What medications can cause elevated alkaline phosphatase (alk phos) levels?

Medications That Commonly Cause Elevated Alkaline Phosphatase

The most common drug classes causing elevated alkaline phosphatase are anticonvulsants (particularly phenytoin and carbamazepine), antibiotics (especially macrolides and rifampin), parenteral nutrition, glucocorticoids, and immunosuppressants. 1, 2, 3

Anticonvulsant Medications

Phenytoin (Dilantin) is a well-documented cause of elevated ALP and can produce extremely high levels. 2, 4

• Phenytoin directly increases serum levels of alkaline phosphatase and gamma-glutamyl transpeptidase (GGT) through hepatic enzyme induction 2
• One case series identified Dilantin toxicity as causing extremely high ALP elevations (>1000 U/L) in an AIDS patient 4
• The mechanism involves induction of liver microsomal enzymes, which can include liver ALP isoenzymes rather than bone ALP 5
• In epileptic patients on long-term phenytoin therapy, 75% showed raised liver ALP with normal bone ALP, indicating hepatic enzyme induction rather than bone disease 5

Carbamazepine monotherapy increases serum ALP in approximately 22% of patients, with bone isoenzyme elevation occurring in 24%. 6

• Increased bone ALP may precede elevation in total ALP activity, so 20% of patients with elevated bone isoenzyme had normal total ALP 6
• This pattern differs from phenytoin, which predominantly elevates liver ALP isoenzymes 5

Antibiotics and Antimicrobials

Macrolide antibiotics (azithromycin, clarithromycin) and rifamycins (rifampin, rifabutin) require monitoring of ALP, AST, and ALT for the first 3 months of therapy. 1

• The American Thoracic Society specifically recommends periodic monitoring during the initial treatment period 1
• These medications can cause hepatitis with cholestatic patterns 1

Parenteral Nutrition

Parenteral nutrition causes ALP elevation through chronic cholestasis in up to 65% of home parenteral nutrition patients. 1

• Excessive intravenous lipid administration (>1g/kg/day) is particularly associated with cholestatic ALP elevation 7
• This represents one of the highest incidence rates among medication-related causes 1

Glucocorticoids and Immunosuppressants

Systemic corticosteroids (dexamethasone, fludrocortisone, methylprednisolone, prednisone, prednisolone) can induce ALP elevation through enzyme induction. 8, 3

• Cyclosporine is associated with ALP elevation, though conversion to tacrolimus may reduce this effect 8
• The mechanism involves hepatic enzyme induction similar to anticonvulsants 3

Age-Related Susceptibility

Older patients (≥60 years) are particularly vulnerable to cholestatic drug-induced liver injury, which comprises up to 61% of drug-induced liver injury cases in this age group. 7, 1

• Medication review is crucial in elderly patients presenting with elevated ALP 7
• The cholestatic pattern is more common than hepatocellular injury in older adults 7

Other Medications

Additional drugs that may elevate ALP include:

• Oral contraceptives: Low-dose formulations (20-30 mcg ethinyl estradiol) are preferred, and should be avoided in women with uncontrolled hypertension 8
• NSAIDs: Should be avoided when possible; consider alternative analgesics like acetaminophen or topical NSAIDs 8
• Angiogenesis inhibitors (bevacizumab) and tyrosine kinase inhibitors (sunitinib, sorafenib) 8

Clinical Monitoring Recommendations

When drug-induced cholestatic injury is suspected, repeat ALP and liver enzymes within 7-10 days to confirm reproducibility and direction of change. 7

• ALP elevation >2× baseline without alternative explanation warrants accelerated monitoring 7
• ALP >3× baseline, or ALP >2× baseline combined with bilirubin >2× baseline, should trigger drug interruption 7
• Cholestatic injury typically improves more slowly than hepatocellular injury, with blood tests returning to baseline within 6 months after removing the offending agent 7