Alagille Syndrome

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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 are shown in the image below.



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Typical facial features of Alagille syndrome. Note broad forehead, deep-set eyes and pointed chin. Courtesy of University of Washington, Seattle (Pago....

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] Notch signaling has been found to regulate formation of 3-dimensional intrahepatic biliary architecture in murine models.[7] A minority (6-7%) of patients have complete deletion of JAG1, and approximately 15-50% of mutations are spontaneous.

Epidemiology

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.

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.[8] 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.[9] 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.[10] 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 have reported an association between Wolff-Parkinson-White syndrome in a subset of patients with Alagille syndrome.[11]

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.[10]

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. Data from one study show that renal involvement was present in 73 (39%) of 187 of the evaluable pediatric Alagille syndrome patients studied, with renal dysplasia being the most common anomaly. The researchers suggested that renal involvement be considered a defining criterion for Alagille syndrome.

Recent data suggest a role for NOTCH2 and JAG1 in proximal nephron structures/podocytes, which contribute to the observed phenotypes of renal dysplasia and proteinuria seen in Alagille syndrome; renal tubular acidosis may be the result of JAG1 expression in the collecting ducts.[12, 13]

Vascular

Vascular lesions have been recently described in 6% of the patients with confirmed Alagille syndrome who were followed by Kamath et al.[14] 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.

Laboratory Studies

Lab studies may include the following:

Imaging Studies

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

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.

Medical Care

Treatment strategies include the following:

Surgical Care

Surgical strategies include the following:

Consultations

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

Diet

Dietary considerations may include the following:

Activity

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

Patients with evidence of hypersplenism should avoid contact sports.

Medication Summary

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

Hydroxyzine (Atarax, Vistaril)

Clinical Context:  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.

Cholestyramine (Questran)

Clinical Context:  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.

Rifampin (Rifadin, Rimactane)

Clinical Context:  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.

Class Summary

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

Phytonadione (AquaMEPHYTON)

Clinical Context:  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.

Vitamin E (Nutr-E-Sol)

Clinical Context:  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.

Ergocalciferol (Calciferol, Drisdol)

Clinical Context:  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.

Vitamin A (Palmitate-A 5000, Aquasol-A)

Clinical Context:  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.

Class Summary

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

Zinc (Galzin, Orazinc, Verazinc, Zincate)

Clinical Context:  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.

Class Summary

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

Ursodeoxycholic acid (Actigall)

Clinical Context:  Decreases cholesterol content of bile.

Class Summary

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

Further Outpatient Care

Further care may include the following:

Further Inpatient Care

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

The following complications are possible:

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 eMedicineHealth's Heart Health Center and Cholesterol Center. Also, see eMedicineHealth's patient education articles Tetralogy of Fallot, High Cholesterol, and Cholesterol FAQs.

Author

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

Disclosure: Nothing to disclose.

Specialty Editors

Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Chief Editor

Carmen Cuffari, MD, Associate Professor, Department of Pediatrics, Division of Gastroenterology/Nutrition, Johns Hopkins University School of Medicine

Disclosure: Received honoraria from Prometheus Laboratories for speaking and teaching; Received honoraria from Abbott Nutritionals for speaking and teaching. for: Abbott Nutritional, Abbvie, speakers' bureau.

Additional Contributors

Robert Baldassano, MD, Director, Center for Pediatric Inflammatory Bowel Disease, Children's Hospital of Philadelphia; Professor, Department of Pediatrics, Division of Gastroenterology and Nutrition, University of Pennsylvania School of Medicine

Disclosure: Received consulting fee from Abbott, Inc for consulting.

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Typical facial features of Alagille syndrome. Note broad forehead, deep-set eyes and pointed chin. Courtesy of University of Washington, Seattle (Pagon RA, Adam MP, Ardinger HH, et al, Eds. Seattle (WA): University of Washington, Seattle; 1993-2014. Available at: www.ncbi.nlm.nih.gov/books/NBK1116/).

Typical facial features of Alagille syndrome. Note broad forehead, deep-set eyes and pointed chin. Courtesy of University of Washington, Seattle (Pagon RA, Adam MP, Ardinger HH, et al, Eds. Seattle (WA): University of Washington, Seattle; 1993-2014. Available at: www.ncbi.nlm.nih.gov/books/NBK1116/).