Quiz
CTRS-INSTIT-PLATEDUC-ONG08/20/07/20
Cortisol deficiency
Cortisol deficiency may result from a primary adrenal process, owing to maldevelopment, malfunction, or destruction of the gland or be secondary to dysfunction of the hypothalamic-pituitary-adrenal axis.39
Alpha-1-antitrypsin deficiency (AATD)
AATD is a rare autosomal recessive condition caused by a mutation in the SERPINA1 gene leading to decreased production of the neutrophil-elastase protective protein alpha-1 antitrypsin, thereby increasing the risk of serious lung and liver disease.1,5
More information about alpha-1-antitrypsin deficiency and references
Cystic fibrosis
Cystic fibrosis is an autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR is expressed in the apical surface of cholangiocytes.30
Biliary atresia
Biliary atresia is a progressive obliterative cholangiopathy of the intrahepatic and extrahepatic bile ducts. It occurs in the perinatal period causing severe, persistent jaundice and acholic stool and, if untreated, is associated with a poor prognosis.4
Neonatal sclerosing cholangitis
Neonatal sclerosing cholangitis is a rare biliary tract disease characterised by severe neonatal-onset cholangiopathy with patent bile ducts.4
More information about neonatal sclerosing cholangitis and references
Primary sclerosing cholangitis
Primary sclerosing cholangitis (PSC) is a rare, idiopathic, heterogeneous, chronic, cholestatic liver disease characterised by inflammation and fibrosis of both the intrahepatic and extrahepatic bile ducts, leading to the formation of multifocal bile duct strictures.54-56
More information about primary sclerosing cholangitis and references
Biliary lithiasis
Biliary lithiasis or gallstone disease is characterised by the presence of stones in the gallbladder, the biliary ducts, or both.24,25
Biliary secretion is strongly decreased by a reduction in the bile acid-dependent fraction of bile secretion. This results in cholestasis with normal serum γ-glutamyl-transferase (GGT) activity.
Choledochal cysts
Choledochal cysts are rare congenital bile duct abnormalities. 33,34
Alagille syndrome
Alagille syndrome is a multisystemic, autosomal dominant disorder caused by a defect in the notch signalling pathway leading to intrahepatic bile duct paucity and resulting in significant cholestasis.1
Cystic fibrosis
Cystic fibrosis is an autosomal recessive disorder caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. CFTR is expressed in the apical surface of cholangiocytes.42
Alpha-1-antitrypsin deficiency (AATD)
AATD is a rare autosomal recessive condition caused by a mutation in the SERPINA1 gene leading to decreased production of the neutrophil-elastase protective protein alpha-1 antitrypsin, thereby increasing the risk of serious lung and liver disease.4,5
More information about alpha-1-antitrypsin deficiency (AATD) and references
Drug toxicity
Drug-induced liver injury (DILI) is a major cause of paediatric liver disease including cholestasis, accounting for almost 20% of cases of acute liver failure in children, and is a major reason for liver transplantation.45
Biliary atresia
Biliary atresia is a progressive obliterative cholangiopathy of the intrahepatic and extrahepatic bile ducts. It occurs in the perinatal period causing severe, persistent jaundice and acholic stool and, if untreated, is associated with a poor prognosis.3
Autoimmune cholangitis
Autoimmune cholangitis (AIC), also known as autoimmune cholangiopathy, is a chronic inflammation of the liver and a variant syndrome of autoimmune hepatitis.9
More information about autoimmune cholangitis and references
Cholestasis and / or cholestatic jaundice
In newborns:
First, confirm the aetiology:1
Those requiring urgent treatment:
Biliary atresia
Urinary infection or sepsis
Cortisol deficiency
Those with an easily detectable aetiology:
Alagille syndrome
Choledochal cyst
Cystic fibrosis
Alpha-1-antitrypsine deficiency
Progressive familial intrahepatic cholestasis type 1 (PFIC1)
PFIC1 is an autosomal recessive childhood bile formation disorder of hepatocellular origin associated with extrahepatic features.31
More information about progressive familial intrahepatic cholestasis type 1 (PFIC1) and references
Progressive familial intrahepatic cholestasis type 2 (PFIC2)
PFIC2 is an autosomal recessive childhood disorder of bile formation in hepatocytes that is not associated with extrahepatic features.32 It is caused by impaired bile salt secretion due to defects in ABCB11 encoding the bile salt export pump protein (BSEP).58
More information about progressive familial intrahepatic cholestasis type 2 (PFIC2) and references
Progressive familial intrahepatic cholestasis type 3 (PFIC3)
PFIC3 is an autosomal recessive childhood disorder of bile formation in hepatocytes caused by mutations in the ABCB4 gene coding for the phospholipid transporter MDR3, which is expressed in the canalicular membrane of hepatocytes.32,58
More information about progressive familial intrahepatic cholestasis type 3 (PFIC3) and references
Cortisol deficiency
Cortisol deficiency may result from a primary adrenal process, owing to maldevelopment, malfunction, or destruction of the gland, or be secondary to dysfunction of the hypothalamic-pituitary-adrenal axis.27
Benign recurrent intrahepatic cholestasis type 1 (BRIC1)
BRIC1 is a hereditary liver disorder characterised by intermittent attacks of intrahepatic cholestasis, generally without progression to chronic liver damage. 31,32
More information about benign recurrent intrahepatic cholestasis type 1 (BRIC1) and references
Benign recurrent intrahepatic cholestasis type 2 (BRIC2)
BRIC2 is a hereditary liver disorder characterised by intermittent attacks of intrahepatic cholestasis, generally without progression to chronic liver damage.31,32
More information about benign recurrent intrahepatic cholestasis type 2 (BRIC2) and references
Tight junction protein 2 (TJP2) deficiency or progressive familial intrahepatic cholestasis type 4 (PFIC4)
TJP2 deficiency or PFIC4 is an autosomal recessive disorder caused by a mutation in the TJP2 gene, encoding the tight junction protein-2, which is involved in the organisation of epithelial and endothelial cell junctions.59 PFIC4 is characterised by early-onset cholestasis with severe progression.4
Progressive familial intrahepatic cholestasis type 5 (PFIC5)
PFIC5 is a severe autosomal recessive liver disorder caused by a mutation in the NR1H4 gene.50
More information about progressive familial intrahepatic cholestasis type 5 (PFIC5) and references
Choledochal cysts
Choledochal cysts are rare congenital bile duct abnormalities. 21,22
Biosynthesis of the primary bile acids, cholic acid (CA) and chenodeoxycholic acid (CDCA), involves numerous enzymes including 3β-HSD and Δ4-3-oxoR.
