eMedicine Specialties > Pediatrics: General Medicine > Gastroenterology

Alagille Syndrome

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

Updated: Oct 22, 2009

Introduction

Background

Alagille syndrome (AS) is an autosomal dominant disorder (OMIM 118450) associated with abnormalities of the liver, heart, skeleton, eye, and kidneys and a characteristic facial appearance.¹ In 1973, Watson and Miller reported 9 cases of neonatal liver disease with familial pulmonary valvular stenosis.² Then in 1975, Alagille et al described several patients with hypoplasia of the hepatic ducts with associated features.³

Typical facial features of Alagille syndrome. Note broad forehead, deep-set eyes and pointed chin.

Pathophysiology

Alagille syndrome is an autosomal dominant disorder with variable expression. Associated abnormalities include those of the liver, heart, eye, skeleton, and kidneys and characteristic facial features. Mild-to-moderate mental retardation also may be present. Mutations in either jagged-1 (JAG1) or notch-2 (NOTCH2) have been reported in patients with Alagille syndrome.^4,5 The syndrome has been mapped to the 20p12-jagged-1 locus, JAG1, which encodes a ligand critical to the notch gene–signaling cascade that is important in fetal development.^6,5 A minority (6-7%) of patients have complete deletion of JAG1, and approximately 15-50% of mutations are spontaneous.

Frequency

United States

The incidence rate is approximately 1 case in every 100,000 live births.

Mortality/Morbidity

Major contributors to morbidity arise from bile duct paucity or cholestatic liver disease, underlying cardiac disease, CNS vasculopathy, Moyamoya 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, are often diagnosed after an index case.

Clinical

Physical

Presentation of Alagille syndrome (AS) varies. Some patients are diagnosed after prolonged neonatal jaundice or when liver biopsy findings reveal 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 also be present.⁷ Studies to assess the impact of higher doses of growth hormone on linear growth in patients with Alagille syndrome are currently underway.
• Head and neck
  • Commonly associated facial features include 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 ages.
• Ophthalmologic
  • Ocular abnormalities are common.⁸ The most frequent ophthalmologic finding is a posterior embryotoxon, which was observed in more than 75% of patients in one large series conducted by Emerick et al.⁹
  • Some of these patients may also have the 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 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 Alagille syndrome at increased mortality risk.
  • Recent data has reported an association between Wolff-Parkinson-White syndrome in a subset of patients with Alagille syndrome.¹⁰
• Hepatic
  • Hepatic disease is a key feature of Alagille syndrome.
  • Most infants 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 are frequently associated with Alagille syndrome.
  • Butterfly hemivertebrae were found in one half of the patients analyzed by Emerick et al in a large series of patients with Alagille syndrome.⁹
  • 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 Alagille syndrome.
  • If noted during the physical examination, diminished deep tendon reflexes 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 Alagille syndrome who were followed by Kamath et al.¹¹ 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

• Alagille syndrome 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. Few patients, generally those with more severe phenotypes, have complete deletion of the JAG1 gene.

Differential Diagnoses

Other Problems to Be Considered

Byler disease
Choledochal cyst
Inspissated bile syndrome

Workup

Laboratory Studies

• Evaluate patients with Alagille syndrome (AS) for chronic liver disease, including parameters of function and differential diagnoses.
  • Fat-soluble vitamin deficiencies are frequently observed in Alagille syndrome.
  • Prolongation of prothrombin time (PT) or activated partial thromboplastin time (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 Alagille syndrome 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 are generally elevated. If significant discrepancies are observed between the degree of elevation of GGT and alkaline phosphatase levels, consider the possibility of occult zinc deficiency or vitamin D deficiency.
• The total bilirubin level during infancy is generally 4-14 mg/dL with a direct fraction generally greater than 30% of total bilirubin. In most 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 Alagille syndrome, 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).
• In infants with cholestatic liver disease, exclude other diagnoses including cystic fibrosis (sweat chlorine or cystic fibrosis DNA testing), hypothyroidism (thyroid functions), galactosemia (urine-reducing substance), sepsis or infection (urinary tract infection or cytomegalovirus), 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 Alagille syndrome. DNA sequencing is required for confirmation of diagnosis in most patients with Alagille syndrome 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 ultrasonography 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 Wolff-Parkinson-White or 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.

Histologic Findings

• Liver biopsy specimens typically exhibit features suggestive of chronic cholestasis and paucity of interlobular bile ducts. 
• Most biopsy findings (wedge or needle) reveal features of bile duct paucity; typically, biopsy findings reveal interlobular bile ducts-to-portal ratio of less than 0.4 in 10 portal tracts. However, biopsy findings during the neonatal period may exhibit ballooning and giant cell transformation of hepatocytes.
• Bile duct proliferation in biopsy samples of young infants has rarely been reported.

