Causes of neonatal cholestasis

Obstruction

Biliary atresia^¶
Biliary cysts
Inspissated bile/mucous plug
Cholelithiasis or biliary sludge
Tumors/masses (intrinsic and extrinsic to the bile duct)
Neonatal sclerosing cholangitis (MIM #617394)^[1]
Spontaneous perforation of the bile ducts

Infection^¶

Viral

Adenovirus, cytomegalovirus, echovirus, enterovirus, herpes simplex virus, HIV, parvovirus B19, rubella

Bacterial

Urinary tract infection, sepsis, syphilis

Protozoal

Toxoplasma

Genetic/metabolic disorders

Inherited cholestatic disorders

Alagille syndrome^¶^Δ (MIM #118450)
Alpha-1 antitrypsin deficiency (PI*Z homozygotes or PI*SZ heterozygotes)^¶ (MIM #613490)
ARC syndrome (arthrogryposis-renal dysfunction-cholestasis) (MIM #208085)
Cystic fibrosis (MIM #219700)
Progressive familial intrahepatic cholestasis (types 1 to 5)^¶^◊ (MIM #211600, MIM #601847, MIM #602347, MIM #615878, MIM #617049)
MYO5B gene mutations (with or without congenital diarrhea due to microvillus inclusion disease)^[2] (MIM #251850, MIM #619868)
NISCH syndrome (neonatal ichthyosis sclerosing cholangitis) (MIM #607626)
Dubin-Johnson syndrome^§^[3] (MIM #237500)
Rotor syndrome (MIM #237450)
Aagenaes syndrome (MIM %214900)^[4]
USP53 gene mutations (MIM #619658)^[5]

Disorders of carbohydrate metabolism

Galactosemia^¶ (MIM #230400)
Fructosemia (MIM #229600)
Glycogen storage disease type IV (MIM #232500)
Transaldolase deficiency (MIM #606003)^[6]

Disorders of amino acid metabolism

Tyrosinemia (type 1)^¶ (MIM #276700)

Disorders of lipid metabolism

Lysosomal acid lipase deficiency (Wolman disease) (MIM #278000), Niemann-Pick type C (MIM #257220), Gaucher type 2 (MIM #230900)
Fatty acid oxidation defects (eg, MIM #201470, MIM #201475)

Disorders of bile acid synthesis

Bile acid synthesis defects (types 1 to 6) (MIM #607765, MIM #235555, MIM #613812, MIM #214950, MIM #616278, MIM #617308)
Cerebrotendinous xanthomatosis (MIM #213700)
Amidation defects (BAAT or SLC27A5 gene mutations)
Zellweger spectrum disorders^◊ (MIM #214100 and others)
Smith-Lemli-Opitz syndrome^◊ (MIM #270400)

Mitochondrial disorders^¥

Urea cycle defect

Citrin deficiency (type II) (MIM #605814)

Congenital disorders of glycosylation

Phosphomannomutase 2 deficiency (MIM #212065)
Phosphoglucomutase 1 deficiency (MIM #614921)
Mannosephosphate isomerase deficiency (MIM #602579)

Alloimmune

Gestational alloimmune liver disease

Toxic

Intestinal failure-associated liver disease (parenteral nutrition)^¶
Drugs (ceftriaxone, erythromycin, sulfa-containing medications)

Miscellaneous

"Idiopathic" neonatal hepatitis
Nonsyndromic paucity of the interlobular bile ducts
Hemophagocytic lymphohistiocytosis
Shock/hypoperfusion
Intestinal obstruction
Congenital portosystemic shunt
Hypothyroidism
Hypopituitarism (eg, in septo-optic dysplasia)

This table summarizes disorders in which cholestasis can be a prominent feature in the neonatal period. For disorders that present with hepatic failure, refer to UpToDate content on acute hepatic failure in infants and children.

HIV: human immunodeficiency virus.

¶ More common disorders causing neonatal cholestasis.

Δ Alagille syndrome is also known as syndromic paucity of the interlobular bile ducts or arteriohepatic dysplasia.

◊ These disorders are classified as secondary bile acid metabolic defects.

§ Presentation of Dubin-Johnson syndrome in neonates and young infants is rare but has been reported^[3].

¥ For mitochondrial hepatopathies, refer to UpToDate table and content on acute liver failure in infants and children.

References:

Grammatikopoulos T, Sambrotta M, Strautnieks S, et al. Mutations in DCDC2 (doublecortin domain containing protein 2) in neonatal sclerosing cholangitis. J Hepatol 2016; 65:1179.
Cockar I, Foskett P, Strautnieks S, et al. Mutations in Myosin 5B in Children With Early-onset Cholestasis. J Pediatr Gastroenterol Nutr 2020; 71:184.
Towaga T, Mizuochi T, Sugiura T, et al. Clinical, Pathologic, and Genetic Features of Neonatal Dubin-Johnson Syndrome: A Multicenter Study in Japan. J Pediatr 2018; 196:161.
Almaas R, Atneosen-Åsegg M, Ytre-Arne ME, et al. Aagenaes syndrome/lymphedema cholestasis syndrome 1 is caused by a founder variant in the 5'-untranslated region of UNC45A. J Hepatol 2023; S0168-8278(23)00410-5.
Bull LN, Ellmers R, Foskett P, et al. Cholestasis Due to USP53 Deficiency. J Pediatr Gastroenterol Nutr 2021; 72:667.
Grammatikopoulos T, Hadzic N, Foskett P, et al. Liver Disease and Risk of Hepatocellular Carcinoma in Children With Mutations in TALDO1. Hepatol Commun; 6:473.

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Causes of neonatal cholestasis