CTRS-INSTIT-PLATEDUC-ONG08/20/07/20
Unconjugated
bilirubin
Bilirubin is mainly
produced from the
break down of red
blood cells.
Red cell breakdown
produces
unconjugated
(“indirect”) bilirubin,
which circulates mostly
bound to albumin,
although some is
“free” and hence
able to enter the brain.
The terms “direct”
and “indirect” refer
to the way laboratories
measure the different
forms.
Unconjugated bilirubin
is metabolised in the
liver to produce
conjugated (“direct”)
bilirubin by uridine
diphosphate
glucuronosyltransferase.
The activity of this
enzyme only rises after
birth to reach adult like
values around the age
of three months.
Conjugation of bilirubin
increases its solubility
and facilitates its
secretion into bile.
Conjugated (“direct”)
bilirubin then passes
into the gut and is
largely excreted.
In the gastrointestinal
tract, bilirubin is modified
by digestive bacteria and
transformed into
urobilinogens . A large
portion remains in the
intestine and is
converted into stercobilin
(responsible for the
brown colour of faeces).
Some is reabsorbed into
the bloodstream and the
remainder is excreted in
the urine (urobilin is
responsible for the
yellow colour of urine).
Conjugated
bilirubin
Urobilinogens
Uridine
diphosphate
glucuronosyl-
transferase
Excreted in bile
Gut bacteria
Enterohepatic
circulation
Excreted in urine
(urobilin)
Excreted in faeces
(stercobilin)
Unconjugated
bilirubin-albumin
complex
The bile acid family is a group of acid steroids synthesised from cholesterol in the liver. Although their best-known role is to aid with the emulsion, digestion and absorption of fats and liposoluble vitamins, other important physiological roles have been identified.1
On secretion of bile acids into bile canaliculi, osmotic pressure is created that accounts for the bile-acid-dependent fraction of bile flow. Bile acids stimulate biliary lipid secretion and form mixed micelles with biliary phospholipids, allowing the solubilisation of cholesterol and other lipophilic compounds in the bile. The mixed micelles also emulsify dietary fats in the intestines, facilitating their absorption.1
The primary bile acids, cholic acid and chenodeoxycholic acid are synthesised from cholesterol by an enzymatic cascade involving nearly 20 enzymes and two complementary chemical pathways, the classic “neutral” pathway and the alternative “acidic” pathway.2,3 Although the neutral pathway is believed to be the major pathway for bile acid synthesis in adults, in the first months of life the acidic pathway is thought to be more important.2,5 In humans and under normal conditions, the acidic pathway contributes little (approximately 10%) to the restitution of daily loss of bile acid.1 It may become the major bile acid biosynthetic pathway in patients with liver diseases.1
The primary bile acids produced include cholic acid (CA), which accounts for approximately 70% of the circulating pool of bile acids, and chenodeoxycholic acid (CDCA), which accounts for approximately 30% of the pool.4
Cholesterol
Cholesterol 7α-hydroxylase
CYP7A1
3β-hydroxy-Δ5 -C27-steroid dehydrogenase
HSD3B7
Sterol 12α-hydroxylase
CYP8B1
Δ4-3-oxosteroid-5β-reductase
AKR1D1
Δ4-3-oxosteroid-5β-reductase
AKR1D1
3α-hydroxysteroid dehydrogenase
AKR1C4
Sterol 27-hydroxylase
CYP27A1
Bile acid CoA synthetase (BACS)
or very long chain acyl CoA
synthetase (VLCS)
Side-chain modification by
4 peroxisomal enzymes
(AMACR, BCOX, BDP, SCPx)
3α-hydroxysteroid dehydrogenase
AKR1C4
Sterol 27-hydroxylase
CYP27A1
Bile acid CoA synthetase (BACS)
or very long chain acyl CoA
synthetase (VLCS)
Side-chain modification by
4 peroxisomal enzymes
(AMACR, BCOX, BDP, SCPx)
Amino acid N-acyltransferase
(BAAT)
Amino acid N-acyltransferase
(BAAT)
7α-hydroxycholesterol
7α-hydroxy
4 cholesten-3-one
7α-12α-dihydroxy
-4 cholesten-3-one
7α-dihydroxy-5β-
cholestan-3-one
5β-cholestan-
3α,7α -diol
3α,7α-dihydroxy-5β-
cholestanoic acid (DHCA)
DHCA-CoA
Chenodeoxycholic
acid
Glyco or tauro-
chenodeoxycholic acid
Glyco or tauro-
cholic acid
Cholic acid
