Centrilobular Liver Necrosis Induced by Hypoxia in Chronic Ethanol-Fed Rats

Abstract

Rats fed ethanol from 21 to 130 days were subjected to one or more episodes of hypoxia (6% O2) in order to determine if ethanol predisposed to centrilobular liver necrosis induced by hypoxia. Pair-fed control rats were fed the diet regimen in parallel with the ethanol-fed rats through an indwelling gastric cannula. The diet and ethanol were fed continuously 24 hr per day so as to maintain high blood alcohol levels in the ethanol-fed rats. Serum enzyme levels, SGOT and SGPT were measured before and after the hypoxic episodes as an indicator of centrilobular necrosis. Animal livers were studied for centrilobular necrosis by light and electron microscopy. Necrosis was documented to be present when flocculent densities were found in hepatocytic mitochondria or the plasma membrane permitted lanthanum entrance into the cell. The results showed that ethanol feeding to maintain high blood alcohol levels did increase the propensity of the liver to undergo centrilobular necrosis when the rats were subjected to hypoxia (1 hr 45 min to 5 hr 30 min). Centrilobular necrosis was observed in the ethanol-fed rats only. Serum enzyme levels (SGPT and SGOT) rose to very high levels in these rats when they were permitted to die of hypoxia. Serum sediment from the ethanol-fed rats contained numerous cell fragments and free organelles. Since the plasma membranes were missing along the sinusoidal face of centrilobular hepatocytes and microbodies were present, it was concluded that the cell fragments in the blood had originated from necrotic hepatocytes.

Dynamic Adaptation of Liver Mitochondria to Chronic Alcohol Feeding in Mice

“…Our findings also help to explain why hypoxia may occur in the liver with alcohol feeding (49,50). Increased mitochondrial respiration and increases in the number of mitochondria consuming oxygen for alcohol metabolism may underlie hypoxia in the liver with alcohol feeding.…”

Mechanisms of alcohol-induced hepatotoxicity studies in rats

“…In the TsukamotoFrench model, the rate of ethanol elimination, which is oxygen dependent, was elevated 2-to 3-fold in rats exposed to ethanol for 2 to 4 weeks; however, when Kupffer cells were destroyed by GdCl 3 , this phenomenon was blocked. Indeed, centrilobular pathological changes are compatible with a mechanism involving hypoxia, and injury was increased when O 2 tension in the liver was decreased (17). Importantly, conditioned media from isolated Kupffer cells from ethanol-treated rats stimulated parenchymal cell oxygen consumption.…”

Roles of endothelin-1 and nitric oxide in the mechanism for ethanol-induced vasoconstriction in rat liver.

“…In the liver, infusion ofethanol into the portal vein elicits vasoconstriction in the hepatic microvasculature, leading to hepatic tissue hypoxia and eventually hepatocellular necrosis (5,6). French et al reported that ethanol-induced perturbation of microcirculation plays an important role in the pathogenesis of alcoholic liver damage (7)(8)(9)(10). Accordingly, a method to inhibit this vasoconstrictive effect of ethanol would be expected to effectively reduce the incidence Preliminary reports of portions ofthis work were presented at the 42nd Annual Meeting of the American Association for the Study of Liver Disease, Chicago, IL, 2-5 November 1991. and morbidity of alcoholic liver damage.…”