Pathophysiology of primary bile acid synthesis disorders

Failure to synthesise normal bile acids reduces the flow of bile, causing cholestasis and the retention of potentially hepatoxic compounds – for example conjugated bilirubin – which are normally excreted in the bile.1 Normally, bile acids facilitate the detachment of γ-glutamyl-transpeptidase (GGT) from the canalicular membrane. This is why BASDs, unlike other causes of cholestasis, do not lead to elevation of plasma GGT.1 As taurine and glycine conjugates of cholic acid (CA) and chenodeoxycholic acid (CDCA) are required to facilitate emulsification and absorption of fats and fat-soluble vitamins, the absence of these bile acids can lead to steatorrhoea, failure to thrive and deficiencies of fat-soluble vitamins. 1

Pathophysiology of 3β-HSD and Δ4-3-oxoR deficiencies

adapted from Jahnel 2017 2

Healthy hepatocyte

Cholesterol

Cholesterol

CYP7A1

CYP7A1

CYP27

CYP27

3β-HSD
Δ4-3-oxoR

3β-HSD
Δ4-3-oxoR

CA+CDCA

BSEP

Neutral
Pathway

Neutral
Pathway

FGFR4

FGFR4

FGF15/19

FGF15/19

Primary bile acids

Toxic bile acid intermediates

ASBT

Enterocyte

Urinary excretion

FGF15/19

FGF15/19

FXR

FXR

NTCP

NTCP

Acidic
Pathway

Acidic
Pathway

Bile acid intermediates

Absence of
primary bile acids

cholestatic

hepatotoxic

Hepatocyte with 3β-HSD
or Δ4-3-oxoR deficiency

1. Clayton PT. Disorders of bile acid synthesis. J Inherit Metab Dis 2011;34(3):593-604.

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;64:864-68.