3α,7α,12α-trihydroxy-5β-
cholestanoic acid (THCA)
5β-cholestan-
3α,7α,12α-triol
7α-12α-dihydroxy-
5β-cholestan-3-one
THCA-CoA
Microsomes
Cytosol
Mitochondria
peroxisomes
hepatocyte
Endoplasmic
reticulum
AMACR: alpha methylacyl-CoA racemase
BCOX: Branched-chain acyl CoA oxydase
BDP: D-bifunctional protein hydratase
SCPx: Sterol carrier protein
The classic pathway, also known as the “neutral” pathway because its intermediate metabolites are neutral sterols, is the main pathway for bile acid synthesis.1-3 It is present only in the liver and synthesises cholic acid and chenodeoxycholic acid.1 This pathway consists of a cascade of reactions catalysed by enzymes located in microsomes, the cytosol, mitochondria and peroxisomes.1 The final step in the synthesis of bile acid is the conjugation of cholic acid and chenodeoxycholic acid to taurine or glycine.3
adapted from Sundaram 20083 and Monte 20091
Cholesterol
Oxysterol 7α-hydroxylase
CYP7B1
3β-hydroxy-Δ5-C27-steroid dehydrogenase
HSD3B7
Side-chain modifications
Sterol 27-hydroxylase
CYP27A1
Amino acid N-acyltransferase
(BAAT)
3β-hydroxy-5-cholestanoic acid
3-oxo-7α-hydroxy-4-cholestanoic acid
3β,7α-dihydroxy-5-cholestanoic acid
Chenodeoxycholic acid
Glyco or tauro-
chenodeoxycholic acid
The alternative pathway involves C27-hydroxylation of cholesterol by sterol 27-hydroxylase as the initial step: side-chain oxidation of cholesterol precedes steroid ring modification.1,3 Thus, acidic intermediate metabolites are formed: this is why this pathway is also known as the “acidic” pathway.1 It primarily produces chenodeoxycholic acid.3
Bile acid synthesis is tightly regulated to ensure homeostatic levels of cholesterol are produced and to provide adequate emulsification in the intestine. An excess of bile acids has a negative feedback effect, repressing further synthesis; conversely, when bile acids levels are low, synthesis is increased.2,6
In the ‘neutral’ pathway, the rate-limiting step is the modification of the steroid nucleus, which takes place in hepatic microsomes and is catalysed by cholesterol 7α-hydroxylase (CYP7A1). The neutral pathway facilitates the transformation of cholesterol to cholic acid and chenodeoxycholic acid, which are further conjugated to glycine or taurine and used as substrates for the bile acid transport pump. The canalicular transport of bile acid is the rate-limiting step of bile secretion. Bile acids are recovered from the intestines by the apical sodium-dependent bile acid transporter and return to the liver via the portal blood. The gene encoding CYP7A1 is highly regulated by negative feedback involving farnesoid X receptor (FXR)-dependent induction of fibroblast growth factor 15/19 (FGF15/19) expression by bile acids in the enterocytes. FGF15/19 binds to the fibroblast growth factor receptor 4-β-klotho complex in hepatocytes, activating signalling pathways that transcriptionally repress CYP7A1 expression.2
Bile acids are mostly restricted to enterohepatic circulation, circulating between the liver, the biliary tree, the intestine, and the portal blood which returns them to the liver. Almost all (95%) the bile acids are recovered from the intestine, mostly in the ileum.1 The liver converts around 500 mg of cholesterol into bile acids per day. This accounts for 90% of the cholesterol that is actively metabolized by the body. The remaining 10% of cholesterol that is synthesised is biosynthesised from steroid hormones.6
Newly synthesised bile acids are secreted into the bile where they are transported to the lumen of the small intestine, where they act as lipid emulsifiers, solubilising nutrients. These nutrients are incorporated into lipoproteins, and are delivered via the portal vein to the liver and metabolised. About 95% of the bile acids are recycled and secreted back into the bile. The remaining 5% are excreted into the faeces.6-7
1. Monte MJ, Marin JJG, Antelo A, Vazquez-Tato J. Bile acids: chemistry, physiology, and pathophysiology. World J Gastroenterol 2009;15:804-16.
