Mechanisms of non-alcoholic steatohepatitis

McClain, Craig J.; Mokshagundam, Sri Prakash L.; Barve, Shirish S.; Song, Zhenyuan; Hill, Daniell B.; Chen, Theresa; Deaciuc, Ion

doi:10.1016/j.alcohol.2004.07.007

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Volume 34, Issue 1 , Pages 67-79, August 2004

Mechanisms of non-alcoholic steatohepatitis

Craig J. McClain
- Department of Internal Medicine, University of Louisville Medical Center, 530 South Jackson Street, ACB 3rd Floor, Louisville, KY 40292, USA
- Corresponding author. Tel.: +1-502-562-3899; fax: +1-502-562-4271.
Sri Prakash L. Mokshagundam
- Department of Internal Medicine, University of Louisville Medical Center, 530 South Jackson Street, ACB 3rd Floor, Louisville, KY 40292, USA
Shirish S. Barve
- Department of Internal Medicine, University of Louisville Medical Center, 530 South Jackson Street, ACB 3rd Floor, Louisville, KY 40292, USA
Zhenyuan Song
- Department of Internal Medicine, University of Louisville Medical Center, 530 South Jackson Street, ACB 3rd Floor, Louisville, KY 40292, USA
Daniell B. Hill
- Department of Internal Medicine, University of Louisville Medical Center, 530 South Jackson Street, ACB 3rd Floor, Louisville, KY 40292, USA
Theresa Chen
- Department of Pharmacology and Toxicology, Room 1319 Research Tower, University of Louisville Health Sciences Center, 500 South Preston Street, Louisville, KY 40202, USA
Ion Deaciuc
- Department of Internal Medicine, University of Louisville Medical Center, 530 South Jackson Street, ACB 3rd Floor, Louisville, KY 40292, USA

Received 30 March 2004; received in revised form 9 July 2004; accepted 13 July 2004.

Editor: T.R. Jerrells

Abstract

In 1980, the term non-alcoholic steatohepatitis was coined to describe a new syndrome occurring in patients who usually were obese (often diabetic) females who had a liver biopsy picture consistent with alcoholic hepatitis, but who denied alcohol use. The causes of this syndrome were unknown, and there was no defined therapy. More than two decades later, this clinical syndrome is only somewhat better understood, and still there is no Food and Drug Administration–approved or even generally accepted drug therapy. Patients with primary non-alcoholic steatohepatitis typically have the insulin resistance syndrome (synonymous with the metabolic syndrome, syndrome X, and so forth), which is characterized by obesity, diabetes, hyperlipidemia, hypertension, and, in some instances, other metabolic abnormalities such as polycystic ovary disease. Secondary non-alcoholic steatohepatitis may be caused by drugs such as tamoxifen, certain industrial toxins, rapid weight loss, and so forth. The cause of non-alcoholic steatohepatitis remains elusive, but most investigators agree that a baseline of steatosis requires a second hit capable of inducing inflammation, fibrosis, or necrosis for non-alcoholic steatohepatitis to develop. Our research group has focused its efforts on the interactions of nutritional abnormalities, cytokines, oxidative stress with lipid peroxidation, and mitochondrial dysfunction in the induction of steatohepatitis, both alcoholic and non-alcoholic in origin. Research findings from other laboratories also support the role of increased cytokine activity, oxidative stress, and mitochondrial dysfunction in the pathogenesis of non-alcoholic steatohepatitis. The objectives of this article are to review the (1) definition and clinical features of non-alcoholic steatohepatitis, (2) potential mechanisms of non-alcoholic steatohepatitis, and (3) potential therapeutic interventions in non-alcoholic steatohepatitis.

Keywords: Non-alcoholic steatohepatitis, Fatty liver, Cytokines, Mitochondria, Oxidative stress