Sex and Hepatic Fibrosis

Population data have long suggested that chronic liver disease progresses at unequal rates in the two sexes for viral hepatitis and other forms of injury with a similar incidence in males and females.In chronic viral hepatitis the major sequelae, such as fibrosis or cirrhosis, are more common in men than in women.Although establishing the actual rate of fibrosis in a patient would require serial liver biopsy, which is seldom done, a reasonable approximation can be inferred from the incidence of fibrosis-related complications.In chronic hepatitis B, hepatocellular carcinoma arises in a fibrotic or cirrhotic liver in the vast majority of cases. 1 A large prospective Taiwanese study of this carcinoma showed that the age-specific incidence of hepatocellular carcinoma was threefold greater in men than in women over the age of 45. 2 Confounders, such as alcohol consumption or tobacco use, were not identified.3 In hepatitis C, male sex is an independent risk factor for disease progression, along with alcohol consumption.4 Alcohol-related liver disease also is largely a male problem despite the reported increased sensitivity of women to adverse effects of alcohol.5 In schistosomal liver disease and hemochromatosis, there is a clear predominance of males, although in both, this is attributed to environmental factors: in the case of schistosomiasis, field workers, who are largely male, may have a greater exposure to the parasite; in the case of hemochromatosis, males experience a longer period of iron accumulation than do females (plus possibly greater alcohol consumption).However, these assumptions do not exclude an intrinsic difference between men and women in the response to chronic liver injury.In this issue of HEPATOLOGY, Yasuda et al. have examined whether estrogen modulates fibrogenesis in experimental injury.Their injury model, administration of dimethylnitrosamine to the rat, produces a panlobular fibrosis.They compared male and female animals.They also manipulated estrogen in several ways, reducing the endogenous hormone with anti-estrogen antibody or ovariectomy as well as increasing estrogen by administering exogenous hormone.In each case, high estrogen was associated with decreased fibrogenesis.The authors also conducted studies with stellate cells in primary culture, showing that estrogen blocks proliferation and fibrogenesis by these cells.Hepatic stellate cells are perisinusoidal cells that in injury display properties of myofibroblasts and, as such, are quantitatively the most important source of collagen and several other extracellular