The neutral pathway, the major pathway in adults, is initiated by CYP7A1, which is the rate-limiting step in the conversion of cholesterol to CA and CDCA. During the first months of life, however, the acidic pathway is essential for the synthesis of primary bile acids. The acidic pathway is initiated by hydroxylation of cholesterol by the sterol 27-hydroxylase (CYP27). Its regulation is not fully understood.
.
Cholic acid and chenodeoxycholic acid are conjugated to glycine or taurine, which are substrates for the bile acid transport pump (BSEP).
Canalicular transport of bile acid is the rate-limiting step of bile secretion.
MYOSIN 5B DEFICIENCY
Myosin 5B deficiency causes microvillus inclusion disease. It is a severe autosomal recessive disease caused by a myosin 5B (MYO5B) mutation and characterised by malabsorption and diarrhoea.48
Bile acids are recovered from the intestines by the apical sodium-dependent bile acid transporter (ASBT).
Bile acids are transported to the liver in the portal blood and enter in the hepatocytes via sodium taurocholate cotransporting polypeptide (NTCP).
The gene encoding CYP7A1 is highly regulated by a negative feedback involving the farnesoid X receptor (FXR)-dependent induction of fibroblast growth factor 15/19 (FGF15/19) by bile acids in enterocytes.
FGF15/19 binds to the fibroblast growth factor receptor 4 (FGFR4)/b-klotho complex in hepatocytes, activating signaling pathways that transcriptionally repress CYP7A1 expression.
UNC45A DEFICIENCY (OSTEO-OTO-HEPATO-ENTERIC SYNDROME (O2HE SYNDROME))
UNC45A deficiency causes osteo-oto-hepato-enteric syndrome. It is an autosomal recessive syndrome secondary to loss of function mutations in the UNC45A gene.60
Defects in the enzymes 3β-HSD and ∆4-3-oxoR, catalysing key reactions in the formation of the primary bile acids (cholic acid and chenodeoxycholic acid), lead to inadequate synthesis of primary bile acids. Consequently, primary bile acids are not synthesized but instead atypical and hepatotoxic bile acid intermediates are formed.
Absence of primary bile acids in the intestine results in fat and fat-soluble vitamin malabsorption.
Bile acid intermediates that are hepatotoxic and cholestatic accumulate.
Suppression of the negative feedback loop further represses biosynthesis, increasing the production of bile acid intermediates, which are excreted in the urine.
Arthrogryposis-renal dysfunction-cholestasis syndrome (ARC syndrome)
ARC syndrome is an autosomal recessive disease characterised by immobility of the limbs and fixation of joints with muscle wasting (neurogenic arthrogryposis multiplex congenita), renal tubular dysfunction and neonatal cholestasis.8
Hepatitis A
Hepatitis A virus (HAV) is an RNA picornavirus which is transmitted through faecal-oral contamination.47
PRIMARY BILE ACID SYNTHESIS DEFECTS (3β-HYDROXY-Δ5-C27-STEROID DEHYDROGENASE (3β-HSD) DEFICIENCY, OR Δ4-3-OXOSTEROID 5β-REDUCTASE (Δ4-3-OXO-R) DEFICIENCY)
These inborn errors of primary bile acid synthesis are rare autosomal recessive cholestatic disorders, leading to inadequate synthesis (or complete absence) of the primary bile acids and resulting in the build-up of atypical and hepatotoxic bile acid intermediates.52
Biliary Lithiasis
Biliary lithiasis or gallstone disease is characterised by the presence of concretions in the gallbladder, the biliary ducts, or both.15,16
Other extrahepatic causes
Such as spontaneous perforation of the common bile duct or congenital stenosis, etc1
Alagille syndrome (AGS)
Alagille syndrome is a multisystemic, autosomal dominant disorder caused by a defect in the Notch signalling pathway leading to intrahepatic bile duct paucity and resulting in significant cholestasis.2