What drugs can cause an increase in bilirubin with an increase in alkaline phosphatase (aLP)?

Drugs That Cause Elevated Bilirubin with Elevated Alkaline Phosphatase

The most common drugs causing concurrent bilirubin and alkaline phosphatase elevation are antibiotics—particularly co-amoxiclav and flucloxacillin—followed by oral contraceptives, estrogenic/anabolic steroids, chlorpromazine, acetaminophen, and penicillin. 1

Primary Offending Medications

Antibiotics (Most Common)

• Co-amoxiclav causes drug-induced jaundice with an incidence of 9.91 per 100,000 prescriptions, predominantly affecting elderly males (≥65 years), with bilirubin ranging from 54-599 μmol/L and resolution typically occurring between 30-90 days 2
• Flucloxacillin causes jaundice at an incidence of 3.60 per 100,000 prescriptions, with similar cholestatic patterns 2
• Penicillin is recognized as causing abnormal liver function tests with hyperbilirubinemia through cholestatic mechanisms 1

Hormonal Agents

• Oral contraceptives cause medication-induced liver injury with cholestasis and elevated conjugated bilirubin 1
• Estrogenic steroids disrupt bile excretion, leading to increased conjugated bilirubin levels 1
• Anabolic steroids similarly cause cholestatic injury with concurrent ALP and bilirubin elevation 1

Antipsychotics

• Chlorpromazine (Thorazine) causes cholestatic liver injury with elevated conjugated bilirubin and alkaline phosphatase 1

Analgesics

• Acetaminophen can result in abnormal liver function tests with hyperbilirubinemia, particularly in overdose or chronic use settings 1

Antiepileptic Drugs (Unique Pattern)

Phenytoin and Related Agents

• Phenytoin causes increased serum levels of alkaline phosphatase through hepatic enzyme induction 3
• Antiepileptic drugs induce liver microsomal enzymes, leading to raised liver ALP-isoenzyme activity (75% of patients) with concurrent elevation of gamma-glutamyl transferase 4
• The pattern typically shows raised liver ALP with normal bone ALP in 75% of cases, distinguishing this from bone-related ALP elevation 4

Antimycobacterial Agents

Rifampin

• Rifampin causes transient abnormalities in liver function tests including elevation in serum bilirubin, alkaline phosphatase, and serum transaminases 5
• Hepatotoxicity manifestations include hepatitis, shock-like syndrome with hepatic involvement, and cholestasis 5
• Reduced biliary excretion of contrast media has been observed, indicating cholestatic effects 5

Clinical Pattern Recognition

Cholestatic Drug-Induced Liver Injury

• The pattern of concurrent bilirubin and ALP elevation indicates cholestatic or mixed drug-induced liver injury 1
• Cholestatic DILI is classified when the R value [(ALT/ULN)/(ALP/ULN)] is ≤2, distinguishing it from hepatocellular injury 1
• Higher serum bilirubin and ALP at DILI onset are associated with prolonged recovery, with the high-risk group showing only 46% probability of recovery by 6 months 6

Age-Related Considerations

• Older patients (≥60 years) are particularly susceptible to cholestatic drug-induced liver injury, comprising up to 61% of cases in this age group 1, 7
• Co-amoxiclav-induced jaundice shows marked male predominance in elderly patients (M:F ratio 7:2 in those ≥65 years) 2

Critical Monitoring Parameters

When to Suspect Drug-Induced Cholestasis

• ALP elevation >2× baseline combined with total bilirubin >2× baseline should trigger accelerated monitoring and consideration of drug interruption 1
• New onset or worsening pruritus, right upper quadrant pain, severe fatigue, or nausea accompanying biochemical changes strongly suggests drug-induced cholestatic injury 1

Prognostic Indicators

• Patients with bilirubin levels ≤1.0× ULN show 86% 10-year survival compared to 41% in those with levels >1.0× ULN 8
• Patients with ALP ≤2.0× ULN demonstrate 84% 10-year survival versus 62% in those with higher levels 8

Important Clinical Pitfalls

• Do not assume non-alcoholic steatohepatitis (NASH) as the cause when ALP is ≥2× ULN, as NASH typically elevates ALT more than ALP 7
• Always confirm hepatobiliary origin of ALP elevation with GGT or ALP isoenzyme fractionation before attributing elevation to drug-induced liver injury 1
• Medication review is mandatory in all cases, particularly scrutinizing antibiotics, hormonal agents, and antiepileptics in the preceding 3 months 1, 7
• Genetic polymorphisms in UDP-glucuronosyltransferases, organic anion-transporting polypeptides, and multidrug resistance proteins predispose certain patients to drug-induced hyperbilirubinemia 9