What medications can cause drug-induced cholestasis?

Medications That Cause Drug-Induced Cholestasis

Several hundred drugs, herbal remedies, and illegal compounds can trigger drug-induced cholestatic liver injury through various mechanisms, with chlorpromazine being the prototype drug causing prolonged cholestasis that can lead to permanent liver damage. 1

Mechanisms of Drug-Induced Cholestasis

Drug-induced cholestasis occurs through two major mechanisms:

1. Inhibition of hepatocellular transporters - Affecting bile secretion at the hepatocellular level 1
2. Idiosyncratic inflammatory/hypersensitive reactions - Occurring at the bile ductular/cholangiocellular level 1

In rare cases, drugs can induce vanishing bile duct syndrome (VBDS) that may progress to biliary cirrhosis 1.

Common Medications Associated with Cholestasis

Sex Steroids and Anabolic Steroids

• Oral contraceptives and anabolic steroids commonly cause pure hepatocellular cholestasis 2

Antibiotics

• Trimethoprim-sulfamethoxazole can cause severe, prolonged cholestasis with intractable pruritus lasting 1-2 years after discontinuation 3
• Ceftriaxone has a high risk of inducing cholelithiasis (gallstone formation) 4

Antipsychotics

• Chlorpromazine is the prototype drug causing prolonged cholestasis (>6 months) and can lead to vanishing bile duct syndrome with permanent liver damage 1

Antiretrovirals

• Atazanavir has a high risk of inducing cholelithiasis 4

Hormonal Agents

• Somatostatin analogues have a high risk of inducing cholelithiasis 4

Anti-Tuberculosis Drugs

• Rifampicin can cause hepatitis (sometimes with cholestasis) 1
• Isoniazid, when used simultaneously with rifampicin, can produce hepatitis with hepatocellular damage seldom associated with cholestasis 1

Risk Factors for Drug-Induced Cholestasis

Several factors increase susceptibility to drug-induced cholestasis:

• Age 1
• Gender 1
• Medication dosage 1
• Co-administered medications 1
• Genetic variations in hepatobiliary transporters (especially BSEP/ABCB11 and MDR3/ABCB4) 5

Diagnosis and Management

Diagnosis

• Based on temporal relationship between drug intake and onset of cholestasis 1
• Characterized by elevated alkaline phosphatase (AP) >2 ULN or ALT/AP ratio <2 1
• Requires exclusion of other causes of cholestasis 1
• Liver biopsy usually not required unless severe, progressive, or prolonged course 1

Management

• The only effective treatment is withdrawal of the suspected drug 1
• Early detection of abnormal liver tests and prompt drug withdrawal are crucial 1
• Ursodeoxycholic acid (UDCA) may beneficially affect cholestasis in approximately two-thirds of cases, but evidence is limited 1
• Corticosteroid therapy may be beneficial in hypersensitivity-induced cholestasis, but controlled trials are lacking 1
• In severe cases, liver transplantation may be required 1

Clinical Course and Prognosis

• The outcome after drug withdrawal is generally good in most cases 1
• Drug-induced cholestatic injury has a better prognosis than hepatocellular injury 1
• Some patients may experience prolonged cholestasis 1
• A minority of patients show persistent liver damage at follow-up 1

Important Clinical Considerations

• Drug-induced cholestasis accounts for approximately 30% of drug-induced liver injury (DILI) cases 1
• The prevalence of DILI is estimated between 1 in 10,000 and 1 in 100,000 patients, though this is likely underreported 1
• Rechallenge with the suspected drug can confirm diagnosis but is potentially harmful and not recommended in clinical practice 1
• Monitor liver function tests carefully when prescribing medications known to cause cholestasis, especially in patients with pre-existing liver conditions 1