Can propylthiouracil cause deranged liver enzymes?

Can Propylthiouracil Cause Deranged Liver Enzymes?

Yes, propylthiouracil (PTU) can cause severe liver injury ranging from asymptomatic elevation of liver enzymes to fulminant hepatic failure and death, and should be reserved only for patients who cannot tolerate methimazole. 1

Severity and Spectrum of Hepatotoxicity

PTU-induced liver injury encompasses a wide spectrum of hepatic damage:

• Asymptomatic elevation of transaminases (AST, ALT, GGT) can occur, representing the mildest form of hepatotoxicity 2
• Acute hepatitis with clinical symptoms including jaundice, nausea, vomiting, and abdominal pain 3
• Subacute hepatitis progressing to liver failure 4
• Fulminant hepatic failure requiring liver transplantation or resulting in death 1, 5, 6

The FDA has issued a black box warning specifically highlighting that severe liver injury and acute liver failure, in some cases fatal, have been reported in patients treated with PTU, including cases requiring liver transplantation in both adult and pediatric patients 1.

Incidence and Risk Factors

• PTU-related liver toxicity occurs in approximately 1% of treated patients 4
• Among patients who develop acute or subacute hepatitis from PTU, liver failure may occur in approximately one-third of cases 4
• Female patients appear to be disproportionately affected, with 13 of 14 reported cases in the literature being female 6

Timing of Onset

The timing of PTU-induced hepatotoxicity is variable and unpredictable:

• Liver enzyme elevations can occur after 5 months of therapy 2
• Clinical hepatitis has been documented after 3 months of treatment 3
• The delayed occurrence after initiation of treatment makes this particularly dangerous, as patients may not be monitored adequately 4

Clinical Presentation

Patients should be monitored for the following signs and symptoms of PTU-induced liver injury:

• Fever, loss of appetite, nausea, vomiting 1
• Fatigue and malaise 1
• Right upper quadrant abdominal pain or tenderness 1
• Dark (tea-colored) urine 1
• Pale or light-colored stools 1
• Jaundice (yellowing of skin or whites of eyes) 1
• Pruritus (itching) 1

Laboratory Findings

Characteristic laboratory abnormalities include:

• Elevated AST and ALT (can reach levels >1500 IU/L in severe cases) 3
• Elevated GGT and alkaline phosphatase 2
• Elevated total bilirubin (can exceed 6.5 mg/dL in acute liver failure) 3
• In unusual cases, transaminases may be elevated with normal bilirubin levels 2
• Coagulopathy in cases progressing to liver failure 3

Management Algorithm

When PTU-induced hepatotoxicity is suspected:

1. Immediately discontinue PTU - This is the most critical intervention, as delayed withdrawal significantly increases risk of progression to liver failure 6, 4

2. Assess severity - Check complete liver panel including AST, ALT, alkaline phosphatase, GGT, total and direct bilirubin, PT/INR, and albumin 3

3. Rule out alternative causes - Obtain serologies for hepatitis A, B, C, EBV, and CMV; assess for autoimmune hepatitis markers if indicated 2

4. Monitor for progression - Serial liver function tests should be obtained; patients with severe elevation or clinical symptoms require hospitalization 3

5. Consider liver transplant evaluation - For patients developing acute liver failure with coagulopathy and encephalopathy, immediate transplant evaluation is warranted 5, 3

6. Switch to alternative therapy - Methimazole can be safely initiated after liver enzymes normalize, as cross-reactivity does not occur 7, 2

Monitoring Recommendations

Despite the absence of formal U.S. guidelines mandating routine liver enzyme monitoring, the evidence strongly supports regular surveillance:

• Monthly alanine aminotransferase (ALT) monitoring is recommended, at least during the first 6 months of PTU therapy 4
• The high incidence of liver toxicity (1%), its potential severity, and delayed occurrence after treatment initiation justify this monitoring approach 4
• Baseline liver function tests should be obtained before initiating PTU 3

Critical Pitfalls to Avoid

Several factors contribute to poor outcomes in PTU-induced hepatotoxicity:

• Delayed recognition - Underestimation of severity and continuation of PTU after liver injury is detected significantly worsens prognosis 4
• Lack of monitoring - Failure to obtain follow-up liver enzymes after starting therapy can result in undetected progression to irreversible liver damage 3
• Continued administration - Even a few days of continued PTU after symptoms develop can lead to fulminant hepatic failure and death 6

Recovery and Rechallenge

• Recovery is usually complete after withdrawal of PTU, with normalization of liver enzymes typically occurring within 2-6 weeks 2
• Rechallenge with PTU is contraindicated - Reintroduction of PTU after hepatotoxicity results in recurrent liver injury 2
• Switching to methimazole is safe and effective, with no cross-reactivity observed 7, 2

Special Populations

Pregnant women require particular consideration:

• PTU may cause liver problems, liver failure, and death in pregnant women and may harm the unborn baby 1
• PTU may be used when an antithyroid drug is needed during or just before the first trimester of pregnancy, but patients must be counseled about hepatotoxicity risks 1
• Switching to methimazole in the second and third trimesters is recommended due to lower hepatotoxicity risk 7