AUTHOR INFORMATION

Section 1 of 11

Authored by Ann Scheimann, MD MBA, Assistant Professor, Department of Pediatrics, Section of Nutrition and Gastroenterology, Baylor College of Medicine and Johns Hopkins Medical Institution

Ann Scheimann, MD MBA, is a member of the following medical societies: North American Society for Pediatric Gastroenterology and Nutrition

Edited by Robert Baldassano, MD, Director, Center for Pediatric Inflammatory Bowel Disease, Associate Professor, Department of Pediatrics, Division of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia, University of Pennsylvania; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Carmen Cuffari, MD, Associate Professor, Department of Pediatrics, Division of Gastroenterology/Nutrition, The Johns Hopkins University School of Medicine; Steven M Schwarz, MD, FAAP, FACN, Chair, Department of Pediatrics, Long Island College Hospital; Professor of Pediatrics, State University of New York, Downstate Medical Center College of Medicine; and Carmen Cuffari, MD, Associate Professor, Department of Pediatrics, Division of Gastroenterology/Nutrition, The Johns Hopkins University School of Medicine

Author's Email:	Ann Scheimann, MD MBA
Editor's Email:	Robert Baldassano, MD

eMedicine Journal, May 31 2006, VOLUME 7, Number 5

INTRODUCTION

Section 2 of 11

Background: Alagille syndrome (AS) is an autosomal dominant disorder (OMIM 118450) associated with abnormalities of the liver, heart, skeleton, eye, kidneys, and characteristic facial appearance. In 1973, Watson and Miller reported 9 cases of neonatal liver disease with familial pulmonary valvular stenosis. Then in 1975, Alagille et al described several patients with hypoplasia of the hepatic ducts with associated features.

Pathophysiology: AS is an autosomal dominant disorder with variable expression. Associated abnormalities include those of the liver, heart, eye, skeleton, kidneys, and characteristic facial features. Mild-to-moderate mental retardation also may be present. The syndrome recently has been mapped to the 20p12-jagged-1 locus (JAG1), encoding a ligand critical to the notch gene signaling cascade importance in fetal development. A minority (6-7%) of patients have complete deletion of the jagged-1 gene, and approximately 15-50% of mutations arise spontaneously.

Frequency:

• In the US: Incidence is approximately 1 in every 100,000 live births.

Mortality/Morbidity: Major contributors to morbidity arise from bile duct paucity or cholestatic liver disease, underlying cardiac disease, and renal disease.

Sex: No difference in penetrance is reported.

Age: Most children are evaluated when younger than 6 months for either neonatal jaundice (70%), or cardiac murmurs and symptoms (17%). Patients who are less affected, such as family members, often are diagnosed after an index case.

CLINICAL

Section 3 of 11

Physical:

• Presentation is variable.

• Some patients are diagnosed after prolonged neonatal jaundice or when liver biopsy demonstrates paucity of intrahepatic bile ducts.



• Others may be diagnosed during evaluation for right-sided heart disease.

• Some individuals are diagnosed by careful examination after an index case is identified in the family.



• Nutrition and growth


• • Children often present with poor linear growth.

  • Altered longitudinal growth is attributed to wasting or inadequate intake, and an element of growth hormone resistance may coexist. Studies to assess the impact of higher doses of growth hormone on linear growth in patients with Alagille syndrome (AS) are currently underway.
  
  
  
• Head and neck


• • Commonly associated facial features are broadened forehead, pointed chin, and elongated nose with bulbous tip.

  • Characteristic facial features may not be obvious during infancy but may become more apparent as the child gets older.
  
  
  
• Ophthalmologic


• • Ocular abnormalities are common in AS. The most frequent ophthalmologic finding is a posterior embryotoxon, which was observed in more than 75% of patients of one large series conducted by Emerick et al.

  • Some of these patients also may have Axenfeld anomaly (ie, iris attachment to Descemet membrane).

  • Other findings reported include retinitis pigmentosa, pupillary abnormalities, and anomalies of the optic disc.
  
  
  
• Cardiovascular


• • Nearly all patients with AS have cardiac murmurs.
  
  
  
  • The most common cardiac lesions are stenoses within the pulmonary tree (peripheral pulmonic stenosis) with, or without, other structural lesions.
  
