Alagille Syndrome (ALGS)


Alagille syndrome (ALGS) is a rare genetic multiorgan disorder characterized by intrahepatic bile duct paucity and symptoms such as pruritus, jaundice, xanthomas, hepatomegaly, splenomegaly, kidney dysplasia, renal tubular acidosis, and vesicoureteral reflux. However, there are patients with other conditions who also present with bile duct paucity and/or other ALGS symptoms, which can make diagnosis difficult.1

The differential diagnoses of Alagille syndrome include biliary atresia, congenital hepatic fibrosis, cystic fibrosis, neonatal jaundice, polycystic kidney disease, progressive familial intrahepatic cholestasis, and tyrosinemia.2

Trichrome stain of liver cirrhosis

Biliary Atresia

Biliary atresia is a rare congenital condition characterized by the blockage of bile ducts in the liver leading to a buildup of bile inside the liver, causing damage and cirrhosis, and eventually liver failure.3 The etiology of biliary atresia is unknown but it could possibly be the result of developmental defects or an autoimmune response.

Some of the symptoms of biliary atresia overlap with those of ALGS and include jaundice, dark urine, acholic stools, weight loss, and irritability. The 2 conditions may be indistinguishable from one another in the neonatal period and ALGS may be misdiagnosed as biliary atresia.

Mutations in the Jagged 1 (JAG1) gene have also been found in a subset of patients with biliary atresia, making a definite diagnosis even more difficult.4 

However, patients with ALGS also present with other features or so-called classic criteria including cholestasis; characteristic facial features such as a broad forehead, deep-set eyes, prominent ears, a straight nose, and a pointed chin; congenital heart disease; skeletal abnormalities like “butterfly” vertebrae; and posterior embryotoxon on top of bile duct paucity. A patient can be diagnosed with ALGS (and not biliary atresia) if they meet at least 3 of these classic criteria.5

Congenital Hepatic Fibrosis

Congenital hepatic fibrosis is a rare disease that also affects the liver. It is characterized by the abnormal development of the portal veins and bile ducts that begins with a malformation of the ductal plate during embryonic development.

The symptoms of congenital hepatic fibrosis include swollen abdomen, an abnormally shaped liver, portal hypertension, hepatic fibrosis, nephromegaly, polycystic kidney disease, gastrointestinal bleeding and hematemesis, and splenomegaly.

Congenital hepatic fibrosis is usually associated with hepatorenal fibrocystic diseases such as polycystic kidney disease, nephronophthisis, and chronic tubulointerstitial disease caused by mutations in many different genes and can be inherited in an autosomal recessive, autosomal dominant, or X-linked manner.6

cystic fibrosis

Cystic Fibrosis

Bile duct paucity can also be found in patients with cystic fibrosis.1 Other symptoms may also overlap between cystic fibrosis and ALGS, such as greasy stool and poor growth. However, patients with cystic fibrosis also have distinct symptoms, including salty-tasting skin, persistent cough, wheezing or shortness of breath, and frequent lung infections such as pneumonia or bronchitis.7

A genetic test can help differentiate between the 2 conditions. While there is a mutation in JAG1 or NOTCH2 genes in ALGS, cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.8

Neonatal Jaundice

Neonatal jaundice is a common condition, especially in preterm infants,9 and occurs because the infant’s liver is not mature enough to maintain healthy levels of bilirubin. However, this usually subsides without the need for treatment, unlike in the case of ALGS. 

Jaundice should subside by itself within 2 weeks of birth.10 However, if it does not and an infant meets 3 of the other classic criteria of ALGS, a genetic test may be necessary to confirm a diagnosis of ALGS.

Polycystic Kidney Disease - ALGS

Polycystic Kidney Disease

Polycystic kidney disease is a genetic condition characterized by multiple cysts growing inside the kidneys.11 Mutations in the PKD1, PKD2, and PKHD1 genes may cause polycystic kidney disease. 

Some patients with ALGS predominantly present with renal findings and little or no hepatic involvement. Renal insufficiency has also been reported in children with ALGS and end-stage liver disease.12

Both JAG1 and NOTCH2 play an important role in the formation of proximal nephron structures and podocytes. This could explain why ALGS causes renal dysplasia and proteinuria. Moreover, since Notch signaling is key for vascular development, its impairment can lead to vasculopathy and renal vascular hypertension in ALGS.

Genetic testing can help differentiate between polycystic kidney disease and ALGS. Increased awareness about ALGS among nephrologists can ensure the right diagnosis is reached.12 

Progressive Familial Intrahepatic Cholestasis

Contrary to ALGS, in progressive familial intrahepatic cholestasis, liver cells produce below-normal amounts of bile. However, a disruption in bile acid homeostasis can lead to a buildup of bile in the liver and cause liver disease. 

Progressive familial intrahepatic cholestasis is caused by mutations in the ATP8B1, ABCB11, or ABCB4 genes. Genetic testing can help differentiate between ALGS and progressive familial intrahepatic cholestasis.13

Tyrosinemia

Tyrosinemia is a hereditary disease caused by mutations in the FAH, TAT, or HPD genes. These mutations impair the breakdown of tyrosine in the liver. Mutations in each of the 3 genes cause a different type of disease, each with its own distinct set of symptoms. Cholestasis is an overlapping symptom of ALGS and tyrosinemia.14 The 2 conditions can be distinguished by genetic testing. 

References

  1. Diaz-Frias J, Kondamudi NP. Alagille syndrome. In: StatPearls [Internet]. StatPearls Publishing; 2021. Accessed May 8, 2021.
  2. Alagille syndrome. Orphanet. Updated March 2009. Accessed May 8, 2021.
  3. Biliary atresia. Cincinnati Children’s.  Updated June 2020. Accessed May 8, 2021.
  4. Dědič T, Jirsa M, Keil R, Rygl M, Šnajdauf J, Kotalová R. Alagille syndrome mimicking biliary atresia in early infancy. PLoS One. 2015;10(11): e0143939. doi:10.1371/journal.pone.0143939.
  5. Saleh M, Kamath BM, Chitayat D. Alagille syndrome: clinical perspectives. Appl Clin Genet. 2016;9:75-82. doi:10.2147/TACG.S86420
  6. Congenital hepatic fibrosis. National Organization of Rare Disorders. Accessed May 8, 2021.
  7. About cystic fibrosis. Cystic Fibrosis Foundation. Accessed May 8, 2021.
  8. Cystic fibrosis. Mayo Clinic. March 14, 2020. Accessed May 8, 2021.
  9. Infant jaundice. Mayo Clinic. March 17, 2020. Accessed May 8, 2021.
  10. Newborn jaundice. NHS. Updated September 4, 2018. Accessed May 8, 2021.
  11. Polycystic kidney disease. Mayo Clinic. October 14, 2020. Accessed May 8, 2021.
  12. Kamath BM, Spinner NB, Rosenblum ND. Renal involvement and the role of Notch signalling in Alagille syndrome. Nat Rev Nephrol. 2013;9(7):409-418. doi:10.1038/nrneph.2013.102 
  13. Progressive familial intrahepatic cholestasis. Medline Plus. Accessed May 8, 2021.
  14. Tyrosinemia. MedlinePlus. Accessed May 8, 2021.

Reviewed by Eleni Fitsiou, PhD, on 7/1/2021.

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