M200. CLOZAPINE-INDUCED HEPATOTOXICITY: TWO CASE REPORTS
Authors: Dias Cintia , Fonseca Lais , Gadelha Ary , Noto Cristiano 
Published: May 2020

Abstract

Background
Liver function tests (LFT) abnormalities secondary to antipsychotics (AP) are common, early, and often mild and transient. Up to 60% of patients on clozapine experience an increase in LFT, at medium-range doses (200–400mg), and usually dose-dependent, with spontaneous resolution in half the cases, no dose reduction needed. Fatal outcomes are extremally rare, with an incidence around 0.001%. The hepatotoxic effects of clozapine have received considerable less attention than its cardiometabolic and hematologic counterparts. Consequently, there are few independents guidelines on how to handle such cases. Our objective is to report 2 cases of mild clozapine-induced liver injury and discuss possible protocols of early detection and management.

Methods
We described 2 cases of clozapine induced hepatitotoxicity in patients with schizophrenia.

Results
CASE 1: 33 y/o, male, caucasian, 5y of illness. Had previously used risperidone and paliperidone, and was currently taking olanzapine, without good response. Clozapine 25mg/d was introduced – in addition to olanzapine 15mg/d – with a 25mg increase every 2d. On D12 of clozapine (150mg/day), he reported nausea, diarrhea and dizziness, worsening the next few days, with confusion and choluria. Blood tests detected increases of ALT (242U/L), serum bilirubin (total 1.59mg/dL; direct 1.29g/dL; indirect 0.3mg/dL) and ESR (60mm/1sth). He was admitted and AP were interrupted. After 48h, presented full clinical recovery. Leukocyte blood count and ESR were still high in the first week, but LFT and bilirubins progressively decreased. All exams normalized in 1m. After 2w, olanzapine was reintroduced, with no LFT changes.

CASE 2
48 y/o, female, caucasian, 15y of illness. Partial response to risperidone and olanzapine. 20d after clozapine was introduced (75mg/d), she reported nausea, vomiting, choluria, abdominal pain and headache. Presented elevated AST (88U/L), ALT (77U/L), CK (732U/L), GGT (141U/L) and ALP (161U/L), decreased Hb (9.6g/dL), mild leukocytosis (10,800/mm3), mild leukocyturia and hematuria, though bilirubin and platelet levels were normal. Clozapine was immediately suspended and olanzapine 10mg/d reintroduced progressively, maintaining partial remission of positive symptoms. Blood counts and LFT were normalized within 1m and no hospitalization was required.

Discussion
Both cases illustrate different presentations of hepatotoxicity by clozapine. Case 1 had no LFT dosage before the introduction and no indicative hepatic risk. With a regular dose evaluation, developed a severe hepatic injury. Case 2 had a history of side effects to previous antipsychotics. She started with normal LFT levels and evolved with mild hepatic injury due to the slow dose increase.
In both cases LFT weren’t requested periodically until clinical symptoms emerged. At this point, it was fundamental to instruct the patient to report any warning clinical signs.
A serialized LFT protocol wouldn’t show benefits to prevent hepatotoxicity in the outcome of our cases. However, some authors recommend monitoring them 4–6m after starting AP, specially the first 4–5w, since it could predict a bad outcome of severe hepatitis. Previous studies point ALT&gt;3ULN or ALP&gt;2ULN or any rise of transaminases with CK or bilirrubin altered as sensitive markers for liver damage. In such cases, the AP should be suspended.
There is no consistent data regarding the indication of clozapine rechallenge after hepatotoxicity. Yet, the early onset of drug injury (1–6w) and the rapid rise in ALT on rechallenge may be a contraindication of a new try or continuous use of the drug.
Considering guidelines on clozapine induced hepatotoxicity are not clear, we suggest the topic to be revisited and better established.