Halothane Hepatitis
🔷 Overview:
Halothane hepatitis is a rare, potentially fatal, immune-mediated hepatotoxicity that occurs after exposure to the volatile anesthetic halothane.
1. Classification
There are two types:
|
Type |
Features |
|
Type I (mild) |
Transient, asymptomatic elevation in liver enzymes, occurs in up to 20% of patients; resolves spontaneously. |
|
Type II(severe)** |
Idiosyncratic, fulminant hepatic failure, associated with high mortality; immune-mediated. Rare (~1 in 10,000–35,000 exposures). |
2. Pathophysiology
A. Metabolism of Halothane
- Primarily metabolized by the liver (~20–25%) via cytochrome P450 (CYP2E1).
- Produces reactive trifluoroacetylated (TFA) intermediates, especially trifluoroacetyl chloride.
B. Mechanism of Injury
- Type II Halothane Hepatitis:
- TFA binds to liver proteins → forms neoantigens.
- Triggers a delayed hypersensitivity reaction (Type II/IV).
- Results in immune-mediated hepatocyte destruction.
- Genetic predisposition (e.g., HLA haplotypes) likely plays a role.
3. Risk Factors
|
Risk Factor |
Notes |
|
Repeated exposure |
Especially within a short interval (e.g., 3–6 weeks) |
|
Middle-aged females |
Especially obese women |
|
Obesity |
Possibly related to increased metabolism or fat solubility |
|
Genetic predisposition |
Certain HLA alleles linked |
|
Autoimmune disorders |
May increase susceptibility |
|
Enzyme induction (CYP2E1) |
E.g., alcohol, isoniazid |
4. Clinical Features
- Onset: 2–14 days post-anesthesia (often ~5–10 days).
- Symptoms:
- Fever, malaise, anorexia
- Jaundice
- Right upper quadrant pain
- Hepatomegaly
- May progress to fulminant hepatic failure, coagulopathy, encephalopathy
5. Laboratory Findings
|
Test |
Findings |
|
LFTs |
Markedly elevated ALT/AST (>>1000 IU/L), ↑ bilirubin, ↑ ALP |
|
PT/INR |
Prolonged |
|
Eosinophilia |
Sometimes present |
|
Serology |
Negative viral markers |
|
Autoantibodies |
May have anti-TFA antibodies |
|
Liver biopsy |
Centrilobular necrosis, eosinophilic infiltration |
6. Diagnosis
- Clinical diagnosis based on history of halothane exposure, symptoms, exclusion of other causes (viral, alcoholic, ischemic hepatitis).
- Anti-TFA antibodies are supportive but not always available.
- Liver biopsy if needed for confirmation.
7. Management
|
Step |
Approach |
|
Supportive care |
ICU admission, monitor LFTs, coagulopathy, encephalopathy |
|
Avoid re-exposure |
Halothane must never be used again in such patients |
|
Liver transplant |
May be needed in fulminant hepatic failure |
|
Corticosteroids |
No proven benefit; sometimes used if autoimmune features dominate |
|
N-acetylcysteine |
May be considered though not proven in halothane toxicity |
8. Prognosis
- Type I: Excellent, full recovery.
- Type II: Mortality up to 50–60% in fulminant cases.
9. Prevention
- Avoid halothane in adults, especially those with prior exposure.
- Use safer alternatives: isoflurane, sevoflurane, desflurane have significantly lower hepatic metabolism (sevo <5%, des <0.02%).
10. Comparison with Newer Agents
|
Agent |
Liver Metabolism |
Hepatotoxicity Risk |
|
Halothane |
~20–25% |
High (Type II hepatitis) |
|
Isoflurane |
~0.2% |
Rare |
|
Sevoflurane |
~5% |
Very rare (Compound A nephrotoxicity more relevant) |
|
Desflurane |
<0.02% |
Extremely rare |