Phenelzine is a monamine oxidase inhibitor (MAO inhibitor) used in therapy of severe depression. Phenelzine therapy is associated with rare instances of clinically apparent acute liver injury.
Phenelzine (fen' el zeen) is a hydrazine derivative and antidepressant that acts through inhibition of monamine oxidase, an enzyme that inactivates several neurotransmitter amines such as norepinephrine and serotonin. By inhibition of catabolism of serotonin and norepinephrine, phenelzine increases brain levels of these neurotransmitters which probably underlie its antidepressant effects. Phenelzine was approved for use as therapy of depression in the United States in 1961, but it is now rarely used because of the availability of more potent and better tolerated antidepressants such as the tricyclic antidepressants and the selective serotonin reuptake inhibitors. Phenelzine is available in generic forms and under the brand name of Nardil as tablets of 15 mg. The usual adult dose of phenelzine is 15 to 30 mg three times daily. Common side effects include drowsiness, dizziness, headache, insomnia, tremor, dry mouth, nausea, increased appetite, weight gain and sexual dysfunction. Phenelzine interacts with many medications as well as many foods and beverages, and patients require careful monitoring and education.
Phenelzine, like most monamine oxidase inhibitors, can cause transient serum aminotransferase elevations in a proportion of patients. These elevations are usually mild, asymptomatic and self-limited and do not require dose modification. Phenelzine has also been associated with cases of acute, clinically apparent liver injury. The liver injury associated with MAO inhibitors typically arises 1 to 3 months after starting therapy and presents with a hepatocellular pattern of serum enzyme elevations. The acute hepatitis-like syndrome can be severe and even fatal. Cholestatic liver injury due to phenelzine has also been described (Case 1). Immunoallergic features (rash, fever, eosinophilia) are uncommon as is autoantibody formation.
Mechanism of Injury
The mechanism by which phenelzine causes serum aminotransferase elevation is not known. It undergoes extensive hepatic metabolism, and a possible cause of liver injury is production of an intermediate of metabolism that is directly toxic to hepatocytes or that induces a hypersensitivity response.
Outcome and Management
The serum aminotransferase elevations that occur on phenelzine therapy are usually self-limited and mild and do not require dose modification or discontinuation of therapy. The clinically apparent, acute liver injury caused by phenelzine is typically self-limited, but progressive and fatal instances of acute hepatitis have been reported. Rechallenge usually causes a prompt recurrence of the liver injury and should be avoided. Patients with phenelzine induced liver injury may have cross sensitivity to other monamine oxidase inhibitors, but should be able to tolerate tricyclic antidepressants or selective serotonin reuptake inhibitors.
Case 1. Severe and prolonged liver injury due to phenelzine.
[Modified from: Bonkovsky HL, Blanchette PL, Schned AR. Severe liver injury due to phenelzine with unique hepatic deposition of extracellular material. Am J Med 1986; 80: 689-92. PubMed Citation]
A 59 year old man developed fatigue and itching followed by jaundice 2 months after starting phenelzine and shortly after a dose escalation from 45 to 60 mg daily. He had no history of liver disease or exposure to viral hepatitis and drank alcohol only moderately. Other medications included colchicine, probenecid, chlordiazepoxide and flurazepam. Physical examination showed jaundice without rash or fever or signs of chronic liver disease. Serum bilirubin was 9.8 mg/dL and serum enzymes were raised (Table). There was no eosinophilia and tests for hepatitis B and autoantibodies were negative. Phenelzine was stopped, but liver tests did not improve rapidly. A liver biopsy showed areas of lobular collapse, inflammation and intrahepatic cholestasis and unusual, amorphous and unidentified extracellular deposits. He was treated with prednisone (15 mg daily) and azathioprine (50 mg daily) with a clinical and biochemical response, but serum enzymes remained mildly abnormal for somewhat more than a year before becoming persistently normal. Follow up liver biopsy showed resolution of the acute injury, but presence of fibrosis and partial cirrhosis.
||Phenelzine (60 mg daily)
|Pattern:|| Cholestatic (R=0.6)|
||3+ (jaundice and hospitalization)
|Other medications:||Colchicine, probenecid, chlordiazepoxide, flurazepam|
|Time After Starting
||Months After Stopping
||Alk P (U/L)
|Phenelzine given for two months
Dates and values estimated from Figure 1.
The monamine oxidase (MAO) inhibitors are no longer commonly used and most reported cases of hepatotoxicity were published before 1990. The described case is unusual because of the prolonged injury and development of cirrhosis, despite prompt discontinuation of the medication. Actually, clinical and histologic long term follow up is rarely available in cases of acute drug induced liver disease, and some degree of residual fibrosis and even cirrhosis may occur particularly if the acute episode is severe and prolonged.
REPRESENTATIVE TRADE NAMES
Phenelzine – Generic, Nardil®
Product labeling at DailyMed, National Library of Medicine, NIH
||CAS REGISTRY NUMBER
References updated: 16 January 2014
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