Alagille Syndrome and PFIC
On this page
Direct answer
Alagille syndrome is a multisystem disorder with paucity of intrahepatic bile ducts, caused mainly by JAG1 mutations and presenting as cholestasis with high gamma-glutamyl transferase. Progressive familial intrahepatic cholestasis, or PFIC, is a group of inherited bile-acid and phospholipid transport defects, and gamma-GT behaviour is the first step in separating them: it is high in Alagille and PFIC-3 but low in PFIC-1 and PFIC-2.
What you must remember
- Alagille genetics: JAG1 mutations account for most cases, with NOTCH2 mutations in a smaller group, both disrupting Notch signalling.
- Alagille features: cholestasis with ductopenia, peripheral pulmonary artery stenosis, posterior embryotoxon, butterfly vertebrae and characteristic facies.
- PFIC-1: ATP8B1 (FIC1) defect with low gamma-GT, diarrhoea and sensorineural deafness.
- PFIC-2: ABCB11 defect of the bile salt export pump, with low gamma-GT and a recognised risk of hepatocellular carcinoma.
- PFIC-3: ABCB4 (MDR3) defect in phospholipid secretion into bile, with high gamma-GT and progressive biliary injury.
- Pruritus care: rifampicin, ursodeoxycholic acid and cholestyramine are the commonly used agents, with biliary diversion considered for refractory itch.
- Definitive care: liver transplantation for progressive liver failure, with cardiac anatomy assessed before surgery in Alagille syndrome.
Where the exam sets its traps
The traps centre on gamma-GT and on the extrahepatic features that define Alagille syndrome.
- Trap: diagnosing Alagille syndrome from a low gamma-GT. Correct: Alagille typically raises gamma-GT, so a low value points to PFIC-1 or PFIC-2.
- Trap: assuming PFIC-3 has low gamma-GT because the child is cholestatic. Correct: PFIC-3 has high gamma-GT, reflecting the ABCB4 phospholipid defect and biliary injury.
- Trap: examining only the liver in suspected Alagille syndrome. Correct: posterior embryotoxon, peripheral pulmonary stenosis and butterfly vertebrae complete the picture and guide surgical planning.
Frequently asked questions
Which gene is most commonly mutated in Alagille syndrome?
JAG1 mutations account for most cases of Alagille syndrome, while NOTCH2 mutations are found in a smaller subset. Both genes encode parts of the Notch signalling pathway.
Why does gamma-GT help separate Alagille syndrome from PFIC-1 and PFIC-2?
Gamma-GT is typically high in Alagille syndrome and low in PFIC-1 and PFIC-2, so it directs further testing. PFIC-3 shares the high pattern and must be separated by gene testing or biopsy.
What makes PFIC-3 different from PFIC-1 and PFIC-2?
PFIC-3 results from an ABCB4 defect in phospholipid secretion into bile, and it shows high gamma-GT. PFIC-1 and PFIC-2 are transport defects with low gamma-GT.
Which drugs are used for cholestatic pruritus in these disorders?
Rifampicin, ursodeoxycholic acid and cholestyramine are commonly used, and each is started and reviewed according to the child's response. Persistent pruritus may prompt biliary diversion or transplant assessment, decided by a paediatric hepatology team.