Hepatic iron overload and hepatocellular carcinoma

Abstract

The liver is the main storage site for iron in the body. Excess accumulation of iron in the liver has been well-documented in two human diseases, hereditary hemochromatosis and dietary iron overload in the African. Hepatic iron overload in these conditions often results in fibrosis and cirrhosis and may be complicated by the development of hepatocellular carcinoma. Malignant transformation usually occurs in the presence of cirrhosis, suggesting that free iron-induced chronic necroinflammatory hepatic disease plays a role in the hepatocarcinogenesis. However, the supervention of hepatocellular carcinoma in the absence of cirrhosis raises the possibility that ionic iron may also be directly hepatocarcinogenic. Support for this possibility is provided by a recently described animal model of dietary iron overload in which iron-free preneoplastic nodules and hepatocellular carcinoma developed in the absence of fibrosis or cirrhosis. The mechanisms by which iron induces malignant transformation have yet to be fully characterized but the most important appears to be the generation of oxidative stress. Free iron generates reactive oxygen intermediates that disrupt the redox balance of the cells and cause chronic oxidative stress. Oxidative stress leads to lipid peroxidation of unsaturated fatty acids in membranes of cells and organelles. Cytotoxic by-products of lipid peroxidation, such as malondialdehyde and 4-hydroxy-2′-nonenal, are produced and these impair cellular function and protein synthesis and damage DNA. Deoxyguanosine residues in DNA are also hydroxylated by reactive oxygen intermediates to form 8-hydroxy-2′-deoxyguanosine, a major promutagenic adduct that causes G:C to T:A transversions and DNA unwinding and strand breaks. Free iron also induces immunologic abnormalities that may decrease immune surveillance for malignant transformation.

Introduction

Iron in its free ferrous or ferric states is ubiquitous in cells and is essential for their normal functioning. But in excess amounts free iron is toxic to cells. Hepatocytes are the main storage site of iron in the body, and under normal conditions these cells are capable of safely storing the transition metal as ferric oxyhydroxyapatite in the core of the ferritin protein. However, at a critical level of iron overload the capacity for safe sequestration is exceeded and denaturation of the protein subunits occurs, releasing ionic iron into the cytoplasm of the hepatocytes. Accordingly, the liver is the organ most likely to be afflicted by iron overloading. The consequences of hepatic iron overload have most fully been documented in patients with hereditary hemochromatosis (HH), a not uncommon genetic disorder in individuals of Celtic descent, and in Africans with dietary iron overload (previously called Bantu visceral siderosis). Its detrimental effects on the liver in other iron storage conditions, such as thalassemia major, sideroblastic anemias, and spherocytosis, have received less attention.

Excess accumulation of iron in the liver of patients with HH is almost invariably complicated by hepatic fibrosis and cirrhosis [1]. Moreover, hepatocellular carcinoma (HCC) often supervenes, almost always in a cirrhotic liver, and the longer the patient survives the more likely is this sequence of events to occur [2], [3]. Hepatic fibrosis and cirrhosis also complicate abnormal hepatic iron storage in patients with African dietary iron overload, although both, but cirrhosis in particular, do so appreciably less often than they do in HH [4], [5], [6]. HCC was initially thought not to occur in dietary iron overload [7], [8], [9]. However, during recent years an increased risk for this complication has been documented in three case/control studies [10], [11], [12], and an animal model for dietary iron overload as a cause of HCC has been reported [13], [14].

Excess hepatic iron accumulation as a cause of HCC is the subject of this review.