Chronic-Binge Model of Alcoholic Hepatitis in Long Evans Rats

Author(s): Teresa Ramirez, Ming Tong, and Suzanne M de la Monte


Background. Alcoholic hepatitis (AH) is largely a histopathologic diagnosis that is based upon the presence of significant inflammation, hepatocellular lipid accumulation, ballooned degeneration of hepatocytes, and Mallory-Denk bodies. Underlying biochemical and molecular abnormalities include increased oxidative and endoplasmic reticulum (ER) stress, mitochondrial dysfunction, insulin resistance, lipid dyshomeostasis, and cell death. Acute AH is often precipitated by binge drinking in the setting of chronic alcohol abuse, and is problematic due to its propensity to progress to chronic alcoholic liver disease with end-points of cirrhosis or liver failure. Improved understanding of AH pathogenesis could aid in the development of new treatments and preventive measures. Study Design. To mimic conditions leading to AH in humans, we generated a chronic-binge model of ethanol exposure in which Long Evans rats were fed with isocaloric liquid diets containing 0% or 37% ethanol (caloric content) for 5 weeks, and during the last 2 weeks, the ethanol diet fed rats were binged with 2 g/kg ethanol 3 times per week. Livers were used for histologic and electron microscopic studies. Results. Ethanol-exposed livers had severe panlobular steatohepatitis with disorganization of the chord-like architecture, foci of necrosis, apoptotic bodies, ballooned degeneration of hepatocytes, giant mitochondria, disrupted ER structure and relationship to mitochondria, and early fibrosis. These findings correspond well with those seen in human AH, except for the absence of Mallory-Denk bodies. Conclusion. The overall findings suggest that chronic-binge models of alcohol feeding produce pathologic lesions that correspond with AH in humans. This approach provides better tools for designing treatment and unraveling mechanisms by which AH progresses to chronic stages of liver disease.

image 10.4303/jdar/235837

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