  
  
  • Hemodynamically significant lesions include atrial septal defect (ASD), ventricular septal defect (VSD), tetralogy of Fallot, patent ductus arteriosus (PDA), and pulmonary atresia (PA). Significant intracardiac lesions place patients with AS at increased mortality risk.
  
  
  
• Hepatic


• • Hepatic disease is a key feature of AS.

  • The majority of infants with AS present with cholestatic jaundice.

  • Hepatosplenomegaly is common.

  • Elevations in serum bile acids often result in severe pruritus and xanthomas (hypercholesterolemia).

  • Fat-soluble vitamin deficiencies, including coagulopathies and rickets, are frequent.
  
  
  
• Skeletal


• • Abnormalities of the vertebrae, ribs, and hands frequently are associated with AS.

  • Butterfly hemivertebrae were found in one half of the patients analyzed by Emerick et al in a large series of patients with AS.

  • Other isolated anomalies include rib anomalies and shortening of the radius, ulna, and phalanges.
  
  
  
• Neurologic


• • Mild developmental delay and mental retardation are reported in some children with AS.

  • Diminished deep tendon reflexes, if noted on physical examination, should direct the clinician to exclude vitamin E deficiency.
  
  
  
• Renal: Occult renal artery stenosis, lipoid nephrosis, or glomerulosclerosis may present with signs and symptoms of chronic hypertension.



• Vascular: Vascular lesions have been recently described in 6% of the patients with confirmed AS who were followed by Kamath et al. These lesions included basilar artery aneurysms, internal carotid artery anomalies, middle cerebral artery aneurysm, Moyamoya disease and aortic aneurysms, coarctation of the aorta, and renal artery stenosis.

Causes:

• AS is an autosomal dominant mutation with variable expression localized to the JAG1 gene (20p12).



• The JAG1 gene product functions as a ligand for the notch-1 receptor. In animal models, interactions between JAG1 ligand and notch-1 receptor play an important role in the determination of ultimate cell fate. A minority of patients, generally with more severe phenotypes, have complete deletion of the JAG1 gene.

DIFFERENTIALS

Section 4 of 11

Biliary Atresia
Congenital Hepatic Fibrosis
Cystic Fibrosis
Jaundice, Neonatal
Polycystic Kidney Disease
Progressive Familial Intrahepatic Cholestasis
Tyrosinemia

Other Problems to be Considered:

Byler disease
Choledochal cyst
Inspissated bile syndrome

WORKUP

Section 5 of 11

Lab Studies:

• Evaluation for chronic liver disease including parameters of function and differential diagnoses


• • Fat-soluble vitamin deficiencies frequently are observed in Alagille syndrome (AS) cases.
  
  
  
  • Prolongation of PT or aPTT is often observed and can be corrected with intravenous vitamin K supplementation followed by oral dosing.
  
  
  
• Several abnormalities of liver function commonly noted in patients with AS reflect chronic cholestasis.



• Hypercholesterolemia (>200 mg/dL) and hypertriglyceridemia (500-2000 mg/dL) are commonly present, reflective of underlying chronic cholestasis.



• Gamma-glutamyl transpeptidase (GGT) and alkaline phosphatase levels generally are elevated. If significant discrepancies exist between the degree of elevation of GGT and alkaline phosphatase, consider the possibility of occult zinc deficiency or vitamin D deficiency.



• The total bilirubin during infancy is generally 4-14 mg/dL with a direct fraction generally greater than 30% of total bilirubin. In the majority of children, elevation of bilirubin levels resolve after the first year of life.



• Serum bile acids are significantly elevated with increased amounts of cholic and chenodeoxycholic acids.



• In older patients with long-standing AS, monitor renal function and screen for hepatocellular carcinoma at routine intervals.



• Suspect vitamin E deficiency in the presence of mild hemolytic anemia and diminished deep tendon reflexes or ataxia.



• Assay the adequacy of vitamin A and D stores via measurement of levels (25-OH vitamin D and vitamin A).



