Experimental toxic cirrhosis in the rat. Kinetics of hepatocyte proliferation during intermittent carbon tetrachloride intoxication

The present paper describes an experiment in which cirrhosis was induced in rats by the repeated injection of carbon tetrachloride. It was the purpose of the experiment to evaluate the parameters of a stochastic model of hepatocyte renewal.The order of magnitude of the cell populations involved was evaluated in relation to histological determinations of the hepatocyte populations of resulting cirrhotic pseudolobules. Birth-rate data were obtained from determinations of the mean fraction of hepatocytes labelling with ³H-thymidine, and of the standard deviation of the labelling fraction. As ³H-thymidine labelling was very variable, but uncorrelated with the timing of carbon tetrachloride injections, a birth-rate function was constructed showing random fluctuations of appropriate magnitude about the mean. A death-rate function was similarly constructed. These functions, with the initial size of the population, constituted the stochastic model.This model is an example of a non-homogeneous birth-and-death process. Its behaviour was studied by Monte Carlo computer simulation. This showed that an initial population of 1,000 cells subjected to the birth-and-death process described will undergo considerable random fluctuations in population size. Accordingly a contribution by anomalous hepatocyte renewal to the abnormal morphology of cirrhosis cannot be excluded in the experimental system described.