Hemosiderin Deposits

Further details of the above study were discussed in U.S. EPA (1994). After the last exposure, methemoglobin levels were elevated in a dose-dependent manner 17 ppm, 0% to 2.9% (no different from controls) 45 ppm, 2.2% to 5.4% and 87 ppm, 4.2% to 23%. The animals exposed at 45 and 87 ppm were anemic with decreases in RBC counts, hemoglobin content, MCHb concentration, and hematocrit, and accompanying increases in erythropoietin foci, reticuloendothelial cell hypertrophy, and hemosiderin deposition in the spleen. The animals in the 87-ppm exposure group were judged cyanotic. In the 17-ppm exposure group, effects were limited to mild splenic congestion. 

In intermediate-duration studies, spleen enlargement occurred in male and female rats treated with approximately 1 mg/kg/day 1,3-DNB in the drinking water for 16 weeks (Cody et al. 1981). Similar results were reported in rats administered 1.5 mg/kg/day 1,3-DNB by gavage for 12 weeks (Linder et al. 1986). Treatment of rats with doses of about 12-14 mg/kg/day 1,3-DNB in the drinking water for 8 weeks induced hemosiderin deposits in the spleen and spleen atrophy and fibrosis (Cody et al. 

Exposure of rats to carbon tetrachloride (up to 160 mg/kg/day for 10 days) by gavage did not alter the primary antibody response to sheep red blood cells, lymphoproliferative responses to mitogen or mixed leukocytes, natural killer cell activity, or cytotoxic T lymphocyte responses also, spleen and thymus weights were comparable to controls (Smialowicz et al. 1991). In rats exposed twice weekly for 4-12 weeks to 3,688 mg/kg/day, there was histologic evidence of hemorrhage, hemosiderin deposition, and lymphocyte depletion in the pancreaticoduodenal lymph node (Doi et al. 1991), an effect which may be secondary to induced hepatic damage. 

Immunological Effects. The effects of carbon tetrachloride on the immune system have not been evaluated in humans. Immune responses were not affected in rats orally exposed to carbon tetrachloride (Smialowicz et al. 1991). Parenteral exposure of animals to carbon tetrachloride has been reported to impair the immune system (Kaminski et al. 1989 Muro et al. 1990 Tajima et al. 1985), and oral exposure caused depletion of lymphocytes, hemorrhage, and hemosiderin deposition in the pancreaticoduodenal lymph node (Doi et al. 1991). These findings are supported by in vitro studies in which the IgM antibody formation response of isolated mouse splenocytes to sheep erythrocytes was inhibited in a dose-dependent manner when the splenocytes were exposed to carbon tetrachloride for 1-3 hours in the presence of cocultured hepatocytes (Kaminski and Stevens 1992). No effects were observed in the absence of cocultured hepatocytes. Mice appear to be more sensitive than rats to carbon tetrachloride-induced immunosuppression, but the biological significance to humans of these reported effects are yet ascertainable from the available data. 

A 66-year-old man took glipizide for 4 weeks and developed brownish, non-pruritic, purpuric, scaling patches on his upper legs and buttocks. Biopsy showed dilated capillaries with surrounding extravasated erythrocytes, perivascular lymphocytic infiltrates, and areas of hemosiderin deposition. After withdrawal of glipizide the rash cleared. 

Rat (Sprague-Dawley) once (GO) 25 M (reduced germinal centers and increased hemosiderin deposits in the spleen) Christian et al. 1986a... 

Reduction of germinal centers and increased hemosiderin deposits were seen histologically in the spleen of Sprague-Dawley rats after a single oral dose of 25 g/kg (Christian et al. 1986a). Mild anemia developed in rhesus monkeys after a single oral dose of 70 g/kg (McConnell et al. 1978a). No effects were found in minks exposed acutely to a lethal dose of 2,3,7,8-TCDD (7.5 g/kg) (Hochstein et al. 

