Iron overload facilitates hepatic fibrosis in the rat alcohol/low-dose carbon tetrachloride model



The role of iron deposition in initiating hepatic fibrosis in iron overload disorders is not clearly established, and it is becoming increasingly recognized that iron may be interacting with other potential liver-damaging agents. The authors therefore examined the interplay of iron and alcohol in rats administered subtoxic doses of carbon tetrachloride (CCl4) vapor at 20 ppm in customized chambers. At birth, the offspring of seven pregnant Porton rats were divided into two groups: one group was fed a normal rat chow diet and the other a diet supplemented with 3% (w/w) carbonyl iron for 10 weeks after weaning. In this latter group, the mothers were fed an iron supplement while breastfeeding. At 10 weeks, the animals from the first group (normal chow) were divided into two groups of six animals and fed a Lieber-DeCarli liquid diet with daily exposure to CCl4 vapor: group 1, liquid diet + CCl;group 2, liquid diet + alcohol 150 kcal/l + CCl4. The animals from the second iron-supplemented group were divided into two groups of six animals and fed a liquid diet with 3% (w/v) carbonyl iron and exposed to CCl4 vapor for 10 weeks: group 3, liquid diet + iron + CCl4;group 4, liquid diet + iron + alcohol supplement + CCl4. Two animals from each group of six had a liver biopsy at 4, 6, and 8 weeks, and all animals were killed after 10 weeks of CCl4 exposure. After the first 10-week iron loading period, the rats fed the carbonyl iron-supplemented diet had a 10-fold elevation in hepatic iron concentration. In the second 10-week (CCl4 exposure) period, fibrosis was scored on a four-point scale in each liver biopsy and in all animals at 10 weeks. At 10 weeks, the animals exposed to iron and alcohol in addition to CCl4 all had an established or developing cirrhosis with the development of fibrosis apparent at 4 weeks. Animals in the other groups had markedly less fibrosis, with none seen in the control group up to 10 weeks. Thus, the addition of iron to alcohol facilitates the development of fibrosis in animals exposed to subtoxic doses of CCl4 vapor. This model should allow a more detailed analysis of the mechanism(s) underlying this process. (HEPATOLOGY 1995; 21:1083–1088.)