Female hepatology: Favorable role of estrogen in chronic liver disease with hepatitis B virus infection

Abstract

Chronic hepatitis B virus (HBV) infection is the most common cause of hepatic fibrosis and hepatocellular carcinoma (HCC), mainly as a result of chronic necroinflammatory liver disease. A characteristic feature of chronic hepatitis B infection, alcoholic liver disease and nonalcoholic fatty liver disease (NAFLD) is hepatic steatosis. Hepatic steatosis leads to an increase in lipid peroxidation in hepatocytes, which, in turn, activates hepatic stellate cells (HSCs). HSCs are the primary target cells for inflammatory and oxidative stimuli, and these cells produce extracellular matrix components. Chronic hepatitis B appears to progress more rapidly in males than in females, and NAFLD, cirrhosis and HCC are predominately diseases that tend to occur in men and postmenopausal women. Premenopausal women have lower hepatic iron stores and a decreased production of proinflammatory cytokines. Hepatic steatosis has been observed in aromatase-deficient mice, and has been shown to decrease in animals after estradiol treatment. Estradiol is a potent endogenous antioxidant which suppresses hepatic fibrosis in animal models, and attenuates induction of redox sensitive transcription factors, hepatocyte apoptosis and HSC activation by inhibiting a generation of reactive oxygen species in primary cultures. Variant estrogen receptors are expressed to a greater extent in male patients with chronic liver disease than in females. These lines of evidence suggest that the greater progression of hepatic fibrosis and HCC in men and postmenopausal women may be due, at least in part, to lower production of estradiol and a reduced response to the action of estradiol. A better understanding of the basic mechanisms underlying the sex-associated differences in hepatic fibrogenesis and carciogenesis may open up new avenues for the prevention and treatment of chronic liver disease.

Liver and gender: Are there differences in fibrous tissue before the onset of fibrosis?

“…1 It confirms that, apart from autoimmune diseases, hepatic fibrosis is largely a male disease. 1,2 This gender susceptibility has been substantiated by other epidemiological and experimental studies. 2 Estrogens have been implicated in this protective role.…”

“…1,2 This gender susceptibility has been substantiated by other epidemiological and experimental studies. 2 Estrogens have been implicated in this protective role. Yang et al reported that before and after age 50, men had 1.8-and 1.2-fold increased risk of having greater severity of fibrosis.…”

“…3 Shigehara et al already showed RNAse activity in bile, 2 and confirming this with ribosomal RNA can hardly be considered exemplary for miRNAs and does not favor the use of EVs alone. We do acknowledge the conclusion that the amount of putatively interesting miRNAs can be confounded by contamination of the sample by free-floating cells.…”

“…Using the centrifugation procedure shown in Fig. 1A, which was adapted from Shigehara et al, 2 we observed that, for hepatocyte-and cholangiocyte-derived miRNAs, less than 1% is represented in the extracellular vesicle fraction (P3, Fig. 1A), whereas the majority (61-73%) of the total miRNA pool remain in the unpelleted fraction (sup3, Fig.…”

“…1 The similarities in clinical manifestations of CCA with many benign disorders, however, often result in a diagnostic delay for patients. Following up on the article by Shigehara et al, 2 the group of Selaru presented data in HEPATO-LOGY identifying another set of microRNAs (miRNAs) in bile that could discriminate between CCA patients and control patients with benign or nontumorigenic strictures. 3 Where Shigehara et al used whole bile as a source for miRNA profiling, the Selaru group focused on a subfraction of bile: the extracellular vesicles (EVs).…”