• For the infant with cholestatic liver disease, exclude other diagnoses including cystic fibrosis (sweat chlorine [CL] or cystic fibrosis [CF]-DNA testing), hypothyroidism (thyroid functions), galactosemia (urine-reducing substance), sepsis or infection (urinary tract infection/cytomegalovirus [UTI/CMV]), and alpha-1 antitrypsin deficiency (serum alpha-1 antitrypsin level with PI typing).



• Less common considerations include inborn errors of bile acid metabolism (urine for bile acids) and progressive familial intrahepatic cholestasis.



• Chromosomal analysis for mutations within the JAG1 gene (20p12) confirms diagnosis of AS. DNA sequencing is required for confirmation of the majority of patients with AS because only 6-7% have complete deletion of the JAG1 gene.

Imaging Studies:

• Diagnostic testing is important to exclude other causes of cholestasis and to evaluate for associated malformations.



• Abdominal ultrasonography screens for renal anomalies and grossly evaluates the hepatobiliary tree and the hepatic parenchyma.



• Further delineation of biliary anatomy may be required. This may be obtained using studies including dimethyl iminodiacetic acid (HIDA) scanning, magnetic resonance cholangiopancreatography, endoscopic retrograde cholangiopancreatography (ERCP) (selected centers), or intraoperative cholangiography.



• Conduct routine sonography in older patients to screen for hepatoma or hepatocellular carcinoma.



• Associated anomalies (eg, vertebral anomalies) may be screened via spine films.

Other Tests:

• Patients may require an ECG to exclude the presence of hemodynamically significant, right-sided cardiac malformations from the diagnosis.



• An ophthalmologic assessment screens for anomalies including posterior embryotoxon, Axenfeld anomaly, and retinal changes.

Procedures:

• A liver biopsy is suggested to evaluate architecture and histology.



• An ERCP or cholangiography evaluates biliary anatomy and excludes choledochal cysts and inspissated bile syndrome from the diagnosis.

TREATMENT

Section 6 of 11

Medical Care:

• Correction of vitamin deficiencies with appropriate vitamin dosage is important for optimal growth and development. Water miscible forms of vitamins A, D, E, and K frequently are poorly absorbed. Complexes of vitamins A, D, E, and K with polyethylene glycol compounds (TPGS) generally are well tolerated by patients and are better absorbed. Zinc deficiency sometimes is observed; zinc is easily replaced via oral compounds.



• Some decreases in the degree of hyperlipidemia have been treated with cholestyramine.



• Pruritus often is recalcitrant to medical therapy and significantly impacts on the quality of life. Trials of antihistamine agents, such as hydroxyzine and diphenhydramine, are helpful to some patients. Several studies have noted beneficial effects of either cholestyramine (12-15 g/d) or rifampin in management of bile acid-induced pruritus found in patients with Alagille syndrome (AS).



• A cardiologist should manage cases of clinically significant cardiac disease.
• All patients, except those with peripheral pulmonic stenosis, require subacute bacterial endocarditis (SBE) prophylaxis.

• Screening for other vascular anomalies, such as aneurysms or stenoses, such be considered.



• Administer standard immunizations along with the hepatitis A vaccine to patients with liver manifestations. Also administer the multivalent pneumococcal vaccine to these patients, particularly if ascites is present due to the risk for spontaneous bacterial peritonitis.

Surgical Care:

• The exclusion of the diagnosis of extrahepatic biliary atresia (EHBA) via exploratory laparotomy and intraoperative cholangiogram is not infrequent in patients with AS. Some studies have noted that 3-5% of patients undergoing the Kasai procedure for EHBA eventually are diagnosed with nonsyndromic bile duct paucity or AS.



• Surgical management for bile acid-induced pruritus includes biliary diversion and eventual orthotopic liver transplantation for those with refractory disease. Whitington et al reported a series of patients treated with partial external biliary diversion for pruritus associated with AS. They noted a decrease in bile salt concentrations and some abatement of pruritus and xanthomas; however, the results for the patients with AS were less striking than with other preoperative diagnoses, including progressive familial intrahepatic cholestasis (PFIC).



• Indications for consideration of liver transplantation include the following:


• • Progressive hepatic dysfunction

  • Severe portal hypertension

  • Failure to thrive

  • Intractable pruritus and osteodystrophy
  
  
  
• Estimated 20-year survival rates are 80% for those not requiring liver transplantation and 60% for those requiring transplantation.



