What is known about venlafaxine-induced hepatotoxicity?/nBackground: A 44-year-old depressed woman

Fråga: What is known about venlafaxine-induced hepatotoxicity? Background: A 44-year-old depressed woman started treatment with venlafaxine (37 mg) seven weeks ago, after therapeutic failure on escitalopram. After a few days, she experienced dyspeptic symptoms and treatment with daily intake of omeprazole was added. During the following weeks, the dose of venlafaxine was increased step-wise to 110 mg but two weeks thereafter, abdominal discomfort re-appeared and worsened with nausea and occasional vomiting the last four days. Upon referral to hospital, it was discovered that liver function tests were highly abnormal (both AST and ALT > 13, LD 8, normal bilirubin). There was no history of alcohol or paracetamol intake.

Sammanfattning: Venlafaxine-induced liver injury has been reported in the literature and several Swedish cases have also been reported to the regulatory authorities, ranging from asymptomatic changes in aminotransferases to serious and potentially life-threatening liver injury. In common for most reported cases is the delayed onset of toxicity and apparent independence of dose level. Upon drug withdrawal, most cases exhibit a prompt improvement and normalisation of liver function tests within the following month.

Svar: It is known that venlafaxine, with a low frequency, may induce pathological changes in liver function tests, and even hepatitis has been described in rare cases (1-6). Postmarketing reports also include hepatic necrosis or liver failure (6) but no published data has been retrieved to substantiate this, except for a case of fatal intoxication with venlafaxine where centrilobular heptatocellular necrosis was found at autopsy (7). In this case, an almost 100-fold higher plasma level than observed at therapeutic doses was found, which suggests that venlafaxine may cause acute hepatotoxicity at very high exposure levels (7). However, all other published reports on venlafaxine-associated liver injury rather indicate an unpredictable individual susceptibility with a delayed onset at therapeutic doses, as discussed below.

It is evident from the literature on venlafaxine-induced hepatotoxicity that the biochemical pattern of liver injury is mainly hepatocellular. In several of these published reports, aminotransferase elevations were similar to the present Swedish case described by the questioner. Bilirubin was usually normal or only slightly elevated. Reactions may occur at low dose levels (5) but were usually manifested when dose levels had been increased to intermediate levels of 75-150 mg daily, after several weeks or even months of treatment. Whether or not venlafaxine-induced hepatotoxicity is dose-dependent alternatively exhibits delayed onset is therefore not entirely clear. However, in favour of the latter is that re-challenge attempts with lower doses proved unsuccessful (6) and probably contributed to a prolonged course of recovery (2, 5). Otherwise, it seems clear that discontinuation of venlafaxine treatment commonly leads to full recovery within a month. The underlying mechanism of toxicity is not clear and it seems possible to classify the reaction as idiosyncratic in nature (6).

It is recommended that the present case be reported to the Swedish Medical Products Agency. In their Adverse Drug Reactions Register, there are 24 reports on venlafaxine and adverse reactions from the hepatic/biliary system in January 2009; essentially all classified as pathological changes in liver function tests (8). However, thirteen of these reports describe serious cases with substantial elevations in both aminotransferases and bilirubin (specified in nine reports). This sign of more severe liver injury is of prognostic importance (9) and two of the case reports had a fatal course (8). Importantly though, causality assessment was complicated in one of these cases by more than one suspected drug, and in the other report it was stated that the patient died from underlying disease (lymphoma). In general, the Swedish cases of venlafaxine-associated liver injury were in agreement with published reports with a delayed onset of toxicity ranging from 3-4 weeks to more than a year, and at daily doses between 75-300 mg, together with a prompt recovery in most cases of drug withdrawal (8).

It is recommended that the present case be reported to the Swedish Medical Products Agency together with possible follow-up data.