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Quetiapine-Induced Hepatocellular Damage
Psychosomatics 2012:53:601– 605
© 2012 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.
Letters to the Editor
Quetiapine-Induced Hepatocellular Damage TO THE EDITOR: Hepatotoxicity is a possible adverse reaction of antipsychotics. The elevation of liver enzymes is usually reversible, but fatal hepatitis also exists. Among the second generation antipsychotics, hepatic adverse reactions related with clozapine, risperidone, and olanzapine have been found.1 Quetiapine-induced hepatotoxicity is relatively rare.1– 4 Here we report a middle-aged woman, who showed hepatocellular damage associated with quetiapine treatment, and the liver profiles returned to normal range soon after switching to other antipsychotics. Mrs. W, a 47-year-old woman with schizophrenia, was admitted because of
FIGURE 1.
auditory hallucinations. At the beginning of her admission, Mrs. W showed normal liver function profiles. After quetiapine 400 mg/d treatment for 1 week, her psychotic symptoms improved. However, bilateral leg edema and elevated liver enzymes, with alanine aminotransferase (ALT) 113 U/L, ␥-glutamyl transpeptidase (GGT) 219 U/L, and alkaline phosphatase (ALP) 547 U/L, developed. Her total bilirubin level was 0.39 mg/dL, and cholestatic hepatitis was less likely. Abdominal computed tomography revealed a 1.2 cm hepatic hemangioma, but it could not explain the elevated liver enzymes. Her autoimmune profiles were within normal limits, and there was no hepatitis B or hepatitis C infection. Therefore, quetiapine-induced hepatocellular damage was suspected. Ten days after tapering of quetiapine to 300
mg/d, the abnormal liver function and leg edema subsided. With improved psychotic symptoms, she was discharged. However, Mrs. W discontinued all of her medications. Risperidone 1 mg/d was taken with irregular compliance. She was hospitalized again 3 months later. The liver profiles were within normal limits at the beginning of her second admission. Due to a previous good response, quetiapine 300 mg/d was given, and gradually increased to 400 mg/d. With this dosage for 10 days, elevated liver function reappeared with ALT 120 U/L, aspartate aminotransferase (AST) 147 U/L, GGT 79 U/L, and ALP 181 U/L. Her total bilirubin was 0.19 mg/dL, and direct bilirubin was 0.02 mg/dL. The pattern was compatible with hepatocellular damage. Quetiapine was tapered off immediately; however, her ALT and
The Association between Dose of Quetiapine and Serum Alanine Aminotransferase (ALT) Level
Psychosomatics 53:6, November-December 2012
www.psychosomaticsjournal.org
601
Letters to the Editor AST kept rising. The antipsychotic was hence shifted to ziprasidone 120 mg/d, then amisulpiride 200 mg/d. Liver profiles of Mrs. W returned to normal within 2 weeks after discontinuing quetiapine. The case of Mrs. W clearly demonstrated quetiapine-induced hepatocellular damage. Her AST, ALT, GGT, and ALP elevated only when quetiapine was prescribed, and they subsided after tapering of quetiapine (Figure 1). Re-challenge of this agent showed a similar pattern to the first exposure. Mrs. W never experienced abnormal liver function without taking quetiapine. Although a tiny hepatic hemangioma was found, its stationary nature could not explain the fluctuation of hepatic enzymes. The concurrent medications are shown in Figure 1. Mrs. W took acetaminophen 1500 mg/d from day 134 to day 136 for the upper respiratory tract infection, but its use was not associated with a trend of hepatic profiles. Although hepatotoxicity associated with venlafaxine has been reported, its dose was not titrated during the second admission. The Naranjo probability scale of the Mrs. W was 11 points, which indicated that quetiapine was very likely to cause her liver function impairment.5 To our knowledge, there were only four cases of quetiapine-induced liver injury in the literature.1– 4 Their dose range of quetiapine was 25–300 mg/d, and the onset of hepatic damage was 3–30 days. The outcome of hepatotoxicity in the two elderly cases was fatal. The maximal ALT level was between 177 and 2582 U/L. Remarkably, the four cases all revealed elevated bilirubin level, implying a cholestatic pattern. It was different from the presentation of Mrs. W. Among these cases, no similar demographic data were revealed. We consider that the quetiapine-induced hepatotoxicity was idiosyncratic. 602
www.psychosomaticsjournal.org
In summary, quetiapine-induced hepatotoxicity is rare but can be fatal without an appropriate treatment. With early intervention, the liver function may return to baseline within 1 month without any sequelae, as with the presentation of Mrs. W. In subjects showing elevated liver profiles and using quetiapine concurrently, quetiapine is a potential etiology. The association between dosage and hepatic function should be assessed carefully. Chein-Heng Lin, M.D. Department of Psychiatry National Taiwan University Hospital Taipei, Taiwan Chih-Min Liu, M.D. Department of Psychiatry National Taiwan University Hospital Taipei, Taiwan Wei-Lieh Huang, M.D. Department of Psychiatry National Taiwan University Hospital Taipei, Taiwan Department of Psychiatry National Taiwan University Hospital Yun-Lin Branch, Douliu City Yunlin County, Taiwan
