Liver Toxicity : Penicillin G and V

Hepatotoxicity

• Rare instances of idiosyncratic liver injury have been reported in persons receiving the first-generation penicillins.
• Many case reports pre-dated availability of serologic testing for viral hepatitis and many described patients with multiple reasons for having liver disease (such as sepsis) and who were receiving other potentially hepatotoxic agents.
• Three distinct forms of liver injury can occur with the first generation penicillins:

(1) transient, asymptomatic elevations in serum aminotransferase levels 

• with prolonged high doses of parenteral penicillin / IM
• usually asymptomatic and resolve rapidly with stopping therapy or switching to another antibiotic
• Jaundice and elevations in alkaline phosphatase are usually absent or mild. 
• most common with oxacillin and carbenicillin, but can occur with parenteral forms of the first generation penicillins as well

(2) minor liver injury 

• associated with severe hypersensitivity reactions, and
• severe hypersensitivity reactions to penicillin, such as Stevens-Johnson syndrome or anaphylaxis, may have an accompanying liver injury and jaundice
• Generalized allergic reactions to penicillin may be accompanied by granulomas in the liver, spleen and kidney, but are usually without evidence of specific hepatitis injury.  
• are associated with hypersensitivity reactions, but liver injury is usually overshadowed by the allergic complications (rash, fever, anaphylaxis). 

(3) idiosyncratic, delayed cholestatic hepatitis.

• isolated case reports
• Symptoms of nausea, abdominal discomfort, jaundice and pruritus generally arise 1 to 4 weeks after starting therapy and often a few days or weeks after completing a course. 
• The serum enzyme pattern is usually cholestatic, but may be hepatocellular if tested soon after onset. 
• Immunoallergic features are common but autoantibody formation is rare
• Most cases are mild-to-moderate in severity and resolve rapidly
• quite rare with the natural penicillins, more common with certain broad spectrum penicillins (cloxacillin, flucloxacillin) and is most common with amoxicillin with clavulanic acid

Management

• asymptomatic rise in serum aminotransferase levels that occurs with high dose penicillin therapy usually resolves rapidly once penicillin is stopped. 
• These patients may tolerate another form of penicillin without recurrence. 
• In the few cases of cholestatic hepatitis that have been described with the first generation penicillins, patients have recovered although recovery was slow in some instances (2 to 6 months).
• Fatal cases of penicillin-associated liver injury have been described but usually in association with severe allergic reactions such as Stevens-Johnson syndrome in which shock and ischemic hepatitis may have contributed to the outcome.  
• Patients with idiosyncratic liver injury attributed to penicillin should not be re-exposed to other penicillins

References:

1. http://livertox.nih.gov/PenicillinGandPenicillinV.htm
2. www.drugs.com