Treatment

Medical Care

• Correction of vitamin deficiencies with appropriate vitamin dosage is important for optimal growth and development in patients with Alagille syndrome (AS). 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) are generally well tolerated by patients and are better absorbed. Zinc deficiency is sometimes observed; zinc is easily replaced via oral compounds.
• Some decreases in the degree of hyperlipidemia have been treated with cholestyramine.
• Pruritus is often 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.¹²
• 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 cholangiography is not infrequent in patients with Alagille syndrome. Some studies have noted that 3-5% of patients undergoing the Kasai procedure for EHBA are eventually diagnosed with nonsyndromic bile duct paucity or Alagille syndrome.
• Surgical management for bile acid–induced pruritus includes biliary diversion and eventual orthotopic liver transplantation for those with refractory disease.¹³ Whitington et al reported a series of patients treated with partial external biliary diversion for pruritus associated with Alagille syndrome.¹⁴ They noted a decrease in bile salt concentrations and some abatement of pruritus and xanthomas; however, the results for the patients with Alagille syndrome were less striking than with other preoperative diagnoses, including progressive familial intrahepatic cholestasis.
• Indications for consideration of liver transplantation include the following:¹⁵
  • 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, ventricular septal defect (VSD) with pulmonary atresia (PA), atrial septal defect (ASD) and VSD, and patent ductus arteriosus (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.
• Consultation with a cardiologist can assist with the diagnosis of Alagille syndrome and therapy for intracardiac disease, as well as other vascular abnormalities.
• Consultation with a nephrologist is indicated if significant structural renal disease is present or if suspicions of evolving renal insufficiency arise.

Diet

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

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

Antipruritics

Pruritus is often recalcitrant to medical therapy and significantly impacts on the quality of life.

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.

Dosing

Adult

25 mg PO tid/qid

Pediatric

0.6 mg/kg/dose PO q6h

Interactions

CNS depression may increase with alcohol or other CNS depressants

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

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

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.

Dosing

Adult

3-4 g PO tid/qid; not to exceed 16-32 g/d PO divided bid/qid

Pediatric

240 mg/kg/d PO divided tid

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

Contraindications

Documented hypersensitivity; complete biliary obstruction

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

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

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.

Dosing

Adult

300 mg/d PO qd or divided bid

Pediatric

10 mg/kg/d PO qd or divided bid; not to exceed adult dose

Interactions

Induces microsomal enzymes, which may decrease effects of acetaminophen, PO anticoagulants, barbiturates, benzodiazepines, beta-blockers, chloramphenicol, PO 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 LFT results occur); cotrimoxazole and probenecid may increase blood level

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Obtain CBC counts 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

Fat-soluble vitamins

These vitamins are used for supplementation of vitamin A, D, E, and K losses.

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.

Dosing

Adult

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

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

Interactions

Effects of warfarin sodium and dicumarol are antagonized by phytonadione

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

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

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 RBCs 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.

Dosing

Adult

400-1200 IU (15-45 mL) PO qd; based on monitoring of levels

Pediatric

15-25 IU/kg/d; based on monitoring of levels

Interactions

Mineral oil decreases absorption of vitamin E; vitamin E delays absorption of iron and increases effects of anticoagulants

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Pregnancy factor with large doses of vitamin E is C; vitamin E may induce vitamin K deficiency; NEC 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

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.

Dosing

Adult

10,000-80,000 IU/d PO plus 1-2 g/d PO of elemental phosphorus

Pediatric

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

Interactions

Cholestyramine and colestipol decrease absorption; magnesium-containing antacids and thiazide diuretics can increase effects

Contraindications

Documented hypersensitivity; hypercalcemia; malabsorption syndrome

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Maintain adequate fluid intake; can cause hypercalcemia, hypercalciuria, and pseudotumor cerebri; caution in impaired renal function and heart disease

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; 1 RE = 1 mcg retinol, and 1 RE of vitamin A = 3.33 units of retinol and 10 u of beta-carotene.

Dosing

Adult

Dietary supplement: 4000-5000 IU/d PO
RDI: 2670 IU/d (females) and 3330 IU/d (males)

Pediatric

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

Interactions

Mineral oil and cholestyramine decrease absorption; oral contraceptives increase plasma levels

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

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

Trace Element

Zinc deficiency is sometimes seen; zinc is easily replaced via oral compounds.

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 on 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.

Dosing

Adult

25-50 mg elemental zinc PO qd or divided bid/tid

Pediatric

<10 years: 0.5-1 mg/kg/d elemental
>10 years: 15-25 mg elemental zinc PO qd

Interactions

May reduce penicillamine and tetracycline effects; iron decreases uptake; bran and dairy products decrease absorption

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in renal impairment; nausea, vomiting, dyspepsia, and pancreatitis reported; administer with food to minimize GI upset

Bile Acid

This agent promotes bile salt excretion via direct stimulation of bile flow and via indirect alterations in composition of bile.

