ANIMAL MODELS OF ALCOHOLIC LIVER INJURY

Alcoholic liver disease (ALD) is a multifactorial disease in humans but not in animals. Even though the disease constitutes a major cause of alcohol-related morbidity and mortality with substantive costs to our society, it is manifested in clinically evident forms in a small fraction of a population who consumes alcohol on a regular basis. The disease is exhibited as three pathologic stages—fatty liver, alcoholic hepatitis, and cirrhosis, but its evolution through these stages is rather heterogeneous in different ethnic, cultural, or environmental backgrounds. These features make it extremely difficult to reproduce ALD in experimental animals. We continue our pursuit for development of an ideal animal model, however, because it serves as a most effective and direct tool to help study the pathogenesis of the disease. Numerous models have been developed in the past, but none has reproduced all histologic and clinical spectra of ALD. Nevertheless, some has been shown to be reproducible and instrumental for gaining new experimental insights into the mechanisms by which ethanol causes liver injury. The variation in the modeling technique naturally reflects the primary focus and bias of each investigator in his or her pursuit for testing the pathogenetic factors. If nutritional factors are of primary interest, for example, manipulation of dietary factors becomes a primary experimental input. If ethanol is considered as a direct hepatotoxin, one uses a model in which ethanol intake is maximized. Historically speaking, the issue of nutrition versus ethanol has incited vigorous research on the topic, but at the same time, polarized the field. Recent studies have confirmed that nutrition and ethanol are important equally in alcoholic liver injury, as discussed in more detail subsequently. A comprehensive review of animal models for alcoholic liver injury recently appeared elsewhere. 11 This article focuses on several models described in recent years that appear to possess significant investigational potential for studies on the pathogenesis of ALD. The investigational potential is determined by assessing how adequately a model meets four main criteria required to serve as a model for alcoholic liver injury. 1Sufficient ethanol intake 2Reproduction of several histologic features of ALD 3Adequate control over intake of nutrients and ethanol 4Ability to test genetic and environmental factors First, a model has to achieve sufficient ethanol intake to produce the heavy and sustained drinking pattern in patients with ALD. 6,26 Second, this ethanol intake, under certain conditions, has to produce progressive alcoholic liver injury that mimics at least several histologic features of ALD. Third, a model should have maximal and independent controllability over intake of nutrients and ethanol to effectively assess their relative roles in the pathogenesis of alcoholic liver injury. Finally, a model should have adaptability and flexibility to allow testing various genetic and environmental factors that may prove to have profound effects on expression of alcoholic liver injury. Based on these criteria, several models were selected for this review. The method of ethanol administration and characteristics of alcoholic liver injury produced in the models are summarized in Table 1.