How should I manage a patient with drug‑induced liver injury presenting with hepatic encephalopathy?

Management of Drug-Induced Liver Injury with Hepatic Encephalopathy

Immediately discontinue the offending drug and initiate ammonia-lowering therapy with lactulose while urgently consulting hepatology for potential liver transplantation evaluation. 1, 2, 3

Immediate Actions

Drug Discontinuation

• Stop the suspected hepatotoxic agent immediately when hepatic encephalopathy develops, as this represents hepatic decompensation and the drug cannot be restarted. 1
• Do not wait for causality assessment—discontinue first, then investigate alternative causes. 2
• For patients in clinical trials, drug interruption is mandatory when hepatic decompensation occurs (including encephalopathy, ascites, or variceal bleeding). 1

Hepatic Encephalopathy Management

• Administer lactulose as first-line therapy for portal-systemic encephalopathy, which reduces blood ammonia levels by 25-50% with clinical response in approximately 75% of patients. 4, 5
• Lactulose dosing should achieve 2-3 soft bowel movements daily. 4
• If lactulose is ineffective or not tolerated, consider rifaximin as an alternative antimicrobial agent with fewer adverse effects than neomycin or metronidazole. 5

Urgent Assessment and Monitoring

Laboratory Evaluation

• Obtain comprehensive liver function tests including ALT, AST, alkaline phosphatase, total and direct bilirubin, and INR immediately. 2
• Repeat blood tests within 2-5 days to assess trajectory and confirm prolongation of INR. 1
• Monitor hepatic and renal function and electrolytes throughout treatment. 6

Hepatology Consultation

• Immediate hepatology referral is mandatory for any patient with evidence of hepatic encephalopathy, as this indicates synthetic dysfunction and potential need for transplantation. 3
• Patients with drug-induced acute liver failure have relatively poor outcomes and high resource requirements. 7

Specific Antidote Therapy

Acetaminophen-Induced Hepatotoxicity

• Administer N-acetylcysteine immediately if acetaminophen is the causative agent, which must be initiated within 24 hours of ingestion for maximum efficacy. 2, 6
• For acetaminophen overdose with hepatic encephalopathy, continue N-acetylcysteine beyond the standard 21-hour protocol if ALT/AST continue rising or INR remains elevated. 6
• Early intravenous N-acetylcysteine is beneficial for acute liver failure and subacute liver failure induced by drugs in adults. 8

Non-Acetaminophen DILI

• Do not use corticosteroids empirically in most cases of idiosyncratic DILI, as efficacy is unproven and may cause harm. 2, 8
• Consider ursodeoxycholic acid (UDCA) only if the pattern is cholestatic, which may benefit approximately two-thirds of cholestatic DILI cases. 2
• For hepatocellular injury with significantly elevated ALT/AST, bicyclol and/or magnesium isoglycyrrhizinate are recommended. 8

Supportive Care and Monitoring

Vitamin K Supplementation

• Attempt vitamin K supplementation to correct prolonged INR prior to assigning causality, unless more immediate measures such as liver transplantation are required. 1
• Repeat INR within 2-5 days after vitamin K administration to determine trajectory. 1

Close Monitoring Protocol

• Monitor patients with hepatic encephalopathy every 3-7 days initially for liver biochemistries. 3
• Assess for signs of progressive hepatic decompensation including worsening encephalopathy, new or worsening ascites, and coagulopathy. 1
• Patients with more advanced disease require monitoring on a more frequent basis than patients in early stages to evaluate for signs of hepatic decompensation. 1

Evaluation for Alternative Causes

Competing Etiologies

• Initiate workup for competing aetiologies including viral hepatitis (HBV, HCV), autoimmune hepatitis, ischemic hepatitis, and biliary obstruction. 1, 2
• Obtain HBsAg, anti-HCV, and HBV DNA if isolated hepatitis B core antibody positivity is present, as HBV reactivation can mimic DILI. 1
• Assess adherence to concomitant medications such as ursodeoxycholic acid, as non-compliance can lead to abrupt elevations mimicking DILI. 1
• Perform abdominal imaging to exclude biliary obstruction, hepatic metastases, or vascular causes. 2

Liver Transplantation Considerations

Transplant Evaluation

• For severe patients with drug-induced liver failure, liver transplantation is recommended as the definitive treatment. 8
• Drug-induced liver injury from idiosyncratic reactions more often leads to death or transplantation than acetaminophen-induced acute liver failure. 7
• Artificial liver support (high-volume plasma exchange, dual plasma molecular adsorption system) may be a beneficial bridge to transplantation. 8

Common Pitfalls to Avoid

• Do not delay drug discontinuation while awaiting definitive causality assessment—the presence of hepatic encephalopathy mandates immediate cessation. 1, 2
• Do not attempt drug rechallenge if hepatic decompensation has occurred, as this is an absolute contraindication. 1
• Do not overlook the need for urgent hepatology consultation—hepatic encephalopathy represents advanced liver failure requiring specialist management. 3
• Do not use multiple hepatoprotective drugs simultaneously that primarily reduce ALT, as combined use is not recommended. 8
• Do not assume lactulose alone is sufficient—these patients require comprehensive management including transplant evaluation. 7