Animal models of NAFLD from the pathologist's point of view

Fatty liver disease is a multifactorial world-wide health problem resulting from a complex interplay between liver, adipose tissue and intestine and initiated by alcohol abuse, overeating, various types of intoxication, adverse drug reactions and genetic or acquired metabolic defects. Depending on etiology fatty liver disease is commonly categorized as alcoholic or non-alcoholic. Both types may progress from simple steatosis to the necro-inflammatory lesion of alcoholic (ASH) and non-alcoholic steatohepatitis (NASH), respectively, and finally to cirrhosis and hepatocellular carcinoma. Animal models are helpful to clarify aspects of pathogenesis and progression. Generally, they are classified as nutritional (dietary), toxin-induced and genetic, respectively, or represent a combination of these factors. Numerous reviews are dealing with NASH animal models designed to imitate as closely as possible the metabolic situation associated with human disease. This review focuses on currently used mouse models of NASH with particular emphasis on liver morphology. Despite metabolic similarities most models (except those with chemically or genetically induced porphyria or keratin 18-deficiency) fail to develop the morphologic key features of NASH, namely hepatocyte ballooning and formation of histologically and immunohistochemically well-defined Mallory-Denk-Bodies (MDBs). Although MDBs are not universally detectable in ballooned hepatocytes in NASH their experimental reproduction and analysis may, however, significantly contribute to our understanding of important pathogenic aspects of NASH despite the obvious differences in etiology.