• Patients with more serious cardiovascular anomalies, including tetralogy of Fallot, pulmonary atresia/ventricular septal defect (PA/VSD), atrial septal defect/ventricular septal defect (ASD/VSD), and PDA, are likely to eventually require cardiac surgery. The 20-year predicted survival by Kaplan-Meier plots for those with significant intracardiac lesions is 40%; the 20-year predicted survival for those without intracardiac lesions is 80%.

Consultations:

• Subspecialty consultation may facilitate diagnosis and provide long-term care.



• Consultation with an ophthalmologist may provide the diagnosis.



• A pediatric hepatologist can assist with management of chronic cholestatic liver disease.



• Cardiology consultation can assist with the diagnosis of AS and therapy for intracardiac disease, as well as other vascular abnormalities.



• Seek nephrology consultations if significant structural renal disease is present or if suspicions of evolving renal insufficiency arise.

Diet:

• Diets higher in carbohydrates and medium chain triglycerides generally are absorbed better in patients with AS.



• Consider drip feeds via nasogastric tube or gastrostomy in patients with poor weight gain and increased caloric requirements secondary to malabsorption and cholestasis or cardiac disease.



• Patients with AS and cholestasis may develop essential fatty acid deficiency if not appropriately supplemented.



• Supplementation of fat-soluble vitamins is necessary.

Activity:

• Activity is not limited unless patient also has significant intracardiac disease.



• Patients with evidence of hypersplenism should avoid contact sports.

MEDICATION

Section 7 of 11

Medications are used to manage bile acid-induced pruritus and supplement fat-soluble vitamin stores.

Drug Category: Antipruritics -- Pruritus is often recalcitrant to medical therapy and significantly impacts on the quality of life.

Drug Name	Hydroxyzine (Atarax, Vistaril) -- Useful adjunct in the management of pruritus with histamine-mediated triggers. Antagonizes H1-receptors in periphery. May suppress histamine activity in subcortical region of CNS.
Adult Dose	25 mg PO tid/qid
Pediatric Dose	0.6 mg/kg/dose PO q6h
Contraindications	Documented hypersensitivity
Interactions	CNS depression may increase with alcohol or other CNS depressants
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Associated with clinical exacerbations of porphyria (may not be safe for porphyric patients); ECG abnormalities (alterations in T-waves) may occur; may cause drowsiness; caution in early pregnancy (when given in substantial doses to pregnant mice, it induced fetal abnormalities); not to be administered IV/SC/IA (thrombosis and digital gangrene can occur); caution in angle-closure glaucoma, peptic ulcer, urinary tract obstruction, and hyperthyroidism

Drug Name	Cholestyramine (Questran) -- Forms a nonabsorbable complex with bile acids in the intestine, which in turn inhibits enterohepatic reuptake of intestinal bile salts. Take other medications at least 1 h before or 4-6 h after cholestyramine. Not to be administered in dry powder form. Mix with plenty of water or applesauce.
Adult Dose	3-4 g PO tid/qid; not to exceed 16-32 g/d PO divided bid/qid
Pediatric Dose	240 mg/kg/d PO divided tid
Contraindications	Documented hypersensitivity; complete biliary obstruction
Interactions	Inhibits absorption of numerous drugs including warfarin, fat-soluble vitamins, thyroid hormone, phenylbutazone, amiodarone, NSAIDs, methotrexate, digitalis glycosides, glipizide, phenytoin, imipramine, niacin, methyldopa, tetracyclines, clofibrate, hydrocortisone, penicillin G, hormonal replacements
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in patients with constipation and phenylketonuria; may result in fat-soluble vitamin deficiencies (hypoprothrombinemia), hyperchloremic acidosis (chloride form of anion exchange resin), and intestinal obstruction

