Trimethoprim-Sulfamethoxazole-Induced Liver Injury
Trimethoprim-sulfamethoxazole (TMP-SMX) causes drug-induced liver injury (DILI) that most commonly presents with a hepatocellular or mixed pattern, though cholestatic injury can occur and may be severe and prolonged, requiring immediate drug discontinuation and supportive care. 1, 2
Diagnosis of TMP-SMX-Related DILI
Essential Diagnostic Steps
Obtain a comprehensive medication history documenting the start date and dose of TMP-SMX, as establishing temporal relationship between drug exposure and liver injury is critical for diagnosis 3
Calculate the R value to classify the injury pattern: R = (ALT/ALT ULN) ÷ (ALP/ALP ULN), where R ≥5 indicates hepatocellular injury, R <2 indicates cholestatic injury, and R 2-5 indicates mixed injury 3, 4
Systematically exclude competing etiologies through first-line testing including viral hepatitis serologies (hepatitis A IgM, hepatitis B surface antigen and core antibody, hepatitis C antibody), autoimmune markers (ANA, anti-smooth muscle antibody, immunoglobulins), and abdominal imaging to rule out biliary obstruction 3
Clinical Presentation Patterns
Hepatocellular pattern (most common): Predominant ALT/AST elevation with R ≥5, indicating direct hepatocyte damage 1, 5
Cholestatic pattern (less common but potentially severe): Predominant alkaline phosphatase elevation with R <2, presenting with jaundice and pruritus that can persist for 1-2 years even after drug discontinuation 1, 2
Mixed pattern: Both transaminase and alkaline phosphatase elevations with R between 2-5 2
Management Algorithm
Immediate Actions
Discontinue TMP-SMX immediately upon suspicion of DILI, as even small rechallenge doses can cause fatal hepatotoxicity in susceptible patients 6
Monitor liver tests 2-3 times weekly initially and observe for signs of hepatic decompensation including ascites, encephalopathy, and coagulopathy 3
Evaluate for potentially severe DILI if ALT ≥3× ULN plus total bilirubin ≥2× ULN, especially if ALP ≤2× ULN, as this indicates higher risk of hepatic failure 3
Follow-Up Monitoring Based on Pattern
Hepatocellular pattern (R ≥5): Repeat testing within 2-5 days to monitor trajectory, as these patients are at higher risk of severe outcomes including hepatic failure 4
Cholestatic pattern (R <2): Repeat testing within 7-10 days, recognizing that cholestatic injury from TMP-SMX can be severe and prolonged with intractable pruritus lasting months to years 4, 2
Continue monitoring until resolution or stabilization regardless of drug discontinuation 3
Supportive Care
Provide symptomatic management for pruritus in cholestatic cases, which may be severe and prolonged 1, 2
Consider exchange plasmapheresis only in cases of severe, prolonged cholestasis with phospholipidosis, though evidence is limited to case reports 7
Critical Pitfalls and Caveats
Never rechallenge with TMP-SMX after suspected DILI, as fatal hepatotoxicity has occurred with as little as two tablets (160 mg trimethoprim/800 mg sulfamethoxazole) in previously exposed patients 6
Recognize that cholestatic injury can be extremely prolonged, with abnormal liver tests and pruritus persisting for 1-2 years despite drug discontinuation 2
Be aware that TMP-SMX hepatotoxicity is unpredictable and idiosyncratic, occurring rarely but with potential for severe outcomes including terminal hepatic failure 5, 6
In transplant patients, maintain heightened suspicion as immunosuppression may alter presentation, though diagnosis and management principles remain the same 5
Document causality using RUCAM scoring across seven domains: temporal relationship, dechallenge response, risk factors, concomitant medications, alternative causes, previous hepatotoxicity reports, and rechallenge (though rechallenge is contraindicated) 3