Iron‐free neoplastic nodules and hepatocellular carcinoma without cirrhosis in Wistar rats fed a diet high in iron

Abstract

Although excess hepatic iron in hereditary haemochromatosis and dietary iron overload in the African causes hepatocellular carcinoma, it usually does so in the presence of cirrhosis. A direct hepatocarcinogenic effect of iron has not been proved. Moreover, an animal model of hepatocellular carcinoma induced by iron overload has not been available. The aim of this study was to develop such a model and to use it to ascertain whether excess hepatic iron is directly hepatocarcinogenic. Sixty Wistar albino rats were fed a chow diet and 60 the same diet supplemented initially with 2% carbonyl iron for 12 months, followed by 0.5% ferrocene for 20 months. Five rats from each group were sacrificed every 4 months for 24 months for histological and biochemical monitoring. By 16 months, hepatocytes in all the rats receiving the iron-supplemented diet showed grade 4 iron overload, comparable in degree with that seen in patients with advanced hereditary haemochromatosis and dietary iron overload. Altered hepatic foci and pre-neoplastic nodules were first seen at 16 months. These increased in size and number with time, were iron-free, stained positively with placental glutathione sulphydryl transferase, and showed the same histological features as the iron-free foci described in patients with hepatocellular carcinoma complicating hereditary haemochromatosis. At 32 months the eight surviving rats in the iron overloaded group were sacrificed. The livers of five of these rats contained pre-neoplastic nodules and one showed, in addition, an iron-free, well-differentiated hepatocellular carcinoma. The tumour stained positively for placental glutathione sulphydryl transferase. Neither cirrhosis nor portal fibrosis was present in this or any iron-loaded animal. We conclude that hepatocellular carcinoma may complicate dietary hepatic iron overload in Wistar albino rats in the absence of fibrosis or cirrhosis, confirming an aetiological association between dietary iron overload and the tumour and suggesting that iron may be directly hepatocarcinogenic.

Hepatic iron overload and hepatocellular carcinoma

“…Moreover, in HCC cell lines and murine models, exogenous iron administration is accompanied by enhanced tumor development and growth [25]. HCC has been documented to occur in iron-overloaded individual patients in the absence of cirrhosis [26][27][28][29], supporting the belief that increased hepatic iron may also cause or promote malignant transformation of hepatocytes directly.…”

“…But in a recent study, HCC developed in Wistar rats that became heavily iron-overloaded after receiving 16 months or more of a diet rich in iron, and it did so in the absence of cirrhosis [25]. In these rats, the iron accumulated in hepatic parenchymal cells and macrophages, a pattern similar to that seen in African dietary iron overload.…”

“…By 20 months, altered iron-free hepatic foci were present in many of the animals. By 28 months these foci had become plentiful, and the foci had changed in character, becoming indistinguishable from the iron-free preneoplastic nodules described by Deugnier and colleagues in humans with iron overload [51], and the foci ultimately developed into typical neoplastic nodules with an expansive pattern [25].…”

Iron Deprivation Suppresses Hepatocellular Carcinoma Growth in Experimental Studies

“…Indeed, iron overload in the liver represents a significant risk factor for development of HCC (11,13,14). Case-control studies and animal model studies have provided evidence that excessive iron accumulation is a cause of HCC (12,(15)(16)(17)(18). Patients with hereditary hemochromatosis (HH), most commonly caused by HFE mutation, show symptoms of profound iron overload and are at an increased risk of developing HCC (8,19).…”

Control of oxidative stress in hepatocellular carcinoma: Helpful or harmful?

“…Iron loading of the liver causes further hepatic oxidative stress that is a main cause of HCC [99] . Iron overload can induce hepatocarcinogenesis in animals and is associated with the high incidence of HCC among African and Taiwanese individuals [100,101] . Iron depletion in HCV and NASHrelated hepatocarcinogenesis should play a more important role in the prevention of HCC.…”