Can levonorgestrel cause Drug-Induced Liver Injury (DILI)?

Levonorgestrel and Drug-Induced Liver Injury (DILI)

Levonorgestrel can rarely cause drug-induced liver injury (DILI), with documented cases primarily associated with levonorgestrel-releasing intrauterine devices, though the risk is extremely low compared to estrogen-containing contraceptives. 1

Evidence on Levonorgestrel and Liver Effects

Progestin-Only Contraceptives and Liver Safety

• Progestin-only contraceptives (including levonorgestrel) generally have fewer hepatic concerns compared to combined hormonal contraceptives containing estrogen 2
• The American Association for the Study of Liver Diseases (AASLD) notes that progestin-only contraceptives do not have the estrogen-associated risks that can affect liver function 2
• Levonorgestrel-releasing intrauterine devices (IUDs) have significantly lower systemic hormone exposure (only 4-13% of levels seen with oral contraceptives), which theoretically reduces potential hepatic effects 2

Documented Cases of Liver Injury

• There is at least one documented case report of acute liver injury associated with a levonorgestrel-releasing IUD, where symptoms resolved after device removal 1
• This represents an extremely rare adverse event, as levonorgestrel IUDs are widely used and generally considered safe

Risk Assessment for Different Patient Populations

Patients with Pre-existing Liver Disease

• For patients with compensated cirrhosis, progestin-only contraceptives like levonorgestrel are considered safer than estrogen-containing options 2
• In patients with decompensated cirrhosis, all hormonal contraceptives should be used with caution due to potential impaired drug metabolism 2
• For liver transplant recipients, progestin-only methods are generally acceptable, even in those with graft failure 2

Patients with Polycystic Liver Disease

• The European Association for the Study of the Liver (EASL) suggests that levonorgestrel-releasing IUDs may be an alternative contraceptive option for patients with polycystic liver disease 2
• This recommendation is based on the lower systemic hormone exposure compared to oral contraceptives 2

Monitoring and Management Recommendations

Monitoring for DILI

• Standard monitoring for DILI includes assessment of liver enzymes (ALT, AST), bilirubin, and alkaline phosphatase 2
• Drug-induced hepatitis is suspected when ALT levels are ≥3 times the upper limit of normal with hepatitis symptoms, or ≥5 times the upper limit of normal without symptoms 2

Management of Suspected DILI

• If DILI is suspected, the causative agent should be promptly discontinued 2
• Alternative causes of abnormal liver function must be excluded before confirming DILI diagnosis 2
• These include viral hepatitis, biliary tract disease, alcohol use, and other hepatotoxic medications 2

Clinical Decision-Making Algorithm

1. For patients without liver disease:

   • Levonorgestrel (oral or IUD) can be safely used with minimal risk of DILI
   • No special liver monitoring is required unless symptoms develop

2. For patients with compensated liver disease:

   • Levonorgestrel is preferred over estrogen-containing contraceptives
   • Consider baseline liver function tests and periodic monitoring

3. For patients with decompensated cirrhosis:

   • Use levonorgestrel with caution, preferably in IUD form to minimize systemic exposure
   • Regular liver function monitoring is recommended

4. If signs of liver injury develop:

   • Evaluate liver enzymes, bilirubin, and alkaline phosphatase
   • Rule out other causes of liver injury
   • Consider discontinuation of levonorgestrel if no other cause is identified
   • Monitor for resolution of liver abnormalities after discontinuation

Important Considerations

• The risk of DILI with levonorgestrel is extremely rare compared to many other medications
• The benefit-risk profile strongly favors use of levonorgestrel contraceptives in most patients, including those with stable liver disease
• Levonorgestrel IUDs provide the lowest systemic exposure and may be preferable in patients with liver concerns
• Individual genetic factors may play a role in susceptibility to DILI, though specific genetic markers for levonorgestrel-induced liver injury have not been identified 3, 4