A healthy 5-year-old girl, who had taken large doses of oral ferrous sulfate 300 mg five times a day (300 mg of elemental iron/day) for 5 years, developed severe hemosiderosis (29). Liver biopsy showed preserved lobular architecture, but the portal tracts were expanded by fibrosis and there was mild septal fibrosis. There was siderosis of the hepatic parenchymal cells and hemosiderin deposition in the Kupffer cells. She had no under-Ijdng hematological disease and her iron absorption was normal. HLA phenotypes and DNA analysis for the most common mutations associated with hemochromatosis excluded homozygous and heterozygous hereditary hemochromatosis. She was successfully treated by phlebotomy. Iron studies 10 years later were normal. 

The answer is b. (Murray, pp 627-661. Scriver, pp 3127-3164. Sack, pp 121-138. Wilson, pp 287-320.) Ferrous iron (Fe ) is the form absorbed in the intestine by ferritin, transported in plasma by transferrin, and stored in the liver in combination with ferritin or as hemosiderin. There is no known excretory pathway for iron, either in the ferric or ferrous form. For this reason, excessive iron uptake over a period of many years may cause hemochromatosis (235200), the likely diagnosis for this man. This is a condition of extensive hemosiderin deposition in the liver, myocardium, pancreas, and adrenals. The resulting symptoms include liver cirrhosis, congestive heart failure, diabetes mellitus, and changes in skin pigmentation. 

Adult male COBS CD (SD)BR rats given 885 mg/kg/day 2-butoxyethanol for 6 weeks showed increased relative, but not absolute, liver weight in all dose groups ( 222 mg/kg/day) (Eastman Kodak 1983 Krasavage 1986). Histological examination of livers revealed hemosiderin deposition in the liver at 443 mg/kg/day and hepatocytomegaly at 885 mg/kg/day. Statistically significant increases were found for serum alkaline phosphatase at 443 mg/kg/day and for serum alanine aminotransferase at 885 mg/kg/day. 

Note Hemorrhagic infarct leads to erythrocyte degradation and hemosiderin deposition. e. Clinical manifestations depend on affected artery... 

A decrease in erythrocyte 6-aminolevulinate dehydratase activity was observed in rats exposed to 200 but not 50 ppm tetrachloroethylene for 4 weeks (Soni et al. 1990). It is not clear if exposure was intermittent or continuous. Rats exposed to 230 or 470 ppm tetrachloroethylene for up to 160 days had splenic congestion and increased hemosiderin deposits (Carpenter 1937). Study limitations include the use of sick animals (parasites, pneumonia), nonstandard study protocols, rats of undefined strain, and inadequate controls. A transient increase in reticulocytes was observed in mice exposed to tetrachloroethylene at 135 and 270 ppm during the first few weeks of an 11.5-week study (Seidel et al. 1992). Microscopic examination of bone marrow revealed no effect on pluripotent stem cells and only a small reduction in erythroid committed cells. Because of a lack of statistical analysis, NOAELs and LOAELs were not clearly identified in the Seidel et al. (1992) study. 

As mentioned above, the majority of patients with cavernomas present with seizures as initial symptom (Moran et al. 1999). It is important to know that in the vast majority of patients these seizures are not related to acute bleeding events, but to hemosiderin deposition adjacent to neurons. Hemosiderin or ferritin is a well-known epileptogenic agent (at least in animal experiments). Being aware of the relation between seizures and hemosiderin deposition is of particular importance if surgical removal of the cavernoma is considered due to conservative untreatable seizures. It is of utmost importance not only to remove those parts of the cavernoma with... 

Fig.2.13a-d. Non-enhanced CT revealed a calcified lesion close to the foramen Monroi (a), T2 delineated a pop-corn like structure typical for a cavernoma (b). After contrast injection (c) an associated developmental venous anomaly was seen in close vicinity. Gradient echo at 1.5 T sequence clarifies the large extent of the hemosiderin deposition of the cavernoma (d)... 

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