Management of AKT Inhibitor-Induced Hepatitis
Immediately discontinue the AKT inhibitor and initiate corticosteroid therapy for Grade 3 or higher transaminitis (ALT >5× ULN), as delayed discontinuation can result in irreversible liver failure and death. 1, 2
Initial Assessment and Severity Grading
Grade the severity of hepatotoxicity using standardized criteria:
- Grade 1: ALT >ULN to 3.0× ULN 1
- Grade 2: ALT >3.0 to 5.0× ULN 1
- Grade 3: ALT >5.0 to 20× ULN 1
- Grade 4: ALT >20× ULN 1
Assess for symptoms indicating severe liver injury: fatigue, nausea, vomiting, right upper quadrant pain, fever, or rash—these symptoms combined with ALT ≥3× ULN indicate more severe injury requiring immediate action. 1, 2
Evaluate for hepatic decompensation by checking:
- Coagulopathy (INR >1.5) 1
- Elevated bilirubin (≥2× ULN) 1
- Worsening jaundice, ascites, or encephalopathy 1, 2
Obtain comprehensive liver function tests: AST, ALT, alkaline phosphatase, GGT, total and direct bilirubin, albumin, and INR to characterize the injury pattern and assess synthetic function. 1
Management Algorithm Based on Severity
Grade 1 Transaminitis (ALT >ULN to 3× ULN)
- Continue close monitoring without specific treatment 1
- Check liver function tests 1-2 times weekly 1
- Continue monitoring for at least five half-lives of the AKT inhibitor and its major metabolites 1, 2
Grade 2 Transaminitis (ALT >3.0 to 5.0× ULN)
- Permanently discontinue the AKT inhibitor if medically feasible 1
- Increase monitoring frequency to every 3 days 1
- Do not restart the medication even at a lower dose 1, 2
Grade 3 Transaminitis (ALT >5.0 to 20× ULN)
- Obtain urgent hepatology consultation for specialized management 1, 3
- Permanently discontinue the AKT inhibitor immediately 1
- Start methylprednisolone 1-2 mg/kg/day or equivalent corticosteroid therapy 1
- Early hepatology consultation (within 7 days) is associated with faster biochemical resolution, particularly through earlier initiation of additional immunosuppression if needed 3
Grade 4 Transaminitis (ALT >20× ULN)
- Immediately hospitalize the patient, preferably at a liver transplant center 1
- Administer methylprednisolone 2 mg/kg/day with a planned 4-6 week taper 1
- Monitor continuously for signs of hepatic decompensation 1
Monitoring During Recovery
Continue monitoring liver tests for at least five half-lives of the AKT inhibitor and its major metabolites after discontinuation. 1, 2
Monitor for signs of hepatic decompensation throughout the recovery period: worsening jaundice, ascites, or encephalopathy. 1, 2
After corticosteroid initiation, monitor ALT levels frequently (at least monthly) for the first 3 months after cessation of therapy to detect withdrawal flares. 1
Perform abdominal ultrasound to assess for structural liver abnormalities, especially when ALT elevation persists. 2
Critical Pitfalls and Caveats
Never restart the AKT inhibitor even at a lower dose if hepatic decompensation occurred during the initial exposure. 1, 2
Do not delay corticosteroid therapy in Grade 3 or higher hepatotoxicity while waiting for hepatology consultation—initiate treatment immediately and consult simultaneously. 1
Medication can only be restarted if another etiology for liver injury is clearly identified and liver abnormalities return to baseline, which is extremely rare with AKT inhibitor-induced hepatitis. 2
Coordinate care with a hepatologist experienced in drug-induced liver injury for patients with Grade 3 or higher transaminitis, or if transaminases remain elevated for ≥6 months despite initial interventions. 1, 2
Refer to hepatology if ALT increases to >5× ULN or if ALT elevation is accompanied by an increase in total bilirubin >2× ULN, as this indicates more severe injury with higher risk of poor outcomes. 2