Ursodeoxycholic acid (Actigall)

Decreases cholesterol content of bile.

Dosing

Adult

3 mg/kg/dose PO bid

Pediatric

10-15 mg/kg/dose PO bid/tid

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

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Overdosage may result in diarrhea

Follow-up

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 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 or 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 Alagille syndrome 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 subacute bacterial endocarditis (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. 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 occurs in many children with Alagille syndrome, 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 Alagille syndrome. Cardiac murmurs are noted in fewer than 95% of patients. Structural anomalies associated with Alagille syndrome range from mild peripheral pulmonic stenosis to severe tetralogy of Fallot. Aneurysms and stenotic lesions have been described within the arterial system (eg, 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 have been described in patients with Alagille syndrome. Renal anomalies include renal artery stenosis, ectopic kidney, single kidney, and ureteral duplications. The development of glomerulosclerosis in patients with Alagille syndrome 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 Alagille syndrome; presence of hepatic disease also alters life expectancy.
• Patients with more significant cardiovascular anomalies (tetralogy of Fallot, pulmonary atresia [PA] with ventricular septal defect [VSD], atrial septal defect [ASD]/VSD, patent ductus arteriosus [PDA]) eventually require cardiac surgery. The 20-year predicted survival rate via Kaplan-Meier plots for individuals with significant intracardiac lesions is 40%; 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

Medicolegal 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

Multimedia

Media file 1: Typical facial features of Alagille syndrome. Note broad forehead, deep-set eyes and pointed chin.

References

1. Krantz ID, Piccoli DA, Spinner NB. Alagille syndrome. J Med Genet. Feb 1997;34(2):152-7. [Medline].

2. Watson GH, Miller V. Arteriohepatic dysplasia: familial pulmonary arterial stenosis with neonatal liver disease. Arch Dis Child. Jun 1973;48(6):459-66. [Medline].

3. Alagille D, Odievre M, Gautier M, Dommergues JP. Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental, and sexual development, and cardiac murmur. J Pediatr. Jan 1975;86(1):63-71. [Medline].

4. McDaniell R, Warthen DM, Sanchez-Lara PA, et al. NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway. Am J Hum Genet. Jul 2006;79(1):169-73. [Medline].

5. Li L, Krantz ID, Deng Y, et al. Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet. Jul 1997;16(3):243-51. [Medline].

6. Krantz ID, Colliton RP, Genin A, et al. Spectrum and frequency of jagged1 (JAG1) mutations in Alagille syndrome patients and their families. Am J Hum Genet. Jun 1998;62(6):1361-9. [Medline].

7. Bucuvalas JC, Horn JA, Carlsson L, et al. Growth hormone insensitivity associated with elevated circulating growth hormone-binding protein in children with Alagille syndrome and short stature. J Clin Endocrinol Metab. Jun 1993;76(6):1477-82. [Medline].

8. Hingorani M, Nischal KK, Davies A, et al. Ocular abnormalities in Alagille syndrome. Ophthalmology. Feb 1999;106(2):330-7. [Medline].

9. Emerick KM, Rand EB, Goldmuntz E, et al. Features of Alagille syndrome in 92 patients: frequency and relation to prognosis. Hepatology. Mar 1999;29(3):822-9. [Medline].

10. Lalani SR, Thakuria JV, Cox GF, Wang X, Bi W, Bray MS. 20p12.3 microdeletion predisposes to Wolff-Parkinson-White syndrome with variable neurocognitive deficits. J Med Genet. Mar 2009;46(3):168-75. [Medline].

11. Kamath BM, Spinner NB, Emmerich KM, et al. Vascular anomalies in Alagille syndrome: a significant cause of morbidity and mortality. Circulation. 2004;110:1354-8. [Medline]. [Full Text].

12. Cynamon HA, Andres JM, Iafrate RP. Rifampin relieves pruritus in children with cholestatic liver disease. Gastroenterology. Apr 1990;98(4):1013-6. [Medline].

13. Kasahara M, Kiuchi T, Inomata Y, et al. Living-related liver transplantation for Alagille syndrome. Transplantation. Jun 27 2003;75(12):2147-50. [Medline].

14. Whitington PF, Whitington GL. Partial external diversion of bile for the treatment of intractable pruritus associated with intrahepatic cholestasis. Gastroenterology. Jul 1988;95(1):130-6. [Medline].

15. [Guideline] Murray KF, Carithers RL Jr. AASLD practice guidelines: Evaluation of the patient for liver transplantation. Hepatology. Jun 2005;41(6):1407-32. [Medline]. [Full Text].