Drug Name	Rifampin (Rifadin, Rimactane) -- Precise mechanism of action is unclear. May involve inhibition of bile acid uptake into hepatocytes and facilitation of excretion of dihydroxy and monohydroxy bile acids and toxic bile acids.
Adult Dose	300 mg/d PO qd or divided bid
Pediatric Dose	10 mg/kg/d PO qd or divided bid; not to exceed adult dose
Contraindications	Documented hypersensitivity
Interactions	Induces microsomal enzymes, which may decrease effects of acetaminophen, oral anticoagulants, barbiturates, benzodiazepines, beta-blockers, chloramphenicol, oral contraceptives, corticosteroids, mexiletine, cyclosporine, digitoxin, disopyramide, estrogens, hydantoins, methadone, clofibrate, quinidine, dapsone, tazobactam, sulfonylureas, theophyllines, tocainide, and digoxin; blood pressure may increase with coadministration of enalapril; coadministration with isoniazid may result in higher rate of hepatotoxicity than with either agent alone (discontinue one or both agents if alterations in LFTs occur); cotrimoxazole and probenecid may increase blood level
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Obtain CBCs and baseline clinical chemistries prior to and throughout therapy; in liver disease, weigh benefits against risk of further liver damage; interruption of therapy and high-dose intermittent therapy are associated with thrombocytopenia that is reversible if therapy is discontinued as soon as purpura occurs; if treatment is continued or resumed after appearance of purpura, cerebral hemorrhage or death may occur; may cause reddish-orange discoloration to tears, saliva, urine, and sweat; may permanently stain soft contact lenses

Drug Category: Fat-soluble vitamins -- These vitamins are used for supplementation of vitamin A, D, E, and K losses.

Drug Name	Phytonadione (AquaMEPHYTON) -- Vitamin K-1 is necessary for the production of factors II, VII, IX, and X by serving as a cofactor during carboxylation of glutamic acid residues.
Adult Dose	Correction of coagulopathy: up to 10 mg IV qd for 3-5 d, then switch to PO Chronic supplementation: 10 mg PO qd or divided bid
Pediatric Dose	Correction of coagulopathy: 2.5-10 mg IV qd for 3-5 d, then switch to PO Chronic supplementation: 2.5-10 mg PO qd
Contraindications	Documented hypersensitivity
Interactions	Effects of warfarin sodium and dicumarol are antagonized by phytonadione
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Transient flushing sensations and taste abnormalities have been noted during parenteral administration, as well as rare occurrences of dizziness, brief hypotension, and cyanosis; hyperbilirubinemia reported in infants given parenteral phytonadione at doses above standard guidelines; patients with elevated PT/PTT may bleed into muscle following IM injection; rate of infusion not to exceed 1 mg/min

Drug Name	Vitamin E (Nutr-E-Sol) -- Antioxidant that prevents the oxidation of vitamins A and C. Protects polyunsaturated fatty acids in membranes from attack by free radicals and protects red blood cells against hemolysis. Nutr-E-Sol is a specially formulated vitamin E complex with polyethylene glycol 1000 succinate to allow direct absorption without biliary emulsification. Formulation of choice for vitamin E replacement therapy in patients with cholestasis. The formulation contains 400 IU vitamin E/15 mL.
Adult Dose	400-1200 IU (15-45 mL) PO qd; based on monitoring of levels
Pediatric Dose	15-25 IU/kg/d; based on monitoring of levels
Contraindications	Documented hypersensitivity
Interactions	Mineral oil decreases absorption of vitamin E; vitamin E delays absorption of iron and increases effects of anticoagulants
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Pregnancy factor with large doses of vitamin E is C; vitamin E may induce vitamin K deficiency; necrotizing enterocolitis may occur when large doses of vitamin E are given; in neonates, increased intraventricular hemorrhage, NEC, sepsis, and hepatic toxicity may occur if administered in large IV doses

Drug Name	Ergocalciferol (Calciferol, Drisdol) -- Also referred to as vitamin D-2. Undergoes metabolic activation in vivo to the biologically active form 1,25-dihydroxyergocalciferol (1,25[OH]2-D2). Stimulates absorption of calcium and phosphate from the intestines and promotes release of calcium from bone into blood. Ergocalciferol 1 mg provides 40,000 IU of vitamin D activity. Available as liquid drops (8000 IU/mL) and 50,000 IU capsules.
Adult Dose	10,000-80,000 IU/d PO plus 1-2 g/d PO of elemental phosphorus
Pediatric Dose	Infants and healthy children: 10 mcg/d PO (400 IU) Vitamin D–dependent rickets: 75-125 mcg/d PO (3000-4000 IU); not to exceed 1500 mcg/d Nutritional rickets and osteomalacia: 25-125 mcg/d PO (1000-5000 IU) in normal absorption; 250-650 mcg/d PO (10,000-25,000 IU/d) if malabsorption present
Contraindications	Documented hypersensitivity; hypercalcemia; malabsorption syndrome
Interactions	Cholestyramine and colestipol decrease absorption; magnesium-containing antacids and thiazide diuretics can increase effects
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Maintain adequate fluid intake; can cause hypercalcemia, hypercalciuria, and pseudotumor cerebri; caution in impaired renal function and heart disease

