Inhibition of liver regeneration by chronic alcohol administration*
L DUGUAY, D COUTU, C HETU, AND J-G JOLY From the Clinical Research Centre, H6pital Saint-Luc, Department of Surgery and Medicine, Universite de Montreal, Montreal, Canada
Liver regeneration is the common mechanism whereby a patient recovers from a liver injury. In the western world, ethanol is thesingle most important aetiological factor associated with liver disease, and it appears crucial to determine if ethanol interferes with liver regeneration. We studied the response to a 70% hepatectomy in 240 rats receiving a nutritionally adequate diet containing 36% of their calories as ethanol for three weeks and their pair-fed controls receiving a liquid diet where ethanol is isocalorically replacedwith carbohydrates. Criteria of liver regeneration were: incorporation of 3H-thymidine in hepatocyte DNA (cpm/10 jg DNA) and number of hepatocyte labelled nuclei on autoradiography per 100 high power fields. Controls displayed the usual response with peak activity of liver regeneration at 24 hours. Consumption of ethanol was associated with a statistically significant reduction of liverregeneration by both criteria for up to 72 hours after a 70% hepatectomy and delayed the peak of regenerative activity by 24 hours. This inhibiting effect was not related to the presence of alcohol in blood nor to hepatic microsomal enzyme induction by ethanol nor to widespread necrosis of hepatocytes. This effect was reversible after one week of abstinence. This impairment of liver cell renewal by ethanolmay be of major significance in the severity and outcome of alcohol-related liver injury.
Liver regeneration is the common mechanism whereby a patient recovers from a liver injury, be it a trauma, an infection or a hepatotoxin. In North America the major cause of liver disease is abusive alcohol consumption which accounts for 80% of liver cirrhosis.' In large urban areas, cirrhosis ofthe liver is the third major cause of deaths in patients between 35 and 54 years old.2 Currently, there is no specific therapy for cirrhosis due to alcohol excess, and treatment consists in ethanol abstinence, bed rest, vitamins, and high caloric diet; accordingly recovery from an alcohol-related liver injury depends on the capacity of the liver to regenerate. Most previous works on themechanisms of ethanol related liver injury have mainly focused on the pathways leading to production of lesions and largely ignored the aspect of repair. It has been demonstrated that heavy alcohol consumption often leads to irreversible liver damage.3.4 Liver injury is explained by the combination of a number of factors deleterious to the liver: intracellular accumulation of protein and of acetaldehyde,microsomal activation of hepatotoxins, alterations in
*Supported by grants MA 6423 and PG-3 from the Medical Research Council of Canada and by a grant from the Conseil de la Recherche en Sante du Quebec. Received for publication 8 July 1981
hepatic redox state, and enhancement of lymphocyte
through impairment of liver cell renewal; considering that this is the only known mechanism whereby apatient recovers from a liver injury, it appears crucial to determine if alcohol interferes with liver regeneration. Previous works by other investigators have yielded conflicting results, some observing an inhibition of liver regeneration by ethanol,67 while others found no effect.8-'0To answer that question we have studied the response to a 70% hepatectomy in rats subjected to chronic ethanoladministration.
Two hundred and forty female Sprague-Dawley rats, obtained from Canadian Breeding Farm and weighing between 130 and 10 g, were used in all the experiments described below, Rats were fed a nutritionally adequate liquid diet containing 36% of total calories as alcohol for three weeks before surgery. Each ethanol-fed rat was pair-fed with a control partner receiving a...