Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Birkl-Toeglhofer, A.
Drug-Induced Liver Injury in Psychiatric Disorders.
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2020. pp. 126
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Fickert Peter
- Haybäck Johannes
- Reininghaus Eva
- Altmetrics:
- Abstract:
- Acute and long-term psychotropic drug treatment is often necessary to improve symptoms and prevent relapses in severe mental disorders, such as bipolar disorder. Beside the beneficial effects of the pharmacological treatment, several adverse effects are known like the induction of metabolic disturbances. As the liver is the main site for metabolism of nutrients and pharmacological agents, an affected hepatic function by improper drug detoxification can be assumed. Although non-alcoholic fatty liver disease (NAFLD), ranging from simple steatosis to non-alcoholic steatohepatitis, is common in the Western population, patients with severe mental disorders have an increased risk for the development of NAFLD. To which extent psychotropic drug influence the underlying molecular mechanism leading to hepatic injury remains unknown. Therefore, to reveal the central physiology behind the emerging biological disturbances due to psychotropic drug treatment, the application of ‘-omics’ technologies and the integration of advanced bioinformatical analyses in combination with basic histopathology is crucial. The assessment of possible interferences of psychotropic drugs on the molecular level of hepatic function are needed to subsequently improve the safety and therapeutic effect of pharmacological treatment in bipolar disorder. This exploratory study addressed the global gene expression in hepatic post mortem tissue of patients with bipolar disorder and psychotropic drug treatment compared to control samples with similar hepatic histopathology. Differentially expressed genes were predominantly downregulated assuming that psychotropic drugs rather reduce gene expression than shifting to an increased state of gene expression. To allocate the differentially expressed genes to their biological function, comprehensive bioinformatical analyses were conducted including pathway and enrichment analyses. Particularly, a decreased expression was observed in the biological pathway of the respiratory energy transport chain. The anticipated resulting diminished cellular energy supply is probably associated with a senescent phenotype which might be also evident in hepatic histopathology. Moreover, gene expression was reduced for genes involved in the metabolism of lipids, amino acids and xenobiotics, where a consequent increase in oxidative stress might entail serious cell damage. Furthermore, protein-protein interactions of the encoding respective differentially expressed genes were assessed in silico to provide insights in terms of their function in an intricate network of proteins. For the examination of gene expression patterns defining or triggering a harmed histopathological phenotype due to psychotropic drugs, gene expression data and histopathological features were integrated. Particularly, histopathological degenerative changes in the liver were associated with the enriched pathways indicating adverse effects on molecular level for psychotropic drugs. In summary, this study highlights an altered hepatic gene expression in patients with bipolar disorder and psychotropic drug treatment. The presence of a diminished cellular energy supply and an increased cellular stress level are defining the molecular pattern in the liver evoked by psychotropic drugs. All of which indicates a differential underlying mechanism initiating or triggering hepatic injury in bipolar disorder with psychotropic drug treatment.