2. Jahnel J, Zöhrer E, Fischler B, et al. Attempt to determine the prevalence of two inborn errors of primary bile acid synthesis: results of a European survey. J Pediatr Gastroenterol Nutr 2017;64:864-8.
3. Sundaram SS, Bove KE, Lovell MA, Sokol RJ. Mechanisms of disease: Inborn errors of bile acid synthesis. Nat Clin Pract Gastroenterol Hepatol 2008;5:456-68.
4. Ashby K, Navarro Almario EE, Tong W, Borlak J, Mehta R, Chen M. Review article: therapeutic bile acids and the risks for hepatotoxicity. Aliment Pharmacol Ther 2018;47:1623-38.
5. Clayton PT. Disorders of bile acid synthesis. J Inherit Metab Dis 2011;34:593-604.
6. Russell DW. The enzymes, regulation, and genetics of bile acid synthesis. Annu Rev Biochem 2003;72:137-74.
7. van Mil SW, Houwen RH, Klomp LW. Genetics of familial intrahepatic cholestasis syndromes. J Med Genet 2005;42:449-63.
Important things to check: the degree and duration of stool discolouration. The colour of the stool should ideally be recorded after elimination of any component likely to change the colour and with the help of a colour chart:2, 14
This chart is used with the kind permission of the AMFE, Association Maladies Foie Enfants, a French association dedicated to liver diseases in children.3
Persistently pale coloured stools may indicated liver disease.14 Complete and prolonged discolouration of stools for 7 days is suggestive of biliary atresia until proven otherwise. However, the sign is not specific to biliary atresia and can also occur, among others, in conditions such as cystic fibrosis, Alagille syndrome, alpha-1 antitrypsin deficiency and neonatal sclerosing cholangitis.2
Unconjugated
bilirubin
Bilirubin is mainly
produced from the
break down of red
blood cells.
Red cell breakdown
produces
unconjugated
(“indirect”) bilirubin,
which circulates mostly
bound to albumin,
although some is
“free” and hence
able to enter the brain.
The terms “direct”
and “indirect” refer
to the way laboratories
measure the different
forms.
Unconjugated bilirubin
is metabolised in the
liver to produce
conjugated (“direct”)
bilirubin by uridine
diphosphate
glucuronosyltransferase.
The activity of this
enzyme only rises after
birth to reach adult like
values around the age
of three months.
Conjugation of bilirubin
increases its solubility
and facilitates its
secretion into bile.
Conjugated (“direct”)
bilirubin then passes
into the gut and is
largely excreted.
In the gastrointestinal
tract, bilirubin is modified
by digestive bacteria and
transformed into
urobilinogens . A large
portion remains in the
intestine and is
converted into stercobilin
(responsible for the
brown colour of faeces).
Some is reabsorbed into
the bloodstream and the
remainder is excreted in
the urine (urobilin is
responsible for the
yellow colour of urine).
