What are the causes of cholestatic liver injury?

Causes of Cholestatic Liver Injury

Cholestatic liver injury can be caused by numerous factors including drugs, genetic disorders, pregnancy, and various diseases affecting the biliary system, with drug-induced cholestasis being one of the most common and potentially reversible causes.

Drug-Induced Cholestatic Liver Injury

Drug-induced cholestatic liver injury represents approximately 30% of all drug-induced liver injury (DILI) cases and has a better prognosis than hepatocellular injury 1. The main mechanisms include:

1. Hepatocellular transporter inhibition: Drugs interfere with bile acid transporters, altering bile secretion at the hepatocyte level 1

2. Idiosyncratic/hypersensitivity reactions: Inflammatory reactions at the bile ductular level causing ductular cholestasis 1

3. Vanishing bile duct syndrome (VBDS): Rare but severe complication that can progress to biliary cirrhosis 1

Common Drugs Associated with Cholestasis:

• Antibiotics: Particularly amoxicillin/clavulanate (most common cause) 2
• Cephalosporins: Can cause severe cholestatic injury 3
• Psychotropic medications: Chlorpromazine (prototype drug causing prolonged cholestasis) 1
• Herbal remedies and supplements: Various compounds can trigger cholestatic injury 1

Risk Factors:

• Age (older patients)
• Gender
• Medication dosage
• Co-administered medications
• Genetic variations in hepatobiliary transporters 1, 2

Other Causes of Cholestatic Liver Disease

Genetic Disorders

• Progressive Familial Intrahepatic Cholestasis (PFIC)
• Benign Recurrent Intrahepatic Cholestasis (BRIC): Characterized by acute episodes of cholestasis, jaundice, and pruritus that resolve completely 1
• Alagille Syndrome: Autosomal dominant multiorgan disease with ductopenia and extrahepatic manifestations 1

Pregnancy-Related

• Intrahepatic Cholestasis of Pregnancy (ICP): Characterized by pruritus, elevated liver enzymes, and increased serum bile acids during pregnancy, with spontaneous resolution after delivery 1

Primary Biliary Disorders

• Primary Biliary Cholangitis (PBC) 4, 5
• Primary Sclerosing Cholangitis (PSC) 4, 5

Other Causes

• Biliary obstruction (stones, strictures, tumors)
• Post-surgical complications
• Infiltrative diseases
• Sepsis and total parenteral nutrition

Diagnostic Approach

For drug-induced cholestasis, diagnosis requires:

• Clinical suspicion
• Careful drug history
• Temporal relationship between drug intake and liver disease
• Exclusion of other disorders 1

Laboratory findings typically show:

• Alkaline phosphatase (AP) >2 ULN
• ALT/AP ratio <2 (for cholestatic pattern) 1

Management

For drug-induced cholestasis:

1. Immediate withdrawal of the suspected drug is the primary treatment 1
2. Monitoring: Follow liver tests until normalization (typically within 3 months)
3. Supportive care: Management of symptoms
4. Experimental therapies: Ursodeoxycholic acid (UDCA) may benefit approximately two-thirds of cases 1, 6
5. Corticosteroids: May help in hypersensitivity-induced cholestasis, though evidence is limited 1

Prognosis

The outcome of drug-induced cholestatic injury is generally good after withdrawal of the offending drug 1. However:

• Some cases may develop prolonged cholestasis
• Chlorpromazine can cause vanishing bile duct syndrome leading to permanent liver damage
• A minority of patients may show persistent liver damage on follow-up 1

Important Caveats

1. Always consider drug-induced cholestasis in patients with new-onset liver enzyme abnormalities, particularly with elevated alkaline phosphatase

2. Prompt recognition and withdrawal of the offending agent is critical to prevent progression to severe liver injury

3. Liver biopsy is usually not required for diagnosis but may be necessary in severe, progressive, or prolonged cases 1

4. Rechallenge with the suspected drug should be avoided as it can be harmful 1

5. The mortality rate of cholestatic DILI can be as high as 10%, emphasizing the importance of early recognition 2