Alagille Syndrome Workup

Updated: Jun 15, 2023
  • Author: Ann Scheimann, MD, MBA; Chief Editor: Carmen Cuffari, MD  more...
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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.

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]


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. 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.


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.


Histologic Findings

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.