Preventive Female Sex Factors Against The Development of Chronic Liver Disease

More than 350 million and 170 million people worldwide are persistently infected with hepatitis B virus (HBV) and hepatitis C virus (HCV), respectively. Chronic HBV infection is the most common cause of cirrhosis and hepatocellular carcinoma (HCC) in the world, while HCV infection is the main cause of cirrhosis and HCC in Japan, Europe, and the United States. Cirrhosis and HCC are predominantly diseases which tend to occur in men and postmenopausal women. Differences in the social environment and the lifestyles of women and men may be involved in the basic mechanisms underlying the sex-associated differences in progression of HCV and HBV infection. In general, males have a greater risk of exposure to hepatitis viruses as well as a greater opportunity for drinking. Environmental factors may result in a higher preponderance of nutritional and exercise-associated problems in males. Females, particularly before menopause, could produce antibodies against HBV surface antigen and e antigen at a higher frequency than males among HBV carriers. The progression time from chronic hepatitis C to cirrhosis is found to be longer in females than in males. Male sex, older age (≥50 years) and cirrhosis are important host-related risk factors for the development of HCC. Therefore, cases of female sex and under 50 years old, namely “premenopausal women” are least vulnerable to HCC.

Hepatocellular carcinoma (HCC) occurs more frequently in males than in females, particularly in high- and intermediate-prevalence areas of the world. Accumulating data have shown that male patients tend to display more aggressive tumor characteristics than female patients at initial presentation. Moreover, the rate of spontaneous survival and survival after treatment is significantly lower in male patients with HCC. The explanation underlying gender disparity in clinicopathologic features and prognosis of the patients remains to be elucidated. Gender-specific lifestyle and social environment, as well as the role of sex hormones in hepatic carcinogenesis, may contribute to the observed gender difference in clinicopathologic aspects of HCC. In this review, we have summarized the clinicopathologic characteristics and survival of patients with HCC in relation to gender.

As a target organ, the liver is particularly susceptible to excess iron levels. Hepatic iron overload induces mitochondrial injury and DNA mutagenesis, being an independent factor associated with hepatic fibrosis along with cell death, and increasing the risk of hepatocellular carcinoma development. In humans with iron overload due to either genetic or acquired causes, fibrosis and cirrhosis are hallmarks of liver disease. The clinical expression of genetic hemochromatosis is 5 to 10 times more frequent in men than in women, especially because of iron losses in women by menstruation and pregnancy. Iron deficiency is prevalent in females of reproductive age. Iron deficiency anemia is more commonly found in females than males. Women, especially before menopause, have lower iron stores in the liver. Hepcidin is a circulatory peptide synthesized in the liver that appears to regulate iron absorption in the duodenum. It is noteworthy that female mice express higher hepcidin levels in the liver than males, although it is not known whether women and men differ in the level of hepatic hepcidin expression. Sex-related differences in body iron storage and metabolism may be a potential candidate to explain in part the observed sex-related differences in many chronic liver diseases.

Approximately 30% of patients with chronic hepatitis C virus (HCV) infection show persistently normal alanine aminotransferase (ALT) levels. Although formerly referred to as ‘healthy’ or ‘asymptomatic’ HCV carriers, and thus historically excluded from antiviral treatment, it has now become clear that the majority of these patients have some degree of histological liver damage.

Although liver disease is usually minimal/mild and fibrosis is generally absent or minimal, the natural history of HCV carriers with persistently normal ALT levels (PNALT) is probably not always so benign, and the possibility of a more severe evolution of liver disease among patients with PNALT cannot be ruled out. Several studies reported a significant progression of fibrosis in approximately 20- 30% of the patients with well-defined ALT normality, and the development of hepatocellular carcinoma in some cases has been described, despite persistent ALT normality. Sudden worsening of disease with ALT increase and histological deterioration has been described after up to 15 years of follow-up.

Recent studies have shown that combined antiviral treatment with pegylated interferon plus ribavirin might allow a sustained virological response in up to 70-80% of patients harboring HCV type 2 or 3, and approximately 50% of those infected with genotype 1. Thus, the advent of these new therapeutic options has shifted treatment targets toward eradication of underlying infection, with therapy decision based on age, severity of disease and likelihood of response rather than on aminotransferase levels.

Females are more resistant to certain infections, and suffer a higher incidence of autoimmune diseases. Immune disease expression is also affected by the reproductive status of the female. Indeed, the decline in ovarian function with menopause is associated with spontaneous increase in pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin-1 and interleukin-6. In general, estradiol seems to have anti-inflammatory effects on neutrophils, while progesterone seems to have pro-inflammatory effects on these cells. In males an increase in blood monocyte number is demonstrated as compared to females during menopause in the follicular phase. Increased potency to lyse other cells is found in postmenopausal females and in males as compared to females with a regular menstrual cycle. This is in line with the fact that natural killer (NK) cell activity is also decreased in postmenopausal females using hormone replacement therapy. In vitro estrogens appear to suppress NK cell activity. Estrogens appear to increase the numbers and function of regulatory T lymphocytes, which inhibit the adaptive immune response. In contrast, progesterone may counteract the estrogen effects. Sex differences in immune responses therefore account for, at least in part, the sex differences in incidence and progression of liver disease.

