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Female Wistar rats with slight iron deficiency anemia were kept on a diet containing 0.5% trimethylhexanoyl (TMH)-ferrocene for up to 79 weeks. In the state of iron deficiency, the heart was free of light-microscopically detectable iron. After 7 weeks of the TMH-ferrocene diet, the first iron-positive granules appeared in perivascular macrophages. Further oral administration caused a progression of iron deposition in these cells, visible in the form of a granular staining but also as a diffuse iron staining of the cytoplasm. Accordingly, at the electron-microscopical level, the iron was stored partly as free ferritin molecules in the cytosol, and partly in lysosomes in the form of ferritin and/or hemosiderin. After 11 weeks, further iron-positive cells with relatively small dark-blue granules were found in the vicinity of capillaries, which could be identified as fibrocytes by means of electron microscopy. In addition, slight iron deposition occurred in the endothelial cells of the cardiac capillaries, likewise mainly in the form of small, uniform siderosomes. The myocytes showed no product of Perls' Prussian blue reaction during the whole period of investigation. From the 11th week onwards, discrete ferritin molecules were detected electron microscopically within lysosomes of these cells. Their amount increased slowly with progression of the TMH-ferrocene feeding period. Free ferritin molecules could be observed in the cytosol of fibrocytes, endothelial cells and myocytes in only very slight concentrations, whilst they were more plentiful in macrophages. In hereditary hemochromatosis and posttransfusional siderosis, the iron is found predominantly in myocytes and appears to cause cell damage, whilst this is not the case in experimental iron overload in rats.

Iron-deficient female Wistar rats were fed a diet, which contained 0.5% trimethylhexanoylferrocene, over a 56-week period. This dietary iron loading resulted in a progressive siderosis and enlargement of the liver with a maximum iron content of 947.0 +/- 148.0 mg (vs. 0.07 +/- 0.04 mg in iron deficiency) and a maximum organ weight of 39.4 +/- 6.6 g (vs. 6.9 +/- 1.4 g in iron-deficient control rats). Up to 43 weeks, whole liver iron rose by increase in iron concentration (max. 28.0 +/- 6.1 mg/g wet weight, w.w.) as well as by enlargement of the organ. Afterwards whole liver iron increased solely by ongoing hepatomegaly. At the commencement of iron loading, stainable iron was almost exclusively stored by hepatocytes equally throughout all areas of the liver lobule. Later, the distribution of iron-loaded hepatocytes became strikingly periportal, and, in addition, Kupffer cells as well as sinus-lining endothelia began to store iron. Animals with a liver iron concentration of more than 10.4 +/- 0.75 mg/g w.w. showed no further increase in ferritin and haemosiderin within hepatocytes. Iron-burdened Kupffer cells/macrophages, however, accumulated permanently, hereby forming intrasinusoidal and portal siderotic nodules and areas. First signs of liver damage such as necrosis of single hepatocytes and mild fibrosis began at a liver iron concentration of 14.7 +/- 1.4 mg/g w.w. With advancement of iron loading, focal necrosis of hepatocytes and iron-burdened macrophages took place, and significant perisinusoidal as well as portal fibrosis developed. Cirrhosis, however, the final stage of impairment in iron overload of the liver in humans, could not be induced in this animal model up to now.

Iron-deficient female Wistar rats were fed a diet which contained 0.5% 3,5,5-trimethylhexanoyl (TMH)-ferrocene over a 57-week period. The state of iron deficiency was characterized by means of the absence of stainable iron in the bone marrow. After the first days on the iron-enriched diet, ferritin-containing siderosomes were found, in numerous erythroblasts up to orthochromatic normoblasts and in reticulocytes, i.e. the dispensed iron was used for haemoglobin synthesis. After 1 week the first macrophages showed a positive Perls' Prussian blue reaction. In the cytoplasm they stored the iron in the form of free ferritin molecules and lysosomally as aggregated ferritin and/or haemosiderin. The iron loading of the macrophages increased in both of the storage qualities proportionally with duration of the feeding period and reached a maximum after 38 weeks. Final stages showed extremely iron-loaded macrophages with high concentrations of free ferritin molecules and large siderosomes, partially flowing together to still greater units. Iron deposits within endothelial cells of bone marrow sinusoids can be observed for the first time after 4 weeks. In these cells the iron is stored as ferritin in siderosomes of relatively small and uniform size; free ferritin molecules in the cytosol were of only slight concentration. The TMH-ferrocene model of iron overload shows in the bone marrow: (1) an unimpeded utilization of the iron component for erythropoiesis, (2) development of excessive iron overload of the bone marrow in macrophages and endothelial cells of sinusoids and (3) a pattern of distribution of iron as seen in secondary haemochromatosis.