References
1. Wright TM, Vandenberg AM: Risperidone- and quetiapine-induced cholestasis. Ann Pharmacother 2007; 41:1518 –1523 2. El Hajj I, Sharara AI, Rockey DC: Subfulminant liver failure associated with quetiapine. Eur J Gastroenterol Hepatol 2004; 16:1415–1418 3. Naharci MI, Karadurmus N, Demir O, Bozoglu E, Ak M, Doruk H: Fatal hepatotoxicity in an elderly patient receiving lowdose quetiapine. Am J Psychiatry 2011; 168:212–213 4. Shpaner A, Li W, Ankoma-Sey V, Botero RC: Drug-induced liver injury: hepatotoxicity of quetiapine revisited. Eur J Gastroenterol Hepatol 2008; 20:1106 –1109 5. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al: A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981; 30:239 –245
Self-Injurious and Aggressive Behavior Associated with a Tacrolimus Overdose TO THE EDITOR: Patients treated with tacrolimus (FK506) are frequently subject to neuropsychiatric complications, which commonly include insomnia, anxiety, and mood disorders. This report describes a case of self-injurious aggressive behavior induced by accidental acute overdose of tacrolimus (TCL) during treatment to prevent allograft rejection after liver transplantation, which has never been reported. TCL has been shown to inhibit the expression of interleukin-2 in T cells, which results in the inhibition of T-cell growth and proliferation, which may explain the adverse event described below. Mr. A, a 55-year-old 60 kg Caucasian, with liver cirrhosis and no previous psychiatric history, was admitted to our hospital for liver transplantation (LTX). The primary immunosuppressive therapy after LTX consisted of TCL (4 mg/d), mycophenolic acid (440 mg/d), and steroid prednisone (15 mg/d). Two months after LTX, 12 mg/d of TCL was inadvertently administered for 3 consecutive days in error. The rest of the medications taken at the time of the tacrolimus overdose were the same (also in dosages) as the primary therapy. Within 1 week, the Mr. A displayed altered mental status, confusion, agitation, irritability, aggressiveness, impulsivity (sudden engagement in inappropriate behaviors). During the same day he threatened a health worker at knife-point with the firm intention to kill, and after 8 hours, committed nonsuicidal self-mutilating violent behavior, sticking his thigh with a hunting knife. Mr. A did not manifest other symptoms or signs of TCL overdose. His psychiatric symptoms completely resolved after reducing the TCL dosage and after the
Psychosomatics 53:6, November-December 2012
© 2012 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.
Letters to the Editor
Quetiapine-Induced Hepatocellular Damage TO THE EDITOR: Hepatotoxicity is a possible adverse reaction of antipsychotics. The elevation of liver enzymes is usually reversible, but fatal hepatitis also exists. Among the second generation antipsychotics, hepatic adverse reactions related with clozapine, risperidone, and olanzapine have been found.1 Quetiapine-induced hepatotoxicity is relatively rare.1– 4 Here we report a middle-aged woman, who showed hepatocellular damage associated with quetiapine treatment, and the liver profiles returned to normal range soon after switching to other antipsychotics. Mrs. W, a 47-year-old woman with schizophrenia, was admitted because of
FIGURE 1.
auditory hallucinations. At the beginning of her admission, Mrs. W showed normal liver function profiles. After quetiapine 400 mg/d treatment for 1 week, her psychotic symptoms improved. However, bilateral leg edema and elevated liver enzymes, with alanine aminotransferase (ALT) 113 U/L, ␥-glutamyl transpeptidase (GGT) 219 U/L, and alkaline phosphatase (ALP) 547 U/L, developed. Her total bilirubin level was 0.39 mg/dL, and cholestatic hepatitis was less likely. Abdominal computed tomography revealed a 1.2 cm hepatic hemangioma, but it could not explain the elevated liver enzymes. Her autoimmune profiles were within normal limits, and there was no hepatitis B or hepatitis C infection. Therefore, quetiapine-induced hepatocellular damage was suspected. Ten days after tapering of quetiapine to 300
mg/d, the abnormal liver function and leg edema subsided. With improved psychotic symptoms, she was discharged. However, Mrs. W discontinued all of her medications. Risperidone 1 mg/d was taken with irregular compliance. She was hospitalized again 3 months later. The liver profiles were within normal limits at the beginning of her second admission. Due to a previous good response, quetiapine 300 mg/d was given, and gradually increased to 400 mg/d. With this dosage for 10 days, elevated liver function reappeared with ALT 120 U/L, aspartate aminotransferase (AST) 147 U/L, GGT 79 U/L, and ALP 181 U/L. Her total bilirubin was 0.19 mg/dL, and direct bilirubin was 0.02 mg/dL. The pattern was compatible with hepatocellular damage. Quetiapine was tapered off immediately; however, her ALT and
The Association between Dose of Quetiapine and Serum Alanine Aminotransferase (ALT) Level
Psychosomatics 53:6, November-December 2012
www.psychosomaticsjournal.org