Conjugated
bilirubin
Urobilinogens
Uridine
diphosphate
glucuronosyl-
transferase
Excreted in bile
Gut bacteria
Enterohepatic
circulation
Excreted in urine
(urobilin)
Excreted in faeces
(stercobilin)
Unconjugated
bilirubin-albumin
complex
Jaundice of the newborns or infants
Unconjugated hyperbilirubinaemia
Mechanical haemolysis
Other causes of haemolysis
Intramedullary haemolysis
Infection-related haemolysis
Immune haemolysis
Constitutional haemolysis
Haemolysis
Default in the conjugation of
indirect bilirubin (UGT1A gene)
Rare genetic deficiency of canalicular
or sinusoidal specific transporter of
conjugated bilirubin
Moderate or severe hereditary
deficiency of enzyme activity
Enzyme immaturity or
enzymatic inhibition
Hepatocellular insufficiency
Cholestasis (decreased bile flow)
Other (hypothyroidism, trisomy 21)
Conjugated hyperbilirubinaemia
AST: < 45 mU/mL
International normalized ratio: < 1.2
Prothrombin ratio: 70-120 %
Factor VII: 70-120 %
Factor X: 70-120 %
Vitamin E: 300-1200 μg/dL
Vitamin A: 1,09-3,07 μmol/L
Vitamin E: 25-42 μmol/L
AST: <39 U/L
ALT: <34 U/L
GGT: <38 U/L
Total bilirubin: <17 μmol/L
Conjugated bilirubin level: <5 μmol/L
adapted from Sundaram 20081 and Monte 20092
Cholesterol
Cholesterol 7α-hydroxylase
CYP7A1
3β-hydroxy-Δ5 -C27-steroid dehydrogenase
HSD3B7
Δ4-3-oxosteroid-5β-reductase
AKR1D1
Δ4-3-oxosteroid-5β-reductase
AKR1D1
3α-hydroxysteroid dehydrogenase
AKR1C4
Sterol 27-hydroxylase
CYP27A1
Bile acid CoA synthetase (BACS)
or very long chain acyl CoA
synthetase (VLCS)
Side-chain modification by
4 peroxisomal enzymes
(AMACR, BCOX, BDP, SCPx)
3α-hydroxysteroid dehydrogenase
AKR1C4
Sterol 27-hydroxylase
CYP27A1
Bile acid CoA synthetase (BACS)
or very long chain acyl CoA
synthetase (VLCS)
Side-chain modification by
4 peroxisomal enzymes
(AMACR, BCOX, BDP, SCPx)
Amino acid N-acyltransferase
(BAAT)
Amino acid N-acyltransferase
(BAAT)
7α-hydroxycholesterol
7α-hydroxy
4 cholesten-3-one
7α-12α-dihydroxy
-4 cholesten-3-one
7α-dihydroxy-5β-
cholestan-3-one
5β-cholestan-
3α,7α -diol
3α,7α-dihydroxy-5β-
cholestanoic acid (DHCA)
DHCA-CoA
Chenodeoxycholic
acid
Glyco or tauro-
chenodeoxycholic acid
Glyco or tauro-
cholic acid
Cholic acid
3α,7α,12α-trihydroxy-5β-
cholestanoic acid (THCA)
5β-cholestan-
3α,7α,12α-triol
7α-12α-dihydroxy-
5β-cholestan-3-one
THCA-CoA
Microsomes
Cytosol
Mitochondria
peroxisomes
hepatocyte
Endoplasmic
reticulum
Sterol 12α-hydroxylase
CYP8B1
AMARC: alpha methylacyl-CoA racemase
BCOX: Branched-chain acyl CoA oxydase
BDP: D-bifunctional protein hydratase
SCPx: Sterol carrier protein
adapted from Sundaram 20081
Cholesterol
Oxysterol 7α-hydroxylase
CYP7B1
3β-hydroxy-Δ5-C27-steroid dehydrogenase
HSD3B7
Side-chain modifications
Sterol 27-hydroxylase
CYP27A1
Amino acid N-acyltransferase
(BAAT)
3β-hydroxy-5-cholestanoic acid
3-oxo-7α-hydroxy-4-cholestanoic acid
3β,7α-dihydroxy-5-cholestanoic acid
Chenodeoxycholic acid
Glyco or tauro-
chenodeoxycholic acid
1. Sundaram SS, Bove KE, Lovell MA, Sokol RJ. Mechanisms of disease: Inborn errors of bile acid synthesis. Nat Clin Pract Gastroenterol Hepatol 2008;5:456-68.
2. Monte MJ, Marin JJG, Antelo A, Vazquez-Tato J. Bile acids: chemistry, physiology, and pathophysiology. World J Gastroenterol 2009;15:804-16
Total bilirubin: 0-1.1 mg/dL
Vitamin A: 20-43 µg/dL
Vitamin E: 2.9 – 16.6 mg/L
Vitamin K1: 80-160 pg/mL
Vitamin A: 30–120 μg/dL
Vitamin D: 20–100 ng/mL
Vitamin E: 5–20 μg/mL
Serum calcium: 8.7 – 9.8 mg/dL
Serum phosphorous: 3.9 – 6.5 mg/dL
PTH: 15 – 65 pg/mL
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
