**7.7 With or without 'liver fibrosis and promoting signals'**

It is interesting that iron-loading is frequently observed in chronic liver diseases regardless of the aetiology. The Fenton reaction is induced by excessive iron. At the same time, it generates unquenchable amounts of free radicals that cause grave cellular and tissue damage and thereby contribute to fibrosis. In addition, excess iron can induce fibrosis-promoting signals in the parenchymal and non-parenchymal cells, which accelerate disease progression and exacerbate liver pathology. Liver fibrogenesis is the normal process of tissue repair. It is mediated via a complex network of interrelated and regulated signalling interactions between the resident parenchymal cells (hepatocytes), non-parenchymal cells, Kupffer cells, hepatic stellate cells (HSCs), liver sinusoidal endothelial cells, biliary epithelial cells, liver associated lymphocytes and non-resident infiltrating immune cells. HSCs located in the space of Disse between the hepatocytes and liver sinusoids play a pivotal role in liver development and regeneration via fibrogenesis [143].

The fruitless regenerative response perpetuates variable repair-related expansion of immature liver cells, inflammation, vascular remodelling and fibrogenesis, which results in more advanced or severe NASH. By degrees, functional hepatic parenchyma is progressively replaced by scar, and the liver becomes enriched with neoplastic immature hepatocytes; this can account for the increased risk of cirrhosis and liver cancer in patients with severe NASH [144].

The histologic features of NASH indicate the ongoing repair responses to chronic hepatocyte lipotoxicity and vary with the severity of lipotoxicity and success of the wound-healing process. The liver can usually undergo repair and regeneration after acute injury or when chronic injury causes a minor increase in the rate of hepatocyte death. Therefore, there is no progressive replacement of hepatic parenchyma with scar, and the risk for liver cancer remains low in numerous patients with minimal hepatic lipotoxicity and mild NASH [120].

In conclusion, the findings indicate that HSCs, during fibrogenesis in vivo, may not be directly subjected to oxidant stress, and when exposed to various oxidant stressors in vitro, do not turn on the fibrogenic machinery.

## **7.8 With or without 'amenorrhea or menopause complicated with Mets'.**

In menopausal women, oestrogen is one of important hormones for the regulation of glucose metabolism, because it has capacity in exerting a protective effect on pancreatic beta cells and plays an important role in regulating appetite and improving insulin resistance in insulin target organs. It is one of the crucial problems that oestrogen may also play an important role in the progression of NAFLD and NASH. It has been empirically considered that postmenopausal women are at an increased risk of NAFLD and might show metabolic features of insulin resistance. For example, increased total and visceral adiposity in peri- and postmenopausal women is associated with an increased risk of insulin resistance, dyslipidaemia, hypertension, diabetes and cardiovascular disease. Furthermore, postmenopausal women with NAFLD are at an increased risk of portal inflammation, ballooning and fibrosis due to their inability to suppress oxidative stress and fibrosis by lowering their oestrogen levels [145].

It is really recognised that oestrogen replacement therapy has some beneficial effects in patients with liver fibrosis. The risk of NAFLD is greater among postmenopausal women than among premenopausal women [146].

It is possible that the loss of protection conferred by oestrogens', combined with other factors, underlies the increased NAFLD risk in postmenopausal women. NAFLD can easily progress to a more dangerous condition called NASH, which indicates there is both inflammation and liver cell damage, along with fat in the liver [147].

In addition, menopause or amenorrhea actually means 'relative iron overload' for women who develop obesity at the same time. These women have a high risk of deteriorating NAFLD/NASH. In such situations, Laennec as a 'hepcidin inducer' might be a preferable and effective treatment. In my experiences, 13 biopsy-proven NASH cases were extremely sensitive to placenta-derived Laennec treatment. In five cases, second liver biopsy revealed a diminishing liver fibrosis and inflammation, as well as a decrease in iron deposition. In these NASH cases, iron deposition was mainly observed in the Kupffer cells [73, 74, 78].