Drug Name	Vitamin A (Palmitate-A 5000, Aquasol-A) -- This vitamin is required for bone development, growth, night vision, and gonadal function. It is a biochemical cofactor. In the past, vitamin A has been expressed in units. It is now expressed as retinol equivalents (RE) or mcg of retinol. One RE is equal to 1 mcg retinol. One RE of vitamin A is equal to 3.33 units of retinol and 10 u of beta-carotene.
Adult Dose	Dietary supplement: 4000-5000 IU/d PO RDI: 2670 IU/d (females) and 3330 IU/d (males)
Pediatric Dose	Use water miscible products Dietary supplement: <6 months: 1500 IU/d PO 6 months to 3 years: 1500-2000 IU/d PO 4-6 years: 2500 IU/d PO 7-10 years: 3300-3500 IU/d PO >10 years: Administer as in adults Deficiency (serum retinol: RBP molar ratio <0.8): <1 year: 10,000 IU/kg/d IM for 5 d, then 7,500-15,000 IU/d for 10 d 1-8 years: 5,000-10,000 IU/kg/d IM for 5 d, then 17,000-35,000 IU/d for 10 d >8 years: 100,000 IU/d IM for 3 d, then 50,000 IU/d for 14 d
Contraindications	Documented hypersensitivity
Interactions	Mineral oil and cholestyramine decrease absorption; oral contraceptives increase plasma levels
Pregnancy	A - Safe in pregnancy
Precautions	Pregnancy category X if dose exceeds RDA (ie, 1000 RE or 3300 IU from supplement); can result in hypervitaminosis A syndrome (eg, fever, malaise, anorexia, vomiting, slow growth, migratory arthralgia, premature epiphyseal closure, tender cortical thickening over the radius and tibia, headache, ICP, lip fissures, dry/cracked skin, alopecia, desquamation, hyperpigmentation, hepatosplenomegaly, jaundice, leukopenia, hypomenorrhea); caution in renal or hepatic impairment

Drug Category: Trace element -- Zinc deficiency is sometimes seen; zinc is easily replaced via oral compounds.

Drug Name	Zinc (Galzin, Orazinc, Verazinc, Zincate) -- Zinc is an essential cofactor for more than 70 enzymes that are important in immune function and cell replication. Dosing guidelines are based upon monitoring of levels. The elemental zinc content depends on the particular salt form. Zinc acetate liquid has 5 mg of elemental zinc per mL. Zinc sulfate suspension has 10 mg elemental zinc per mL and zinc sulfate tablets contain 23% elemental zinc.
Adult Dose	25-50 mg elemental zinc PO qd or divided bid/tid
Pediatric Dose	<10 years: 0.5-1 mg/kg/d elemental >10 years: 15-25 mg elemental zinc PO qd
Contraindications	Documented hypersensitivity
Interactions	May reduce penicillamine and tetracycline effects; iron decreases uptake; bran and dairy products decrease absorption
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in renal impairment; nausea, vomiting, dyspepsia, and pancreatitis reported; administer with food to minimize GI upset

Drug Category: Bile acid -- This agent promotes bile salt excretion via direct stimulation of bile flow and via indirect alterations in composition of bile.

Drug Name	Ursodeoxycholic acid (Actigall) -- Decreases cholesterol content of bile.
Adult Dose	3 mg/kg/dose PO bid/qid
Pediatric Dose	10-15 mg/kg/dose PO bid/qid
Contraindications	Documented hypersensitivity
Interactions	Bile acid sequestering agents (eg, cholestyramine, colestipol) and aluminum-containing antacids may adsorb bile acids and reduce absorption; estrogens, oral contraceptives, and clofibrate increase secretion of cholesterol from liver and may counteract effectiveness of ursodeoxycholic acid
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Overdosage may result in diarrhea

FOLLOW-UP

Section 8 of 11

Further Inpatient Care:

• Patients may require inpatient treatment for nutritional support, cardiovascular disease, and chronic liver disease.