Regardless of etiology, hepatocellular carcinoma (HCC) develops much more frequently in males than in females in almost all populations. Although sex hormones and X-chromosome-linked genetic factors are considered to be important, the precise mechanism has not yet been elucidated. Recent clinical and experimental studies have revealed that interleukin-6 (IL-6) and the inflammationmediated signal transduction pathways, including nuclear factor-kappaB (NF-kB), seem to play key roles in the gender difference in hepatocarcinogenesis. In particular, a report by Naugler et al. showing that estrogen-mediated inhibition of IL-6 production by Kupffer cells explains the gender disparity in HCC development, gives considerable attention to the association between IL-6 and hepatocarcinogenesis. Investigating the factors causing a gender difference in hepatocarcinogenesis is very important to clarify the carcinogenic pathway and the therapeutic target for HCC.

Oxidative stress, such as the generation of reactive oxygen species (ROS), plays a causative role in the development of hepatic fibrosis. Hepatic fibrosis is a complex dynamic process which is mediated by death of liver cells (hepatocytes) and activation of hepatic stellate cells (HSCs). Multivariate analysis with patients with chronic hepatics C showed that the male sex was associated with advanced fibrosis, which was independent of age at the time of a hepatitis C virus (HCV) infection and of alcohol consumption, and that the progression of hepatic fibrosis began to accelerate at 50 years of age, irrespective of the duration of the virus infection. Judging from these data together with the average menopausal age of 50 years, among premenopausal females without either factors of a male sex or an older age, the transition of hepatic fibrosis to the end-stage cirrhosis appears to require a longer time. The principal estrogen secreted by the ovary and the most potent naturally occurring estrogen is estradiol, which is a potent endogenous antioxidant. Estradiol inhibits ROS generation, antioxidant enzyme loss, and hepatocyte death, and it is also able to attenuate oxidative stress-induced transforming growth factor-β (TGF-β) expression and HSC activation, enhancing antifibrotic activity. Whereas another female sex steroid, progesterone acts in opposition to the favorable effects of estradiol. The stimulatory effect of progesterone on TGF-β expression and HSC activation is blocked by estradiol. These findings suggest that estradiol and progesterone affect coordinately processes related to the slow progression of hepatic fibrosis in females.

In the livers of humans, cats, and guinea pigs, nerve endings are distributed all over the hepatic lobules. Nerve endings in the intralobular spaces are localized mainly in the Disse spaces, and are oriented towards the hepatic stellate cells (HSCs), sinusoidal endothelial cells (SECs) and hepatocytes. They are especially closely related to HSCs. Various neurotransmitters such as substance P (SP) exist in the nerve endings. In addition, HSCs possess endothelin (ET) and adrenergic receptors, and contract in response to the corresponding agonists. In contrast, nitric oxide (NO) inhibits the contraction of HSCs. HSCs thus appear to be involved in the regulation of hepatic sinusoidal microcirculation by contraction and relaxation. In the cirrhotic liver, intralobular innervation is decreased, but NO is overexpressed in the SECs. These findings indicate that the sinusoidal microcirculation through NO rather than through intralobular innervation may be involved in cirrhotic liver. Moreover, estrogen plays an important role in the enhancement of NO production in the SECs of cirrhotic liver and reduces the portal pressure

Increasing evidence indicates that hepatic fat accumulation is related to hepatic fibrosis, inflammation, apoptosis, and cancer. Males generally have larger visceral fat areas than females. Menopause is associated with a shift towards relatively more fat as well as towards the deposition of more fat in the abdominal region. Estrogen treatment of male-to-female transsexuals can increase the amount of subcutaneous adipose tissue; thus, estrogen changes the male type of visceral fat distribution into a female type of fat accumulation. Visceral fat accumulation arises through enlarged adipocytes, which release adiponectin, leptin, tumor necrosis factor-α (TNF-α), and fatty acids. Adiponectin inhibits the enlargement of adipocytes and fat accumulation. Adiponectin levels are consistently higher in females than in males. Persistent TNF-α stimuli lead to adipogenesis and impairment of mitochondria in hepatocytes and result in induction of oxidative stress. In experimental studies, when incubated with adiponectin, hepatic stellate cells undergo a number of antifibrogenic changes. Whereas leptin may play a role in the development of hepatic fibrosis. Hepatic steatosis spontaneously becomes evident in an aromatase-deficient mouse. Estrogen replacement reduces hepatic steatosis and restores the impairment in mitochondrial fatty acid β-oxidation to a wild-type level. In fact, tamoxifen, as an antiestrogen, has been shown to be associated with an increased risk of developing hepatic steatosis and non-alcoholic steatohepatitis (NASH) in non-obese female patients with breast cancer.< /p> < p>Understanding the sex-associated difference is necessary to inform the rational design of treatment strategies directed at visceral obese individuals who may develop from hepatic steatosis to cirrhosis and hepatocellular carcinoma.

Sex and gender specific medicine is one of the most important issues to be promoted in recent medical care, from the viewpoint of the establishment of evidence-based medicine for the best therapies as well as patients' quality of life and also national health economics. Medical doctors should understand and elucidate the mechanisms underlying sex or gender differences regarding the incidence or etiology, clinical features, and each natural history or response to specific therapies.

Sex or gender differences have been generally observed among various liver diseases, such as viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis and hepatocellular carcinoma. The mechanisms of these differences, however, are still obscure in spite of the world-wide reports, probably because there are variances in the regions, suggesting that such differences seem to exist in racial genes and cultural life style.

In this chapter, sex and gender specific medicine in the category of chronic liver diseases is reviewed by going through related original papers with personal opinions and comments.