Can lisinopril (angiotensin-converting enzyme inhibitor) cause hepatomegaly (enlarged liver) in patients, particularly those with pre-existing liver disease?

Can Lisinopril Cause Hepatomegaly?

Yes, lisinopril can cause hepatomegaly as part of drug-induced liver injury (DILI), though this is a rare adverse effect that typically presents with hepatocellular or cholestatic injury patterns. 1, 2

FDA-Recognized Hepatotoxicity Risk

The FDA drug label explicitly warns that ACE inhibitors including lisinopril have been associated with a syndrome starting with cholestatic jaundice or hepatitis that can progress to fulminant hepatic necrosis and sometimes death. 1 The label mandates that patients who develop jaundice or marked elevations of hepatic enzymes should discontinue lisinopril immediately and receive appropriate medical treatment. 1

Clinical Presentation and Hepatomegaly

Lisinopril-induced liver injury can manifest with hepatomegaly as documented in case reports:

• A 30-year-old woman developed hepatocellular disease with mild hepatomegaly eight months after starting lisinopril 10 mg daily, presenting with icterus, right-upper-quadrant tenderness, and elevated liver enzymes. 2 CT imaging confirmed hepatomegaly with hepatocellular disease. 2

• The hepatotoxicity pattern can be either hepatocellular (more common) or cholestatic, with both patterns potentially causing liver enlargement. 2, 3, 4

Time Course and Risk Factors

Lisinopril-induced hepatotoxicity can occur at highly variable timeframes:

• Cases have been reported as early as 3 weeks and as late as 27 months after drug initiation. 3, 5
• The typical presentation window appears to be 2-8 months after starting therapy. 2, 5

Patients with pre-existing liver disease face significantly higher risk of adverse outcomes including mortality when they develop drug-induced liver injury. 6

Monitoring and Management Algorithm

For patients starting lisinopril:

1. Establish baseline liver function tests (AST, ALT, alkaline phosphatase, total bilirubin) before initiating therapy. 6

2. Monitor transaminases within 4-8 weeks after starting treatment, then every 3 months during long-term therapy. 6

3. Discontinue lisinopril immediately if:

   • Transaminases rise to ≥3× upper limit of normal (ULN) 6
   • ALT ≥8× ULN with or without symptoms 6
   • ALT ≥3× ULN with total bilirubin ≥2× baseline (Hy's Law criteria) 6
   • Jaundice develops 1
   • Clinical hepatomegaly with elevated liver enzymes appears 2

4. If hepatic decompensation occurs, the drug cannot be restarted under any circumstances. 6

Diagnostic Workup When Hepatomegaly Develops

When lisinopril-associated hepatomegaly is suspected:

• Obtain comprehensive liver function tests including AST, ALT, alkaline phosphatase, GGT, total and direct bilirubin, and platelet count. 7
• Perform abdominal ultrasound to assess liver size, texture, and rule out focal lesions. 7, 2
• Consider liver elastography if available to assess for fibrosis. 7
• Exclude competing etiologies through viral hepatitis serologies, autoimmune markers, and imaging to rule out biliary obstruction. 2, 4
• Liver biopsy may be necessary if the diagnosis remains unclear, which typically shows portal inflammation with lymphocytic infiltrates in hepatocellular injury or cholestasis with duct injury in cholestatic patterns. 2, 5, 4

Prognosis and Recovery

Most cases show rapid improvement after drug discontinuation, with normalization of liver enzymes within 2 months. 2 However, severe cases can be life-threatening with prolonged cholestasis lasting 14 months or progressing to biliary cirrhosis and death. 5, 4

Critical Pitfall to Avoid

Do not continue lisinopril in patients with pre-existing advanced liver disease (Child-Pugh B or C), as ACE inhibitors are absolutely contraindicated in cirrhotic patients with ascites due to risks of acute renal failure, hyponatremia, and diuretic resistance. 6 For patients with severe liver disease requiring ACE inhibition, lisinopril may be preferred over prodrug ACE inhibitors since it does not require hepatic activation. 8