• Patients with evidence of undernutrition and failure of conservative measures may benefit from gastrostomy placement for initiation of nocturnal drip feedings.



• Patients may require cardiac catheterization and cardiac or vascular surgery/procedures for significant symptomatic lesions.



• Complications of chronic liver disease, including variceal hemorrhage, refractory ascites, and spontaneous bacterial peritonitis (as well as development of hepatocellular carcinoma), occur in patients with Alagille syndrome (AS) and long-standing liver involvement. These patients merit strong consideration for liver transplantation.

Further Outpatient Care:

• Monitor patient's nutritional status. Screen patients for fat-soluble vitamin deficiencies.



• Consultation with a pediatric cardiologist for management of structural cardiac/vascular disease, and hyperlipidemia is advised.



• Manage chronic cholestatic liver disease, including pruritus, cirrhosis and portal hypertension, ascites, and screening for hepatocellular carcinoma, when appropriate.



• Manage chronic renal disease.

Transfer:

• Patients with AS and significant cardiovascular or hepatic disease merit consultation with a subspecialist. Consider transferring patient if signs of decompensation are evident upon presentation or if they are likely to evolve during hospitalization; patient also must be stable for transfer.

Deterrence/Prevention:

• Patients with significant intracardiac disease require SBE prophylaxis. Consider trials of bile acid-binding resins (eg, cholestyramine) to those with significant hyperlipidemia and pruritus.



• Supplementation of fat-soluble vitamins, alteration in dietary intake (higher carbohydrate/medium chain triglyceride), and immunizations (hepatitis B, hepatitis A, Pneumovax) may minimize the development of complications of cholestatic chronic liver disease.

Complications:

• Hepatic complications arise from cholestasis and cirrhosis. Infants may present with neonatal jaundice. Either jaundice resolves by age 2 years or cholestasis persists. Unrecognized deficiencies of fat-soluble vitamins (A, D, E, K) can contribute to morbidity (eg, osteopenia, hemolytic anemia) and mortality (eg, intracranial hemorrhage, aberrant intracerebral vessels secondary to abnormal notch or JAG1 expression) from bleeding events. Severe intractable pruritus leaves many children with AS miserable, prompting consideration for liver transplantation. Several patients have developed hepatocellular carcinoma in early adulthood.



• Major contributors to morbidity arise from bile duct paucity or cholestatic liver disease, underlying cardiac disease, and renal disease.



• Structural cardiac disease and hyperlipidemia or atherosclerosis contribute to morbidity and mortality of AS. Cardiac murmurs are noted in fewer than 95% of patients with AS. Structural anomalies associated with AS range from mild peripheral pulmonic stenosis to severe tetralogy of Fallot. Aneurysms and stenotic lesions have been described within the arterial system (carotids, aorta, renal), as has the development of changes similar to Moyamoya disease. Hyperlipidemia commonly is manifested as xanthomas. Patients have high levels of plasma cholesterol, low-density lipoprotein (LDL), and apoprotein B, predisposing to the development of atherosclerosis.



• Structural renal disease as well as glomerulosclerosis and nephrosclerosis are described in patients with AS. Renal anomalies are renal artery stenosis, ectopic kidney, single kidney, and ureteral duplications. The development of glomerulosclerosis in patients with AS has been attributed to hypercholesterolemia and lecithin cholesterol acyltransferase (LCAT) deficiency, as well as stimulation of excessive production of extracellular matrix. One patient has been reported to require renal transplantation.

Prognosis:

• Cardiac disease and liver disease can significantly impact the life expectancy of patients with AS; presence of hepatic disease also alters life expectancy.



• Patients with more significant cardiovascular anomalies (tetralogy of Fallot, PA/VSD, ASD/VSD, PDA) eventually require cardiac surgery. The 20-year predicted survival rate via Kaplan-Meier plots for individuals with significant intracardiac lesions is 40%, and for those individuals without significant intracardiac lesions the survival rate is 80%.