16. Bekassy AN, Garwicz S, Wiebe T, et al. Hepatocellular carcinoma associated with arteriohepatic dysplasia in a 4-year-old girl. Med Pediatr Oncol. 1992;20(1):78-83. [Medline].

17. Danks DM, Campbell PE, Jack I, et al. Studies of the aetiology of neonatal hepatitis and biliary atresia. Arch Dis Child. May 1977;52(5):360-7. [Medline].

18. Gottrand F, Clavey V, Fruchart JC, Farriaux JP. Lipoprotein pattern and plasma lecithin cholesterol acyl transferase activity in children with Alagille syndrome. Atherosclerosis. Jun 1995;115(2):233-41. [Medline].

19. Hoffenberg EJ, Narkewicz MR, Sondheimer JM, et al. Outcome of syndromic paucity of interlobular bile ducts (Alagille syndrome) with onset of cholestasis in infancy. J Pediatr. Aug 1995;127(2):220-4. [Medline].

20. Kay MH, Wyllie R, Steffen RM. Use of ursodeoxycholic acid in the treatment of arteriohepatic dysplasia. Clin Pediatr (Phila). Nov 1996;35(11):593-6. [Medline].

21. Martin SR, Garel L, Alvarez F. Alagille's syndrome associated with cystic renal disease. Arch Dis Child. Mar 1996;74(3):232-5. [Medline].

22. Miguet JP, Mavier P, Soussy CJ, Dhumeaux D. Induction of hepatic microsomal enzymes after brief administration of rifampicin in man. Gastroenterology. May 1977;72(5 Pt 1):924-6. [Medline].

23. Oestreich AE, Sokol RJ, Suchy FJ, Heubi JE. Renal abnormalities in arteriohepatic dysplasia and nonsyndromic intrahepatic biliary hypoplasia. Ann Radiol (Paris). Feb-Mar 1983;26(2-3):203-9. [Medline].

24. Quiros-Tejeira RE, Ament ME, Heyman MB, et al. Variable morbidity in alagille syndrome: a review of 43 cases. J Pediatr Gastroenterol Nutr. Oct 1999;29(4):431-7. [Medline].

25. Rabinovitz M, Imperial JC, Schade RR, Van Thiel DH. Hepatocellular carcinoma in Alagille's syndrome: a family study. J Pediatr Gastroenterol Nutr. Jan 1989;8(1):26-30. [Medline].

26. Russo PA, Ellis D, Hashida Y. Renal histopathology in Alagille's syndrome. Pediatr Pathol. 1987;7(5-6):557-68. [Medline].

27. Shulman SA, Hyams JS, Gunta R. Arteriohepatic dysplasia (Alagille syndrome): extreme variability among affected family members. Am J Med Genet. Oct 1984;19(2):325-32. [Medline].

Keywords

Alagille syndrome, AS, Alagille's syndrome, Alagille-Watson syndrome, arteriohepatic dysplasia, syndromic bile duct paucity, pulmonary valvular stenosis, hypoplasia of the hepatic ducts, mental retardation, treatment, diagnosis

Contributor Information and Disclosures

Author

Ann Scheimann, MD, MBA, Associate 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
Disclosure: Nothing to disclose.

Medical Editor

Robert Baldassano, MD, Director, Center for Pediatric Inflammatory Bowel Disease, Division of Gastroenterology and Nutrition, Associate Professor, Department of Pediatrics, The Children's Hospital of Philadelphia, University of Pennsylvania
Robert Baldassano, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Gastroenterological Association, and North American Society for Pediatric Gastroenterology and Nutrition
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

CME Editor

Steven M Schwarz, MD, FAAP, FACN, AGAF, Professor of Pediatrics, Children's Hospital at Downstate, SUNY-Downstate Medical Center
Steven M Schwarz, MD, FAAP, FACN, AGAF is a member of the following medical societies: American Academy of Pediatrics, American College of Nutrition, American College of Physician Executives, American Gastroenterological Association, American Pediatric Society, Gastroenterology Research Group, New York Academy of Medicine, North American Society for Pediatric Gastroenterology and Nutrition, and Society for Pediatric Research
Disclosure: TAP Pharmaceuticals Honoraria Speaking and teaching; Curemark, LLC Consulting fee Board membership; Centocor, Inc. Grant/research funds Independent contractor

Chief Editor

Carmen Cuffari, MD, Associate Professor, Department of Pediatrics, Division of Gastroenterology/Nutrition, Johns Hopkins University School of Medicine
Carmen Cuffari, MD is a member of the following medical societies: American College of Gastroenterology, American Gastroenterological Association, North American Society for Pediatric Gastroenterology, Hepatology and Nutrition, and Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

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