75-Year-Old Woman With Elevated Liver Enzymes

DISCUSSION
Elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels may result from a variety of factors. Mild elevations are commonly caused by alcohol consumption, hemochromatosis, medications, nonalcoholic fatty liver disease, and viral hepatitis (with which elevations may range from mild to marked).¹ Moderate to marked elevations of ALT and AST are commonly seen with acute biliary obstruction, alcoholic hepatitis, toxic injury, and ischemic injury.²

Abnormal liver enzyme levels are common with use of psychotropic drugs, such as antipsychotics and mood stabilizers.³ In a systematic review that examined the effects of antipsychotics on liver function tests, a median 4% of patients experienced elevated ALT, AST, or gamma-glutamyl transferase (GGT) levels (defined as more than triple the normal level) or alkaline phosphatase (ALP) level (defined as more than twice the normal level).³ Of the studies reviewed, five noted an interval of one to six weeks between initiation of antipsychotic drugs and detection of liver function test abnormalities. None of the included studies reported severe or fatal hepatic injury.

For the atypical antipsychotic quetiapine, elevations in ALT and AST occurred in about 5% and 3% of patients, respectively, in clinical trials of the drug as monotherapy for schizophrenia or bipolar mania.⁴ These elevations were usually transient, occurring within the first three weeks of treatment initiation and subsiding with continued treatment.

There are rare published reports, however, of serious and even fatal hepatotoxicity induced by quetiapine. One 59-year-old woman developed fulminant hepatic failure (FHF) six weeks after she began taking quetiapine in addition to carbidopa/levodopa for Parkinson disease. She reported nausea, vomiting, poor appetite, and abdominal pain and required a six-week hospitalization, with multidrug treatment that continued after discharge. Liver biopsy identified acute hepatitis with confluent bridging necrosis, a sign that the liver injury was drug-induced. The authors concluded that, because drug-induced hepatotoxicity is the most common cause of FHF in many parts of the world, clinicians should evaluate a patient’s medications for a potential cause.⁵

In another case report, elevated liver enzymes were identified one month after a 58-year-old woman taking several other medications began treatment with quetiapine (100 mg/d). She developed liver failure and died after a three-week hospitalization. The authors concluded that liver failure was caused by an idiosyncratic reaction to a relatively low dose of quetiapine. This case supports the advisability of close monitoring of liver enzyme levels during quetiapine treatment.⁶

Naharci et al reported a case of a 77-year-old woman treated with quetiapine (12.5 mg bid for nine days). She developed acute hepatic failure leading to multi-organ system failure and died eight days later. Liver failure was attributed to an idiosyncratic reaction to low-dose quetiapine. The authors concluded that liver function monitoring is essential with quetiapine administration, especially in elderly or fragile patients.⁷

The initial recommended dosage of quetiapine for elderly patients (defined as age 65 or older) is 50 mg/d, with the dose increased in increments of 50 mg/d, based on clinical response and tolerability. In clinical trials, the mean plasma clearance of quetiapine was reduced by 30% to 50% in the elderly, so dosing adjustments may be necessary in this age-group.⁴ Gareri et al recommended that atypical antipsychotics be prescribed for elderly patients for the shortest necessary duration and at the lowest effective dose.⁸

For hepatically impaired patients, recommended initial dosing is 25 mg/d, with increases of 25 to 50 mg/d until an effective and tolerable dose is reached.⁴ Further, because quetiapine is primarily metabolized via the cytochrome P450 liver enzymes CYP3A4 and CYP2D6,⁹ when the clinician prescribes a potent CYP3A4 inhibitor (eg, ketoconazole) to a patient taking quetiapine, the quetiapine dosage needs to be reduced. Conversely, when prescribing a ­CYP3A4 inducer (eg, phenytoin), the quetiapine dosage should be adjusted upward.⁴

Even when an apparently well-tolerated, effective quetiapine dosage has been reached, clinicians and patients should remain alert to the warning signs of potentially serious events. Adverse effects of atypical antipsychotics, including quetiapine, were summarized by Gareri et al and rated on a scale ranging from no effect to severe effect.⁸ The most severe adverse effects for quetiapine were hypotension and prolonged QTc interval. Weight gain was identified as a moderate effect, and sedation, gastrointestinal problems (nausea, vomiting, and constipation), and anticholinergic effects as mild. Some effects—tardive dyskinesia, seizures, and hepatic—were deemed “uncertain”; this rating suggests the need for careful monitoring of patients (who should be informed of signs and symptoms that should be reported to the clinician).⁸

Atasoy et al reviewed the records of 110 patients to assess the effect of atypical antipsychotics on liver function tests. The patients’ records included both baseline liver function tests and repeat testing at six months. Forty-eight patients received quetiapine; 33 patients, olanzapine; and 29 patients, risperidone. Liver enzymes were elevated in 27.1% of the quetiapine group, 30.3% of the olanzapine group, and 27.6% of the risperidone group. In two patients taking olanzapine, liver enzyme levels reached three to four times normal but returned to normal when treatment was stopped. The authors concluded that baseline liver enzyme studies should be done prior to initiation of treatment with atypical antipsychotics, as well as periodically thereafter, especially for patients with preexisting hepatic disorders, those being treated with other potentially hepatotoxic drugs, or those who exhibit signs or symptoms of hepatic impairment.¹⁰

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