Patient Education:

• For excellent patient education resources, visit eMedicine’s Heart Center and Cholesterol Center. Also, see eMedicine’s patient education articles Tetralogy of Fallot, High Cholesterol, and Cholesterol FAQs.

MISCELLANEOUS

Section 9 of 11

Medical/Legal Pitfalls:

• Failure to exclude the possibility of biliary atresia in the cholestatic infant with presumed Alagille syndrome



• Failure to recognize and treat fat-soluble vitamin deficiencies to minimize complications



• Failure to appropriately evaluate for cardiac murmurs, cerebrovascular symptoms and hypertension



• Failure to screen for possible malignancy (hepatocellular carcinoma) in the older patient with long-standing liver disease

TEST QUESTIONS

Section 10 of 11

CME Question 1: Which of the following is not commonly found in patients with Alagille syndrome?

A: Hemivertebrae
B: Deletion of 20p12
C: Posterior embryotoxon
D: Peripheral pulmonic stenosis
E: Intrahepatic bile duct paucity

The correct answer is B: Fewer than 8% of patients with Alagille syndrome have complete deletions of the JAG1 gene localized to 20p12.

CME Question 2: A patient with cholestatic jaundice presents with the following laboratory data: Hgb (8 g/dL), prothrombin time 14.9 seconds, albumin 3.0 g/dL, alkaline phosphatase (1200 IU normal limit [200-400 IU]), gamma-glutamyl transpeptidase (GGT) (590) (normal limit 60-140). On examination, the child has ascites, slightly diminished deep tendon reflexes, xanthomas, and an erythematous exudative rash around the anus. Which of the following would not be appropriate for further evaluation?

A: Vitamin E level
B: Factor VII level
C: 25-OH vitamin D level
D: Serum zinc level
E: Vitamin A level

The correct answer is B: This patient manifests several suspicious signs for fat-soluble vitamin deficiencies, including anemia (secondary to hemolysis), prolongation of prothrombin time, diminished deep tendon reflexes, and elevation of alkaline phosphatase. The combination of low-serum albumin and perianal rash could represent treatable zinc deficiency. The clinical history suggests chronic liver disease with cholestasis, not fulminant hepatic failure; therefore, assessment of clotting factors prior to trial of vitamin K supplementation would have very little long-term clinical implications.

Pearl Question 1 (T/F): Patients with Alagille syndrome develop xanthomas due to marked hypercholesterolemia from elevated serum bile acids.

The correct answer is True: Patients with Alagille syndrome have marked hypercholesterolemia arising from elevations in serum bile acids.

Pearl Question 2 (T/F): The inheritance pattern for Alagille syndrome is autosomal recessive.

The correct answer is False: Alagille syndrome is an autosomal dominant disorder with variable expression localized to the JAG1 gene on chromosome 20p12.

Pearl Question 3 (T/F): The presence of a posterior embryotoxon is diagnostic for Alagille syndrome.

The correct answer is False: Posterior embryotoxon represents the accumulation of pigment on the inner aspect of the cornea near the junction of the iris and cornea. A posterior embryotoxon can be found in approximately 10% of normal eyes; Byler disease and alpha-1 antitrypsin deficiency can also be found.

Pearl Question 4 (T/F): A variety of cardiovascular disorders are associated with Alagille syndrome (AS).

The correct answer is True: Patients with AS may present with the following cardiovascular problems: (1) Cardiac murmurs, which are present in more than 95% of patients with AS. The majority has stenosis within the pulmonary tree (peripheral pulmonic stenosis). Hemodynamically significant lesions found in patients with AS include the atrial septal defect, ventricular septal defect, tetralogy of Fallot, patent ductus arteriosus, and pulmonary atresia. (2) Patients with AS have elevated levels of plasma cholesterol, low-density lipoprotein (LDL), and apoprotein B predisposing to the premature development of atherosclerosis. (3) Patients with AS have a higher incidence of structural renal disease ranging from duplications to renal artery stenosis, as well as glomerulosclerosis or nephrosclerosis attributed to hypercholesterolemia or lecithin cholesterol acyltransferase (LCAT) deficiency.

BIBLIOGRAPHY

Section 11 of 11

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