Alagille Syndrome

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.

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.

United States statistics

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

Sex- and age-related demographics

No difference in penetrance is reported between sexes.

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.

Cardiac disease and liver disease can significantly affect the life expectancy of patients with Alagille syndrome.

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%.

Morbidity/mortality

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

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.

Rock et al reported nine cases of bilateral papilledema in children with Alagille syndrome; five of the cases were associated with intracranial hypertension.[11]

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.[12]

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.[13, 14]

Vascular

Vascular lesions have been recently described in 6% of the patients with confirmed Alagille syndrome who were followed by Kamath et al.[15]  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.

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.

An international, multicenter study by Mouzaki et al concluded that the long-term hepatic outcomes of patients with Alagille syndrome can be predicted based on serum total bilirubin (between the ages of 12-24 months) combined with fibrosis on liver biopsy and the presence of xanthomata on physical examination.[16]

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

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

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

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.

A liver biopsy is suggested to evaluate architecture and histology.

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.

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 achieved with cholestyramine therapy. 

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, should 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, owing to the risk of spontaneous bacterial peritonitis. 

Treatment of cholestatic pruritus 

Pruritus is often recalcitrant to medical therapy and significantly affects 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 the management of bile acid–induced pruritus found in patients with Alagille syndrome.[17]  

Maralixibat

The ileal bile acid transport (IBAT) inhibitor maralixibat (Livmarli) was approved in September 2021 for treatment of cholestatic pruritus in patients with Alagille syndrome aged 1 year and older. The indication was expanded to include children aged 3 months and older in March 2023. Approval was based on the ICONIC study and 5 years of data from supportive studies in 86 patients with Alagille syndrome. On average, patients administered maralixibat for 22 weeks maintained pruritus reduction, whereas those in the placebo group who were withdrawn from maralixibat after week 18 returned to baseline pruritus scores by week 22.[18]  

Odevixibat 

A second iBAT inhibitor, odevixibat (Bylvay) was also approved by the FDA in June 2023 for treatment of cholestatic pruritus in patients with Alagille syndrome aged 1 year and older. Approval was based on the phase 3 ASSERT trial that showed the scratching score decreased significantly from baseline with odevixibat treatment compared with placebo (-1.7 vs -0.8; P = 0.002).[19, 20]   

 

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.[21] Whitington et al reported a series of patients treated with partial external biliary diversion for pruritus associated with Alagille syndrome.[22] 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:[23]

• 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. Among children with cholestatic liver disease, 1-year and 5-year survival after liver transplantation is significantly lower in children with Alagille syndrome than in children with biliary atresia.[24]

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%.

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 the patient also has significant intracardiac disease. Patients with evidence of hypersplenism should avoid contact sports.

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

Class Summary

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.

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.

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.

Class Summary

Inhibitors of ileal bile acid transport (IBAT) act locally in the distal ileum to decrease reuptake of bile acids and increase clearance of bile acids through the colon, thereby, reducing bile acid serum concentration.

Maralixibat (Livmarli)

Indicated for cholestatic pruritus in patients with Alagille syndrome aged 3 months and older.

Odevixibat (Bylvay)

Indicated for cholestatic pruritus in patients with Alagille syndrome aged 12 months and older. 

Class Summary

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.

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.

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.

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.

Class Summary

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.

Class Summary

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

Ursodiol (Actigall, Urso Forte)

Decreases cholesterol content of bile.

Further care may include the following:

• 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.

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.

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.

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.