Drug-Induced Steatosis and Steatohepatitis: The Search for Novel Serum Biomarkers Among Potential Biomarkers for Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis
Drug-induced steatosis (DIS) and drug-induced steatohepatitis (DISH) are two of several types of drug-induced liver injury (DILI). They can be caused by various drugs and may present as acute, potentially lethal disorders or as chronic slowly progressive liver injury. Despite the fact that they are distinct disorders, the slow progressive forms of DIS and DISH are often confused with or misdiagnosed as non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH), which are much more common and, by definition, not caused by drugs. Currently the only way to identify DIS is via imaging studies or a liver biopsy, while DISH can be identified only through liver biopsy. In addition, diagnosis of either DIS or DISH requires an exhaustive clinical evaluation and comprehensive causality assessment to rule out other possible causes and determine the association with the suspected drug. Furthermore, it is difficult, using existing methods, to monitor the progression of DIS and DISH and to determine the underlying mechanism. Therefore, there is a great unmet need for non-invasive biomarkers that will be able to identify the development of DIS or DISH during drug development and to monitor for progression or regression of the disorder during treatment or following drug discontinuation. Recent developments in the fields of NAFLD and NASH have introduced several novel biomarkers that show promise for the diagnosis, monitoring, and severity assessment of these common diseases. Given the significant overlap in possible underlying mechanisms and histological pattern between NAFLD/NASH and DIS/DISH, these postulated NAFLD and NASH biomarkers may have a potential application to DIS and DISH. This article reviews the existing medical literature and other publically available information pertaining to novel serum biomarkers for NAFLD and NASH, and explores the concurrent identification of these biomarkers for DIS and DISH.
The authors thank Natasha Cole for her help in the preparation of this review paper.
Compliance with Ethical Standards
Conflict of interest
Dr. Lauren Pavlik has no conflicts of interest related to this paper. Dr. Naga Chalasani serves as a consultant to several pharmaceutical companies for activities related to NAFLD and DILI, but has no conflicts of interest that are directly relevant to the content of this paper. Dr. Arie Regev and Dr. Paul Ardayfio are full-time employees of Eli Lilly, but have no conflicts of interest that are directly relevant to the content of this paper.
No sources of funding were used to assist in the preparation of this study.
- 2.Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology. 2012;142(7):1592–609.CrossRefGoogle Scholar
- 8.National Institute of Health. LiverTox: phenotypes of drug induced liver injury; 2016. https://www.livertox.nih.gov/Phenotypes_intro.html. Accessed 25 Oct 2018.
- 12.Madrazo BL. Diagnosis of nonalcoholic steatohepatitis without liver biopsy. Gastroenterol Hepatol. 2017;13(6):378–80.Google Scholar
- 13.Park CC, Nguyen P, Hernandez C, Bettencourt R, Ramirez K, Fortney L, et al. Magnetic resonance elastography vs transient elastography in detection of fibrosis and noninvasive measurement of steatosis in patients with biopsy-proven nonalcoholic fatty liver disease. Gastroenterology. 2017;152(3):598–607.e2.CrossRefGoogle Scholar
- 22.Vuppalanchi R, Jain AK, Deppe R, Yates K, Comerford M, Masuoka HC, et al. Relationship between changes in serum levels of keratin 18 and changes in liver histology in children and adults with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2014;12(12):2121–30.e1-2.Google Scholar
- 25.Miyazaki, Miwa S, Kodama H, Yamada H, Nagata K, Toriumi W, et al. Hepatic and intestinal changes in rats treated with T-0126, a microsomal triglyceride transfer protein (mtp) inhibitor. J Toxicol Sci. 2007;32(2):161–77.Google Scholar
- 26.Stein EA, Dufour R, Gagne C, Gaudet D, East C, Donovan JM, et al. Apolipoprotein B synthesis inhibition with mipomersen in heterozygous familial hypercholesterolemia: results of a randomized, double-blind, placebo-controlled trial to assess efficacy and safety as add-on therapy in patients with coronary artery disease. Circulation. 2012;126(19):2283–92.CrossRefGoogle Scholar
- 29.Murata Y, Ogawa Y, Saibara T, Nishioka A, Fujiwara Y, Fukumoto M, et al. Unrecognized hepatic steatosis and non-alcoholic steatohepatitis in adjuvant tamoxifen for breast cancer patients. Oncol Rep. 2000;7(6):1299–304.Google Scholar
- 32.He L, Deng L, Zhang Q, Guo J, Zhou J, Song W, et al. Diagnostic value of CK-18, FGF-21, and related biomarker panel in nonalcoholic fatty liver disease: a systematic review and meta-analysis. Biomed Res Int. 2017;2017:9729107.Google Scholar
- 34.Church RJ, Kullak-Ublick GA, Aubrecht J, Bonkovsky HL, Chalasani N, Fontana RJ, et al. Candidate biomarkers for the diagnosis and prognosis of drug-induced liver injury: an international collaborative effort. Hepatology. https://doi.org/10.1002/hep.29802 (Epub 2018 Jan 22).
- 35.Clarke JI, Dear JW, Antoine DJ. Recent advances in biomarkers and therapeutic interventions for hepatic drug safety—false dawn or new horizon? Expert Opin Drug Saf. 2016;15(5):625–34.Google Scholar
- 37.FDA, CDER. Application number 203858Orig1s000. Other reviews. Mipomersen and lomitapide consultation; 2012. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203858Orig1s000OtherR.pdf. Accessed 25 Oct 2018.
- 38.Amryt Pharmaceuticals DAC. Lojuxta: EPAR- product information; 2018. https://www.ema.europa.eu/documents/product-information/lojuxta-epar-product-information_en.pdf. Accessed 25 Oct 2018.