Stål P
Department of Gastroenterology and Hepatology, Karolinska Institutet, Huddinge University Hospital, Sweden.
Dig Dis. 1995 Jul-Aug;13(4):205-22. doi: 10.1159/000171503.
Although essential for life, iron in excessive amounts may be toxic. The liver is particularly subject to the toxic effects of iron, since it is the major site of iron storage. Several inherited and acquired human disorders may result in hepatic iron overload, the most common of which are genetic hemochromatosis (GH) and transfusional iron overload. GH is an inherited disorder of iron metabolism, and in patients with GH excess iron absorbed from the gut is transported through the portal vein to the liver. The mechanisms by which excess iron exerts its cytotoxic effects include enhanced formation of free radicals and peroxidation of organelle membrane lipids. Lipid peroxidation can lead to structural and functional alterations in lysosomes, mitochondria and the endoplasmic reticulum. With massive iron overload, such iron-induced alterations may cause cell death, also known as sideronecrosis. At this stage, fibrogenesis is initiated and, if the excess iron is not removed, the increased deposition of collagen progresses to cirrhosis. However, the mechanisms underlying iron-induced fibrosis remain unclear. Transformation of fat-storing cells to collagen-producing myofibroblasts has been proposed to be induced either by iron; by lipid peroxides or other cellular factors released from iron-loaded, damaged hepatocytes; or by profibrogenic factors produced by activated Kupffer cells. In addition, iron may enhance the cytotoxic and, possibly, fibrogenic effects of other liver cell-damaging agents, such as alcohol or hepatotrophic viruses. Once cirrhosis is manifest, patients with GH demonstrate a 200-fold increase in the risk for development of hepatocellular carcinoma. In vitro, iron has been shown to possess mutagenic properties, but the results from in vivo models in which the genotoxic effects of iron overload have been studied are variable. Similarly, although iron has mitostimulatory effects on hepatocytes in vivo and preneoplastic cells in vitro, its role in tumor promotion and/or progression still remains unclear. Cirrhosis itself is of central importance in the carcinogenic process, but whether or not iron acts as an additional risk factor in this process, alone or by enhancing the tumorigenic properties of other hepatocarcinogens, has yet to be established.
尽管铁对生命至关重要，但过量的铁可能具有毒性。肝脏特别容易受到铁的毒性影响，因为它是铁储存的主要部位。几种遗传性和获得性人类疾病可能导致肝脏铁过载，其中最常见的是遗传性血色素沉着症（GH）和输血性铁过载。GH是一种铁代谢的遗传性疾病，在GH患者中，从肠道吸收的过量铁通过门静脉运输到肝脏。过量铁发挥其细胞毒性作用的机制包括自由基形成增加和细胞器膜脂质过氧化。脂质过氧化可导致溶酶体、线粒体和内质网的结构和功能改变。随着大量铁过载，这种铁诱导的改变可能导致细胞死亡，也称为铁坏死。在这个阶段，纤维化开始，如果过量的铁不被清除，胶原蛋白沉积增加会发展为肝硬化。然而，铁诱导纤维化的潜在机制仍不清楚。有人提出，储脂细胞向产生胶原蛋白的肌成纤维细胞的转化是由铁、脂质过氧化物或从铁过载、受损肝细胞释放的其他细胞因子，或由活化的库普弗细胞产生的促纤维化因子诱导的。此外，铁可能会增强其他肝细胞损伤剂（如酒精或嗜肝病毒）的细胞毒性以及可能的纤维化作用。一旦肝硬化显现，GH患者发生肝细胞癌的风险会增加200倍。在体外，铁已被证明具有致突变特性，但研究铁过载遗传毒性作用的体内模型结果各不相同。同样，尽管铁在体内对肝细胞和体外癌前细胞具有促有丝分裂作用，但其在肿瘤促进和/或进展中的作用仍不清楚。肝硬化本身在致癌过程中至关重要，但铁是否单独或通过增强其他肝癌致癌物的致瘤特性在此过程中作为额外的危险因素，尚未确定。
