What causes cholestasis of pregnancy?

What Causes Cholestasis of Pregnancy

Intrahepatic cholestasis of pregnancy results from a multifactorial interaction between genetic susceptibility (particularly mutations in hepatocanalicular transport proteins), hormonal influences (elevated estrogen and progesterone metabolites), and environmental factors that overwhelm the liver's capacity to transport bile acids during pregnancy. 1

Genetic Factors

Genetic mutations in bile transport proteins are the primary underlying cause in genetically susceptible women. The most important genetic variants involve:

• ATP-binding cassette (ABC) transporter proteins, including ABCB4 (phosphatidylcholine floppase), ABCB11 (bile salt export pump), ABCBC2 (conjugated organic anion transporter), and ATP8B1 (FIC1) 1
• Bile acid sensor farnesoid X receptor (FXR) regulatory genes 1
• ABCB11 gene variants can cause autosomal recessive forms associated with benign recurrent intrahepatic cholestasis (BRIC), particularly in early-onset or severe cases 2
• Familial clustering strongly suggests genetic susceptibility, with family history being a significant risk factor 1

The genetic defects cause mild malfunction of hepatocanalicular transporters that becomes clinically apparent when their transport capacity for hormones and bile acids is exceeded during pregnancy 1.

Hormonal Mechanisms

Elevated pregnancy hormones trigger cholestasis in genetically predisposed women through direct effects on bile transport:

• Estrogen metabolites, particularly D-ring estrogen metabolites, have demonstrated cholestatic potential in experimental and clinical studies 3
• Progesterone metabolites, especially sulfated 3α,5α isomers, accumulate in ICP patients and may reflect selective defects in canalicular secretion of steroid sulfates 3
• Higher hormone levels explain the increased ICP incidence in twin pregnancies and the observation that high-dose oral contraceptives and progesterone can trigger ICP 1
• Bile acid synthesis appears reduced in ICP patients, with retention of primary conjugated bile acids in blood and altered bile acid profiles (cholic acid predominates instead of chenodeoxycholic acid) 3

Pre-existing Hepatobiliary Disease

Women with underlying liver or biliary disease have substantially elevated risk:

• Hepatitis C infection increases ICP risk 3.5-fold (rate ratio 3.5,95% CI 1.6-7.6) 1
• Nonalcoholic liver cirrhosis increases risk 8.2-fold (rate ratio 8.2,95% CI 1.9-35.5) 1
• Gallstones and cholecystitis increase risk 3.7-fold (rate ratio 3.7,95% CI 3.2-4.2) 1
• Nonalcoholic pancreatitis increases risk 3.2-fold (rate ratio 3.2,95% CI 1.7-5.7) 1

Additional Risk Factors

Several pregnancy-related and demographic factors increase susceptibility:

• Multiple gestations (twins or higher-order multiples) due to higher hormone levels 1
• Advanced maternal age 1
• Prior history of ICP carries up to 90% recurrence risk in subsequent pregnancies 4
• Environmental factors interact with genetic predisposition, though specific triggers remain poorly defined 1, 3

Pathophysiologic Mechanism

The final common pathway involves impaired bile acid transport from hepatocytes into bile canaliculi:

• Genetic transporter defects reduce baseline transport capacity 1
• Pregnancy hormones and their metabolites further inhibit these already compromised transporters 3
• Bile acids accumulate in maternal serum and cross the placenta, leading to elevated levels in amniotic fluid, cord blood, and meconium 1
• This creates the clinical syndrome of pruritus and elevated serum bile acids that characterizes ICP 1, 4

Critical caveat: While the pathophysiology involves genetic, hormonal, and environmental interactions, the exact mechanisms remain incompletely understood, and genetic testing is currently performed only in research settings and not routinely applicable for diagnosis or risk stratification 1. However, mutation analysis of ABCB4 should be considered if cholestasis with elevated gamma-GT persists after delivery 1.