Medications That Cause Elevated Alkaline Phosphatase
Multiple drug classes can cause elevated alkaline phosphatase through cholestatic liver injury or enzyme induction, with the most clinically significant being antiepileptics (particularly phenytoin), antibiotics (especially macrolides and antituberculous agents), and immunosuppressants.
Antiepileptic Drugs
Antiepileptic drugs are among the most common medication-related causes of elevated ALP, primarily through hepatic enzyme induction rather than true hepatotoxicity.
- Phenytoin (Dilantin) can cause increased serum levels of alkaline phosphatase and gamma-glutamyl transpeptidase (GGT) 1
- In one case series, phenytoin toxicity was identified as the cause of extremely high ALP elevation (>1000 U/L) in a patient with AIDS 2
- Long-term antiepileptic therapy commonly causes persistently raised serum ALP, with 75% of affected patients showing elevated liver ALP isoenzyme (not bone) along with raised GGT but normal bone ALP 3
- Levetiracetam has been reported to cause significant ALP elevation in pediatric patients, with normalization after drug discontinuation 4
- The mechanism appears to be induction of liver microsomal enzymes, including liver ALP, rather than hepatotoxicity or drug-induced cholestasis 3
Antibiotics and Antimicrobials
Macrolide antibiotics and antituberculous drugs require specific monitoring for ALP elevation, particularly during the first 3 months of therapy.
- Azithromycin and clarithromycin require periodic monitoring of alkaline phosphatase, AST, and ALT for the first 3 months of therapy 5
- Rifampin and rifabutin can cause hepatitis and require AST or ALT determination based on symptoms, though ALP monitoring is implied in hepatic monitoring 5
- Other antibiotics with hepatotoxic potential include imipenem (requires periodic hepatic enzyme monitoring) and sulfonamides/trimethoprim-sulfamethoxazole 5
Immunosuppressants and Chemotherapy
- Patients receiving mercaptopurine (Purinethol) or azathioprine (Imuran) concomitantly with allopurinol may develop asymptomatic rises in serum alkaline phosphatase or serum transaminase 6
- Allopurinol itself can cause reversible clinical hepatotoxicity with rises in serum alkaline phosphatase; if anorexia, weight loss, or pruritus develop, evaluation of liver function should be performed 6
Parenteral Nutrition and Lipid Formulations
- Parenteral nutrition can cause ALP elevation through chronic cholestasis, with a reported incidence of up to 65% in home parenteral nutrition patients 7
- Excessive intravenous lipid administration (>1 g/kg/day) is particularly associated with this complication 7
Glucocorticoids
- Glucocorticoids can result in increased alkaline phosphatase activity through enzyme induction 8
- This is a well-recognized non-hepatotoxic cause of ALP elevation 8
Important Clinical Considerations
Older patients (≥60 years) are particularly susceptible to cholestatic drug-induced liver injury, which comprises up to 61% of DILI cases in this age group 7.
- A thorough medication review is crucial when evaluating elevated ALP, as drug-induced causes are common and often reversible 7
- Drug-induced cholestasis should be distinguished from enzyme induction: the former may present with symptoms (anorexia, weight loss, pruritus) while the latter is typically asymptomatic 6, 3
- When antiepileptic drugs cause elevated ALP, it is typically the liver isoenzyme that is elevated (with normal bone ALP), which can be confirmed by measuring GGT or ALP isoenzymes 3
Monitoring Recommendations
- For patients on macrolides, monitor alkaline phosphatase, AST, and ALT periodically for the first 3 months 5
- For patients on allopurinol with pre-existing liver disease, periodic liver function tests are recommended during early stages of therapy 6
- For patients on antiepileptics with persistently elevated ALP, measure GGT and consider ALP isoenzyme fractionation to differentiate liver from bone source 3
- Discontinue the offending medication if symptomatic hepatotoxicity develops (anorexia, weight loss, pruritus, jaundice) 6