601
Letters to the Editor AST kept rising. The antipsychotic was hence shifted to ziprasidone 120 mg/d, then amisulpiride 200 mg/d. Liver profiles of Mrs. W returned to normal within 2 weeks after discontinuing quetiapine. The case of Mrs. W clearly demonstrated quetiapine-induced hepatocellular damage. Her AST, ALT, GGT, and ALP elevated only when quetiapine was prescribed, and they subsided after tapering of quetiapine (Figure 1). Re-challenge of this agent showed a similar pattern to the first exposure. Mrs. W never experienced abnormal liver function without taking quetiapine. Although a tiny hepatic hemangioma was found, its stationary nature could not explain the fluctuation of hepatic enzymes. The concurrent medications are shown in Figure 1. Mrs. W took acetaminophen 1500 mg/d from day 134 to day 136 for the upper respiratory tract infection, but its use was not associated with a trend of hepatic profiles. Although hepatotoxicity associated with venlafaxine has been reported, its dose was not titrated during the second admission. The Naranjo probability scale of the Mrs. W was 11 points, which indicated that quetiapine was very likely to cause her liver function impairment.5 To our knowledge, there were only four cases of quetiapine-induced liver injury in the literature.1– 4 Their dose range of quetiapine was 25–300 mg/d, and the onset of hepatic damage was 3–30 days. The outcome of hepatotoxicity in the two elderly cases was fatal. The maximal ALT level was between 177 and 2582 U/L. Remarkably, the four cases all revealed elevated bilirubin level, implying a cholestatic pattern. It was different from the presentation of Mrs. W. Among these cases, no similar demographic data were revealed. We consider that the quetiapine-induced hepatotoxicity was idiosyncratic. 602
www.psychosomaticsjournal.org
In summary, quetiapine-induced hepatotoxicity is rare but can be fatal without an appropriate treatment. With early intervention, the liver function may return to baseline within 1 month without any sequelae, as with the presentation of Mrs. W. In subjects showing elevated liver profiles and using quetiapine concurrently, quetiapine is a potential etiology. The association between dosage and hepatic function should be assessed carefully. Chein-Heng Lin, M.D. Department of Psychiatry National Taiwan University Hospital Taipei, Taiwan Chih-Min Liu, M.D. Department of Psychiatry National Taiwan University Hospital Taipei, Taiwan Wei-Lieh Huang, M.D. Department of Psychiatry National Taiwan University Hospital Taipei, Taiwan Department of Psychiatry National Taiwan University Hospital Yun-Lin Branch, Douliu City Yunlin County, Taiwan
References
1. Wright TM, Vandenberg AM: Risperidone- and quetiapine-induced cholestasis. Ann Pharmacother 2007; 41:1518 –1523 2. El Hajj I, Sharara AI, Rockey DC: Subfulminant liver failure associated with quetiapine. Eur J Gastroenterol Hepatol 2004; 16:1415–1418 3. Naharci MI, Karadurmus N, Demir O, Bozoglu E, Ak M, Doruk H: Fatal hepatotoxicity in an elderly patient receiving lowdose quetiapine. Am J Psychiatry 2011; 168:212–213 4. Shpaner A, Li W, Ankoma-Sey V, Botero RC: Drug-induced liver injury: hepatotoxicity of quetiapine revisited. Eur J Gastroenterol Hepatol 2008; 20:1106 –1109 5. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al: A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981; 30:239 –245
Self-Injurious and Aggressive Behavior Associated with a Tacrolimus Overdose TO THE EDITOR: Patients treated with tacrolimus (FK506) are frequently subject to neuropsychiatric complications, which commonly include insomnia, anxiety, and mood disorders. This report describes a case of self-injurious aggressive behavior induced by accidental acute overdose of tacrolimus (TCL) during treatment to prevent allograft rejection after liver transplantation, which has never been reported. TCL has been shown to inhibit the expression of interleukin-2 in T cells, which results in the inhibition of T-cell growth and proliferation, which may explain the adverse event described below. Mr. A, a 55-year-old 60 kg Caucasian, with liver cirrhosis and no previous psychiatric history, was admitted to our hospital for liver transplantation (LTX). The primary immunosuppressive therapy after LTX consisted of TCL (4 mg/d), mycophenolic acid (440 mg/d), and steroid prednisone (15 mg/d). Two months after LTX, 12 mg/d of TCL was inadvertently administered for 3 consecutive days in error. The rest of the medications taken at the time of the tacrolimus overdose were the same (also in dosages) as the primary therapy. Within 1 week, the Mr. A displayed altered mental status, confusion, agitation, irritability, aggressiveness, impulsivity (sudden engagement in inappropriate behaviors). During the same day he threatened a health worker at knife-point with the firm intention to kill, and after 8 hours, committed nonsuicidal self-mutilating violent behavior, sticking his thigh with a hunting knife. Mr. A did not manifest other symptoms or signs of TCL overdose. His psychiatric symptoms completely resolved after reducing the TCL dosage and after the
Psychosomatics 53:6, November-December 2012