Why Intrahepatic Cholestasis Occurs in Pregnancy
Intrahepatic cholestasis of pregnancy occurs when genetically susceptible women experience pregnancy-induced hormonal surges that overwhelm the capacity of defective hepatocanalicular bile transport proteins, leading to accumulation of bile acids in maternal serum. 1, 2
Multifactorial Pathogenesis
The development of ICP requires the convergence of three key factors:
Genetic Susceptibility
Mutations in hepatocanalicular transport proteins are the primary underlying cause in genetically predisposed women, including defects in ATP-binding cassette (ABC) transporter B4 (phosphatidylcholine floppase), ABC transporter B11 (bile salt export pump), ABC transporter C2 (conjugated organic anion transporter), and ATP8B1 (FIC1). 1, 2
Gene variants in bile acid regulators, particularly the farnesoid X receptor (FXR), have also been identified in some ICP patients. 1
The ABCB11 gene variant, which encodes the bile salt export pump, can cause severe early-onset ICP and is associated with benign recurrent intrahepatic cholestasis. 3
Familial clustering of ICP cases and ethnic differences strongly support genetic factors, with up to 90% recurrence risk in subsequent pregnancies. 1, 4
Hormonal Triggers
Elevated pregnancy hormones—particularly estrogen and progesterone metabolites—directly impair bile transport in genetically susceptible women. 1, 2
The central role of hormones is demonstrated by higher ICP incidence in twin pregnancies (where hormone levels are elevated) and the observation that high-dose oral contraceptives and progesterone can trigger ICP outside of pregnancy. 1
These hormonal factors explain why ICP typically manifests in the second or third trimester when hormone levels peak, and why symptoms spontaneously resolve within 4-6 weeks after delivery. 1
Environmental and Pre-existing Disease Factors
Women with underlying hepatobiliary disease have substantially elevated risk, including those with hepatitis C (rate ratio 3.5), nonalcoholic liver cirrhosis (rate ratio 8.2), gallstones and cholecystitis (rate ratio 3.7), and nonalcoholic pancreatitis (rate ratio 3.2). 1, 2
Multiple gestations and advanced maternal age also increase susceptibility. 1, 2
Environmental factors contribute to geographic variation in ICP prevalence, ranging from 0.4-1% in most of Europe and North America to 5-15% in Chile and Bolivia. 5
The Final Common Pathway
Mild malfunction of hepatocanalicular transporters triggers cholestasis when their transport capacity for hormones or bile acid substrates is exceeded during pregnancy. 1 This results in:
Impaired bile acid transport from hepatocytes into bile canaliculi. 2
Accumulation of bile acids in maternal serum (>10 μmol/L diagnostic threshold). 1, 4
Increased flux of bile acids from mother to fetus, evidenced by elevated levels in amniotic fluid, cord blood, and meconium. 1, 2
Clinical Implications
Understanding this pathophysiology explains why:
ICP resolves spontaneously after delivery when hormonal triggers are removed. 1
Women with prior ICP are at high risk for recurrence in subsequent pregnancies. 1, 4
Genetic testing for ABCB4 mutations should be considered if cholestasis persists beyond 6 weeks postpartum, suggesting an underlying chronic hepatobiliary disorder unmasked by pregnancy. 1, 4