Pathophysiology of iron toxicity.
There are several inherited and acquired disorders that can result in chronic iron overload in humans, and the major clinical consequences are hepatic fibrosis, cirrhosis, hepatocellular cancer, cardiac disease, and diabetes. It is clear that lipid peroxidation occurs in experimental iron overload if sufficiently high levels of iron within hepatocytes are achieved. Lipid peroxidation is associated with hepatic mitochondrial and microsomal dysfunction in experimental iron overload, and lipid peroxidation may underlie the increased lysosomal fragility that has been detected in liver samples from both iron-loaded human subjects and experimental animals. Reduced cellular ATP levels, impaired cellular calcium homeostasis, and damage to DNA may all contribute to hepatocellular injury in iron overload. Long-term dietary iron overload in rats can lead to increased collagen gene expression and hepatic fibrosis, perhaps due to activation of hepatic lipocytes. The mechanisms whereby lipocytes are activated in iron overload remain to be elucidated; possible mediators include aldehydic products of iron-induced lipid peroxidation produced in hepatocytes, tissue ferritin, and/or cytokines released by activated Kupffer cells.
Britton
R S
RS
Department of Internal Medicine, St. Louis University Health Sciences Center, Missouri 63110.
Ramm
G A
GA
Olynyk
J
J
Singh
R
R
O'Neill
R
R
Bacon
B R
BR
D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D006432:Hemochromatosis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D007501:Iron / Q000633:toxicity*; D007728:Kupffer Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000473:pathology; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D016207:Cytokines; D007501:Iron