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

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.

Effects of estradiol and progesterone on the proinflammatory cytokine production by mononuclear cells from patients with chronic hepatitis C

AIM:To investigate the effects of estradiol (E2) and progesterone on the unstimulated and oxidative stressstimulated production of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-8, and macrophage chemotactic protein (MCP)-1 by peripheral blood mononuclear cells (PBMCs) from patients with chronic hepatitis C and healthy controls. METHODS:The PBMCs were separated from agematched 72 males and 71 females with and without chronic hepatitis C, who were divided into two groups based on a mean menopausal age of 50 years. Oxidative stress was induced by hydrogen peroxide in the cells incubated in serum-free media. Cytokines in the culture supernatant were measured by an enzyme-linked immunosorbent assay. RESULTS:The highest levels of the spontaneous production of TNF-α, IL-1β, IL-8, and MCP-1 by the unstimulated PBMCs were in the older male patients with chronic hepatitis C and the lowest levels were in the premenopausal female healthy controls. E2 inhibited the cytokine production by the unstimulated PBMCs from the older male and post-menopausal female patients, which was further stimulated by progesterone. The exposure to hydrogen peroxide in the PBMCs from the younger male and pre-menopausal female healthy subjects induced the production of cytokines. The change rates of the hydrogen peroxide-stimulated cytokine production were suppressed by E2 and enhanced by progesterone. CONCLUSION:These findings suggest that E2 may play a favorable role in the course of persistent liver injury by preventing the accumulation of monocytes-macrophages and by inhibiting proinflammatory cytokine production, whereas progesterone may counteract the favorable E2 effects.

A patient with spinal metastasis from hepatocellular carcinoma discovered from neurological findings

Although spinal tumors are uncommon, they may reduce survival or cause serious functional disorders in the extremities. Metastatic spinal tumors from malignant tumors can induce symptoms of spinal cord compression, such as paraplegia, quadriplegia, and vesicorectal disturbance, which are aggravated with progression of the diseases and time. We report a patient with hepatocellular carcinoma (HCC) who was suspected of having spinal lesions based on neurological findings, and a metastatic spinal tumor was found by imaging examination. Assuming that metastasis had occurred at the time lumbar pain developed, the patient reached the level of gait disturbance within only 4 mo, showing a rapid advancement of symptoms. If early diagnosis had been possible, treatment could be performed before acute myelopathy progressed to complete paralysis. We speculate that the terminal stage of HCC is not only liver failure associated with intrahepatic lesions but also metastasis to other regions, treatment for individual pathologies therefore, will be needed, which constitutes an important issue.