Drug-induced steatohepatitis

Abstract

Drug induced steatohepatitis (DISH), a form of drug induced liver injury (DILI) is characterized by intracellular accumulation of lipids in hepatocytes and subsequent inflammatory events, in some ways similar to the pathology seen with other metabolic, viral and genetic causes of non alcoholic fatty liver disease and steatohepatitis (NAFLD and NASH). Areas covered: This paper provides a comprehensive review of the main underlying mechanisms by which various drugs cause DISH, and outlines existing preclinical tools to predict it and study underlying pathways involved. The translational hurdles of these models are discussed, with the example of an organotypic liver system designed to address them. Finally, we describe the clinical assessment and management of DISH. Expert Opinion: The complexity of the interconnected mechanistic pathways underlying DISH makes it important that preclinical evaluation of drugs is done in a physiologically and metabolically relevant context. Advanced organotypic tissue models, coupled with translational functional biomarkers and next-generational pan-omic measurements, may offer the best shot at gathering mechanistic knowledge and potential of a drug causing steatohepatitis. Ultimately this information could also help predict, detect or guide the development of specific treatments for DISH, which is an unmet need as of today.

Keywords: DILI; Drug-induced steatohepatitis; NASH; liver; organotypic.

Conflict of interest statement

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Figures

Figure 1

Drug Induced Steatohepatitis (DISH) is a form of drug induced liver injury (DILI) that shares pathological features characterized by lipid accumulation and inflammatory changes, similar to non alcoholic steatohepatitis arising due to other causes.

Figure 2

Mechanisms involved in Drug Induced Steatohepatitis (DISH). Accumulation of lipids and triglycerides within hepatocytes is driven by one or more of four different mechanisms: 1. Increased fatty acid synthesis. 2. Decreased fatty acid β-oxidation: 3. Decreased lipoprotein export and 4. Increased mobilization and uptake of fatty acids. Subsequent mitochondrial dysfunction, peroxisomal fatty acid oxidation and induction of CYP2E1 are responsible for increased lipid peroxidation and oxidative stress. The consequent induction of inflammatory cytokines like TGF-β, TNF-α and IL-8 results with inflammatory cell recruitment and stellate cell activation with extracellular matrix production.

Figure 3

Assessment of Steatohepatitis in an Organotypic Model. (A) The previously described model uses liver-derived blood flow parameters to restore transmural perfusion, circulatory hemodynamics and transport gradients in the system. Primary hepatocytes from 5 donors were exposed to amiodarone (AMI) or obeticholic acid (OCA) in the system for 48 hours prior to performing transcriptomics and measuring lipid accumulation by Nile Red staining. (B) Heatmap of fatty acid beta oxidation genes reveals down-regulation by AMI while OCA selectively up-regulates multiple genes. (C) Both drugs down-regulated the lipid/cholesterol transporters of the ABCA family but OCA strongly up-regulated ABCG5 and ABCG8 (D) Fatty acid and triglyceride synthesis pathway genes were upregulated by AMI but mostly down-regulated by OCA. (E -G) These steatogenic potential of amiodarone was also reflected in the marked accumulation of lipid droplets evidenced by Nile red staining in the amiodarone treated hepatocytes (F) relative to the DMSO (E) and obeticholic acid (G) treated conditions.