophysiology
NOTCH2 signaling has been found to regulate formation of 3-dimensional intrahepatic biliary architecture in murine models.[ Bile is produced in the liver and moves through the bile ducts into the small intestine, where it helps to digest fat. In AGS, the bile builds up in the liver and causes scarring that prevents elimination of waste products

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

Prominent, wide forehead

Deep-set eyes with moderate hypertelorism

Small, pointed chin

Straight nose with a bulbous tip

Facial features

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 the intestines. 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.

Clinical Features
in serum bile acids often result in severe pruritus & xanthomas. Xanthomas (hypercholesterolemia) are fatty deposits on the skin (abdomen, knees, elbows, hands, and around the eyes and are harmless).

Clinical Features
Malabsorption and growth problems.  diarrhea because of malabsorption.  failure to thrive in infants  poor growth and delayed puberty in older children.  may develop bone fractures, eye problems, blood-clotting problems, and learning delays

Clinical Features
HEART.  nearly all patients with AGS have cardiac murmurs(2nd only to liver disease)  peripheral and branch pulmonic stenosis (67% of patients), and pulmonary atresia (PA)  tetralogy of Fallot (7-16%)  atrial septal defect (ASD)  ventricular septal defect (VSD)  patent ductus arteriosus (PDA)  significant intracardiac lesions place patients with AGS at increased mortality risk.

Right pulmonary arteriogram demonstrating multiple stenoses (black arrows) in n Alagille syndrome patient with prior surgery for tetralogy of Fallot, peripheral pulmonic stenoses, and a butterfly vertebrae (white arrow).

Clinical Features
BLOOD VESSELS.  People with AGS may have abnormalities of the carotid arteries which can lead to internal bleeding 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.

Aneurysm of the external carotid artery in an adolescen t with Alagille syndrome

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.

Clinical Features
SKELETAL Abnormalities include rib anomalies and shortening of the radius, ulna, and phalanges Butterfly hemivertebrae found in about 33 87% of the patients with AGS on X- ray rarely causes spine problem

Butterfly vertebrae of T5 and T6, with vertebral anomalies at T4, T7, T8 and T9 in an infant with AGS.

Clinical Features
OPHTHALMOLOGIC  The most frequent ophthalmologic finding is a posterior embryotoxon (an extra circular line on the surface of the eye prominent Schwalbe's ring & usually doesn t affect vision),seen > 75%. Reported to occur in 20% of normal eyes.

Posterior embryotox on and prominent Schwalbe s line (arrows).

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

Clinical Features
RENAL  dysplastic or cystic kidneys.  solitary kidney, and duplicated ureters .  decreased function  occult renal artery stenosis, lipoid nephrosis, or glomerulosclerosis causing chronic hypertension  tubular disease, including renal tubular acidosis, tubulointerstitial nephropathy

Diffuse renal cystic dysplasia in a patient with AGS

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 %

Investigations
Liver biopsy The typical feature is paucity of bile ducts; this can be difficult to recognize in biopsies obtained in infancy. Paucity can be progressive with time .

Investigations
Cholangiography, direct visualization of the intrahepatic and extra hepatic biliary tree after injection of opaque material.

Endoscopic retrograde cholangiopancreatography (ERCP)

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)

Investigations
Hyperbilirubinemia with SB = 4 -14mg/dl usually in infancy, direct fraction generally 30% Serum bile acids are significantly elevated with increased amounts of cholic & chenodeoxycholic acids. Alanine aminotransferase (ALT- is liver specific) aspartate aminotransferase (AST) are elevated.

Investigations
ECG & echocardiogram. An ophthalmologic assessment Ultrasonography (US) provides information about the size, composition, and blood flow of the liver. An x ray of the spine Examinations of the blood vessels and kidneys

Investigations
Chromosomal analysis for mutations within the JAG1 gene (20p12) confirms diagnosis of AGS Prenatal testing is available at specialized centers

Diagnosis
To make a diagnosis , a positive liver biopsy (bile duct paucity) and the presence of at least 3 out of 5 major criteria: liver symptoms heart abnormalities or murmurs skeletal abnormalities posterior embryotoxon facial features typical of AGS

Diagnosis
Diagnosis of AGS can be made if the JAG1 gene mutation alone is present even with no major symptom .

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

Treatment
Multidisciplinary approach is required  Medical  Surgical

Suggested Medical
CLINICAL IMPAIRMENT Malnutrition resulting from malabsorption of dietary longchain triglycerides Fat-soluble vitamin malabsorption: Vitamin A deficiency (night blindness, thick skin) Vitamin E deficiency (neuromuscular degeneration)

Management

MANAGEMENT Replace with dietary formula or supplements containing mediumchain triglycerides

Replace with 10,000 15,000 IU/day as Aquasol A Replace with 50 400 IU/day as oral - tocopherol

Vitamin D deficiency (metabolic Replace with 5,000 8,000 IU/day bone disease) of D2 or 3 5 g /kg/day of 25hydroxycholecalciferol

Vitamin K deficiency (hypoprothrombinemia) Micronutrient deficiency Deficiency of water-soluble vitamins Retention of biliary constituents such as cholesterol (itch or xanthomas) Progressive liver disease; portal hypertension (variceal bleeding, ascites, hypersplenism) End-stage liver disease (liver failure)

Replace with 2.5 5.0 mg every other day as water-soluble derivative of menadione Calcium, phosphate, or zinc supplementation Supplement with twice the recommended daily allowance Administer choleretic bile acids and ursodeoxycholic acid, 15 20 mg/kg/day Interim management (control bleeding; salt restriction; spironolactone) Transplantation

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 and diphenhydramine Rifampin mechanism of action is unclear. May involve inhibition of bile acid uptake into hepatocytes Hydrating the skin keeping fingernails trimmed

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

Surgical Care
Partial external biliary diversion (PEBD) has been used when Pruritus is recalcitrant to medical therapy. Cardiac surgery- in serious cardiac defect.

Prognosis

Depends on degree of cardiac, hepatic and central nervous system involvement.

Conclusion
AGS is a rare genetic condition which can be confused with other causes of cholestasis. A high index of suspicion is needed

THANK YOU

References

Nelson Textbook Of Paediatrics 18th Edition Childhood Liver Disease Research & Education Network

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