What are the causes of intrahepatic cholestasis?

Causes of Intrahepatic Cholestasis

Intrahepatic cholestasis results from impaired bile formation within the liver parenchyma and can be broadly categorized into hepatocellular causes (affecting bile secretion at the hepatocyte level), cholangiocytic causes (affecting bile ducts), and infiltrative disorders. 1, 2

Primary Categories of Intrahepatic Cholestasis

Hepatocellular Cholestasis

These conditions impair bile secretion at the hepatocyte or canalicular membrane level:

• Drug-induced cholestasis – The most common acquired form, caused by inhibition of hepatocellular transporter expression/function (particularly the bile salt export pump BSEP) or idiosyncratic inflammatory reactions at the bile ductular level 3, 4

  • Chlorpromazine is the prototype drug causing prolonged cholestasis >6 months and can lead to vanishing bile duct syndrome 3
  • Risk factors include age, gender, dose, and co-administered medications 3

• Intrahepatic cholestasis of pregnancy (ICP) – Affects 0.4–2.0% of European pregnancies, presenting with intense pruritus (typically worse at night) in the second or third trimester, elevated ALT and fasting bile acids, with spontaneous resolution within 4–6 weeks postpartum 3

  • Pathogenesis is multifactorial involving genetic variants in hepatocanalicular transport proteins (ABCB4, ABCB11, ATP8B1, FXR), hormonal factors (estrogen/progesterone metabolites), and environmental triggers 3, 4, 5

• Sepsis and endotoxemia – Systemic infection can impair hepatocyte bile secretion 2

• Viral hepatitis – Acute or chronic viral infections may present with cholestatic features 2

• Alcoholic and nonalcoholic steatohepatitis – Advanced fatty liver disease can develop secondary intrahepatic cholestasis, particularly in severe disease stages 2, 6

• Total parenteral nutrition – Prolonged TPN administration can induce cholestasis 2

Genetic/Hereditary Cholestatic Disorders

• Progressive familial intrahepatic cholestasis (PFIC) types 1,2, and 3 – Rare chronic progressive disorders of childhood characterized by low gamma-glutamyltransferase (PFIC1 and 2) or elevated GGT (PFIC3), severe pruritus, and various extrahepatic manifestations 3

  • PFIC1: ATP8B1 gene mutations
  • PFIC2: ABCB11 gene mutations (bile salt export pump)
  • PFIC3: ABCB4 gene mutations (phospholipid transporter) 3

• Benign recurrent intrahepatic cholestasis (BRIC) types 1 and 2 – Acute episodic cholestasis in adolescents/adults with complete resolution between episodes, caused by missense mutations in ATP8B1 and ABCB11 genes 3

• Alagille syndrome – Autosomal dominant multiorgan disease with chronic progressive cholestasis, ductopenia, and characteristic extrahepatic features (cardiac, renal, skeletal abnormalities, typical facies), caused by JAG1 gene mutations in 70% of cases 3

Cholangiocytic/Bile Duct Disorders

• Primary biliary cholangitis (PBC) – Autoimmune destruction of small intrahepatic bile ducts, diagnosed by positive antimitochondrial antibodies (AMA ≥1:40) with cholestatic enzyme profile 1, 7

• Primary sclerosing cholangitis (PSC) – Chronic progressive inflammation and fibrosis of intrahepatic and/or extrahepatic bile ducts 1

• Vanishing bile duct syndrome – Can be drug-induced (particularly chlorpromazine) or occur in other contexts, leading to permanent liver damage and potential progression to biliary cirrhosis 3

Infiltrative Disorders

Malignant infiltration:

• Hematologic malignancies (lymphoma, leukemia) 2
• Metastatic cancer to the liver 2

Benign infiltration:

• Sarcoidosis (granulomatous hepatitis) 2, 6
• Amyloidosis 2
• Storage diseases 2

Key Pathophysiologic Mechanisms

The underlying mechanisms involve: 3, 8

• Inhibition of canalicular transporter function (BSEP, MDR3/ABCB4, MRP2/ABCB2)
• Impaired sinusoidal membrane function
• Interference with microfilament/microtubule function affecting bile secretion
• Inflammatory or hypersensitivity reactions at the cholangiocellular level
• Altered bile acid metabolism

Critical Clinical Pitfall

Do not assume isolated GGT elevation indicates cholestasis – GGT elevation may simply reflect enzyme induction by alcohol or drugs rather than true cholestatic disease 1. Confirm cholestasis by demonstrating alkaline phosphatase >1.5× ULN with GGT >3× ULN to establish hepatobiliary origin 1.