Hepatic effects of inhalational anaesthetic agents

[SH4:p64]

Hepatic blood flow

• Isoflurane, sevoflurane, desflurane causes vasodilation in hepatic circulation
  * Hepatic blood flow is maintained
  * Portal vein blood flow is increased
• Halothane causes vasoconstriction in hepatic circulation

Drug clearance

• Inhalational anaesthetic agents causes decrease in hepatic metabolic clearance of drugs such as propranolol
  * By >50%

Liver function tets

• Enflurane and desflurane cause transient increases in plasma alanine aminotransferase
• Isoflurane and desflurane cause transient increases in plasma alpha glutathione transferase
• Hepatic dysfunction is most likely to be due to inadequate hepatocyte oxygenation
  * Enzyme induction increases O2 demand and increases risk of inadequate oxygenation

Hepatotoxicity

• Centrilobular necrosis

Halothane

Two types of hepatotoxicity:

• Mild, self-limited form
• Severe, rare form

Mild form of halothane hepatotoxicity

• Incidence
  = ~20% of postop patients
• Nonspecific drug effect
  * Due to decrease in hepatic blood flow
  --> Reduced hepatic oxygenation
• Symptoms and signs:
  * Fever
  * Lethargy
  * Nausea
  * Minor increase in liver transaminase

Halothane hepatitis

• Incidence
  = 1 in 10,000 to 30,000
• Immune-mediated
• Symptoms and signs:
  * Fever
  * Rash
  * Arthralgia
  * Eosinophilia
• Risk factors
  * Female gender
  * Middle age
  * Obesity
  * Prior exposure to halothane
  * Family history

Mechanism

• Formation of reactive oxidative trifluoroacetyl (TFA) halide metabolite
  --> Covalently bound to liver microsomal proteins on hepatocyte surfaces
  --> Neoantigens
  --> Triggers immune response
• Metabolism of halothane is genetically determined

Evidence of immunogenic basis

• Presence of IgG antibodies in at least 70% of patients
  * Directed against liver microsomal proteins

Enflurane, isoflurane, and desflurane

• Mild self-limited hepatic dysfunction can also happen with enflurane, isoflurane, and desflurane
  * Related to inadequate hepatocyte oxygenation

Immune-mediated hepatitis can also occur:

• Much lower incidence due to lower metabolism
• Risk is increased when patient has previously been sensitized against trifluoroacetyl proteins
• Overall risk (after previous exposure to halothane) is probably less than overall risk of anaesthetics

Sevoflurane

• Due to chemical structure of sevoflurane, metabolism of sevoflurane cannot lead to production of acetyl halide
  --> Cannot form trifluoroacetylated liver protein
  --> Cannot cause immune-mediated hepatitis or cross-reaction
• Compound A is hepatotoxic in animals
  * But concentration in circuit is far lower than toxic level in animals
  * Compound A is also nephrotoxic