Management of Hepatotoxicity Induced by the Use of Olanzapine

To the Editor:

Olanzapine is an atypical antipsychotic that is widely used in the treatment of psychotic disorders (Ciudad et al. 2005). Olanzapine, which is primarily metabolized in the liver, is converted into inactive metabolites by the p450 enzyme system (Todorović et al. 2016). The occurrence of hepatotoxicity induced by the use of olanzapine is expressed by the researchers (Pae et al. 2005). Definition of hepatotoxicity is based on biological parameters “elevation of alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma glutamyl transferase (GGT)” or clinical abnormalities (Lewis 2000). In such cases, generally the dose of olanzapine is reduced or the drug is completely discontinued and the treatment of the patient fails. The aim of this study is to report the case for whom elevated liver enzymes were observed, but the process was managed without changing treatment dose and drug and to discuss this case with literature information. This study has characteristics of being the first in the literature concerning management of the process.

A 15-year-old male patient was brought by his family upon his complaints as strange speeches, hearing unavailable voices, and seeing unavailable images. In the history received from the family, it was learnt that the patient was talking to himself for almost 1 month, he said he has been living since ancient ages, and he claimed presence of divine powers. In the family of the patient, who had no history of alcohol, substance abuse, and chronic drug use and no diagnosed chronic disease, there was no chronic liver disease or psychiatric disease history. During psychiatric examination, it was observed that the self-care of the patient decreased, he had suspicious looks, he was speaking in a disorganized manner, he had grandiose and nihilistic delusions, he had visual and audible hallucinations, his affects were blunted, and his associations decelerated. Within the scope of The Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-5) diagnostic criteria, the patient diagnosed with schizophreniform disorder was hospitalized in our clinic and his treatment was planned. Initial laboratory examinations of the patient were within normal limits, and during his hospitalization period, laboratory examinations were regularly repeated. As the pharmacological treatment, risperidone was used in the patient at the first stage and extrapyramidal system's side effects were observed. Antipsychotic treatment of the patient who could not benefit from risperidone treatment and whose extrapyramidal system findings could not regress despite the use of biperiden was replaced with olanzapine. The drug dose used by the patient, who substantially benefited from the use of olanzapine, was gradually increased to 20 mg/day in 2 weeks. In the liver function tests of the patient, whose laboratory examinations were within normal limits before the use of olanzapine, an increase was observed in the second week of olanzapine usage; AST: 49 U/L (normal range: 5–34 U/L), ALT: 84 U/L (normal range: 0–55 U/L), GGT: 34 IU/L (normal range: 7–21 U/L), lactate dehydrogenase (LDH): 267 U/L (normal range: 125–243 U/L).

Laboratory tests, which were performed with regular intervals, ensured to determine elevated liver enzymes without reaching to serious levels and causing clinical findings in the patient. Total and direct bilirubin, amylase, lipase, vitamin D, thyroid function tests, blood lipid levels, and bleeding time examinations performed in line with suggestions in the patient who was consulted at pediatric gastroenterology clinic of our hospital were found within normal range; antinuclear antibody, liver–kidney microsomal antibody, antimitochondrial antibody, smooth muscle antibody, perinuclear antineutrophil cytoplasmic antibody, and viral serology examinations were found as negative. Abdominal ultrasonography performed was assessed as normal. Thus, the increase in the liver function tests of the patient, who had no medical problem explaining hepatotoxicity, was considered to be related to the use of olanzapine. No drug and dose change was done in the patient, who substantially benefited from the use of olanzapine, and in accordance with the suggestion of our pediatric gastroenterology clinic, ursodeoxycholic acid 2 × 250 mg/day and d-alpha-tocopherol (vitamin E) 1 × 400 IU/day were added to the treatment. In the examinations of the patient, whose liver function tests were closely followed up, which were done after 1 week, AST, 23 U/L; ALT, 28 U/L; GGT, 20 U/L; and LDH, 228 U/L were found to be within normal limits. The patient, whose psychiatric complaints considerably reduced, continued the use of olanzapine 20 mg/day and he was discharged. In the control examinations in the second and fourth weeks, follow-up and treatment of the patient with no elevated liver enzyme were continued. During the maintenance of olanzapine treatment, no side effect was observed in the patient except for mild extrapyramidal system findings. Also, no side effect related to the administration of ursodeoxycholic acid and d-alpha-tocopherol was determined.

Numerous drugs cause hepatotoxicity clinically or biologically. Neuropsychiatric drugs constitute 16% of these drugs (Biour et al. 1996). Atypical antipsychotics such as clozapine, olanzapine, amisulpride, risperidone, and quetiapine may cause dose-independent and asymptomatic hepatotoxicity and sometimes this situation can be serious and sustained (Gaertner et al. 2001; Mouradian-Stamatiadis et al. 2002). Elevated liver enzymes that occurred 2–8 weeks after the medication and could not be explained by another etiologic reason was assessed as drug-induced hepatotoxicity (Gaertner et al. 2001). In our case, the liver enzyme levels, which were within normal limits just before the use of olanzapine, elevated 2 weeks after the use of olanzapine in accordance with the identification, and no etiologic reason except for the use of olanzapine was determined for this elevation. In the literature, immunoallergic hepatitis, acute hepatocellular–cholestatic liver injury, and hepatocellular hepatitis associated with the use of olanzapine are reported (Raz et al. 2001; Jadallah et al. 2003; Tchernichovsky and Sirota 2004).

In a study conducted on rats, it was reported that hepatotoxicity induced by olanzapine was caused by the formation of free oxygen radicals and associated oxidative stress and mitochondrial damage. In the same study, it was stated that free oxygen radicals scavengers, antioxidants, endocytosis inhibitors, and adenosine triphosphate generators can prevent hepatotoxicity induced by the use of olanzapine (Eftekhari et al. 2016). The d-alpha-tocopherol (vitamin E) used in our case is accepted as an antioxidant (Traber and Atkinson 2007). In addition, it is known that ursodeoxycholic acid we used prevents apoptosis by modulating mitochondrial membrane perturbation, protects hepatocytes against oxidative injury by providing the induction of antioxidants, and has an antioxidant property (Rodrigues et al. 1998; Lapenna et al. 2002). In the patients treated by atypical antipsychotics, the rate of asymptomatic liver enzyme elevation is ∼50% (Atasoy et al. 2007) and this situation concerns the clinicians and mostly causes to change the benefited drugs or not to use the drug at efficient doses. In the light of the case and literature data that we have shared, we are in the opinion that hepatotoxicity induced by the use of olanzapine can be prevented by the use of ursodeoxycholic acid and d-alpha-tocopherol (vitamin E) in early period (the liver enzyme levels without reaching to severe levels), it is not required to change the antipsychotic treatment applied or to reduce the dosage, and further studies regarding this matter are required.