Management of AKT Inhibitor-Induced Hepatitis
Immediately discontinue the AKT inhibitor as soon as hepatotoxicity is suspected, as delayed discontinuation can result in irreversible liver failure and death. 1
Initial Assessment and Severity Grading
Grade the severity of transaminitis using standardized criteria: Grade 1 (ALT >ULN to 3.0× ULN), Grade 2 (ALT >3.0 to 5.0× ULN), Grade 3 (ALT >5.0 to 20× ULN), and Grade 4 (ALT >20× ULN). 2
Assess for symptoms of severe liver injury including fatigue, nausea, vomiting, right upper quadrant pain, fever, or rash, as these symptoms combined with ALT ≥3× ULN indicate more severe injury requiring immediate action. 1
Evaluate for hepatic decompensation by checking for coagulopathy (INR >1.5), elevated bilirubin (≥2× ULN), worsening jaundice, ascites, or encephalopathy, which indicate severe liver injury requiring urgent intervention. 3, 1
Obtain baseline liver function tests including AST, ALT, alkaline phosphatase, GGT, total and direct bilirubin, albumin, and INR to characterize the injury pattern and assess synthetic function. 2
Management Based on Severity
Grade 1 Transaminitis (ALT >ULN to 3.0× ULN)
Continue close monitoring without specific treatment, checking liver function tests 1-2 times weekly. 2
Do not restart the AKT inhibitor unless another clear etiology for liver injury is identified and liver abnormalities return to baseline. 1
Grade 2 Transaminitis (ALT >3.0 to 5.0× ULN)
Permanently discontinue the AKT inhibitor if medically feasible. 2
Increase monitoring frequency to every 3 days. 2
Consider prednisone 0.5-1 mg/kg/day if no improvement occurs after 3-5 days of observation. 2
Grade 3 Transaminitis (ALT >5.0 to 20× ULN)
Obtain urgent hepatology consultation for specialized management. 2
Permanently discontinue the AKT inhibitor immediately. 2
Start methylprednisolone 1-2 mg/kg/day or equivalent corticosteroid therapy. 2
Consider liver biopsy if the patient is steroid-refractory or if diagnostic uncertainty exists. 2
Refer to hepatology as ALT >5× ULN meets criteria for specialist evaluation. 1
Grade 4 Transaminitis (ALT >20× ULN)
Immediately hospitalize the patient, preferably at a liver transplant center. 2
Permanently discontinue the AKT inhibitor without consideration for rechallenge. 2
Administer methylprednisolone 2 mg/kg/day with a planned 4-6 week taper. 2
Add second-line immunosuppression (such as mycophenolate mofetil) if transaminases don't decrease by 50% within 3 days of corticosteroid therapy. 2
Monitoring and Follow-Up
Continue monitoring liver tests for at least five half-lives of the AKT inhibitor and its major metabolites after discontinuation. 1
Monitor for signs of hepatic decompensation including worsening jaundice, ascites, or encephalopathy throughout the recovery period. 1
For mild transaminitis, repeat liver function tests every 1-2 weeks until normalization. 2
For moderate to severe transaminitis, more frequent monitoring is required, with daily monitoring during the acute phase for Grade 3-4 elevations. 2
After corticosteroid initiation, monitor ALT levels frequently (at least monthly) for the first 3 months after cessation of therapy to detect withdrawal flares. 3
Critical Caveats and Pitfalls
Do not restart the AKT inhibitor even at a lower dose if hepatic decompensation occurred during the initial exposure. 1
Avoid restarting the medication unless another etiology for liver injury is clearly identified and documented, and only after complete normalization of liver enzymes. 1
The presence of any ALT elevation with bilirubin ≥2× ULN or INR >1.5 suggests potential acute liver failure requiring immediate evaluation and hospitalization. 2
Perform abdominal ultrasound to assess for structural liver abnormalities, especially when ALT elevation persists beyond initial assessment. 1
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. 3, 1