ABSTRACT
Hemosiderin formation is a structural indication of iron overload. We investigated further adaptations of the liver to excess iron. Five patients with livers showing iron-rich inclusions larger than 2 µm were selected from our database. The clinical features of patients and structures of the inclusions were compared with those of 2 controls with mild iron overload. All patients had severe iron overload with more than 5000 ng/mL of serum ferritin. Etiologies were variable, from hemochromatosis to iatrogenic iron overload. Their histological stages were either portal fibrosis or cirrhosis. Inclusion bodies were ultra-structurally visualized as aggregated hemosiderins in the periportal macrophages. X-ray analysis always identified, in addition to a large amount of iron complexes including oxygen and phosphorus, a small amount of copper and sulfur in the mosaic matrixes of inclusions. There were no inclusions in the control livers. Inclusion bodies, when the liver is loaded with excess iron, may appear in the macrophages as isolated organella of aggregated hemosiderins. Trace amounts of copper-sulfur complexes were always identified in the mosaic matrices of the inclusions, suggesting cuproprotein induction against excess iron. In conclusion, inclusion formation in macrophages may be an adaptation of the liver loaded with excess iron.
Subject(s)
Hemochromatosis/diagnosis , Inclusion Bodies/chemistry , Iron Overload/diagnosis , Liver Cirrhosis/diagnosis , Liver/metabolism , Macrophages/chemistry , Adult , Aged , Case-Control Studies , Cation Transport Proteins/genetics , Cation Transport Proteins/metabolism , Copper/metabolism , Female , Gene Expression , Hemochromatosis/genetics , Hemochromatosis/metabolism , Hemochromatosis/pathology , Hemochromatosis Protein/genetics , Hemochromatosis Protein/metabolism , Hemosiderin/chemistry , Hemosiderin/metabolism , Humans , Inclusion Bodies/pathology , Inclusion Bodies/ultrastructure , Iron/metabolism , Iron Overload/genetics , Iron Overload/metabolism , Iron Overload/pathology , Liver/pathology , Liver/ultrastructure , Liver Cirrhosis/genetics , Liver Cirrhosis/metabolism , Liver Cirrhosis/pathology , Macrophages/pathology , Macrophages/ultrastructure , Male , Middle Aged , Mutation , Receptors, Transferrin/genetics , Receptors, Transferrin/metabolismABSTRACT
In biology, redox reactions are essential and sometimes harmful, and therefore, iron metabolism is tightly regulated by cuproproteins. Since the state of copper in iron overload syndromes remains unclear, we investigated whether copper metabolism is altered in these syndromes. Eleven patients with iron overload syndromes participated in this study. The clinical diagnoses were aceruloplasminemia (n=2), hemochromatosis (n=5), ferroportin disease (n=2), and receiving excess intravenous iron supplementation (n=2). Liver specimens were analyzed using a light microscope and transmission electron microscope equipped with an X-ray analyzer. In addition to a large amount of iron associated with oxygen and phosphorus, the iron-rich hemosiderins of hepatocytes and Kupffer cells contained small amounts of copper and sulfur, regardless of disease etiology. Two-dimensional imaging clearly showed that cuproproteins were distributed homogenously with iron complexes within hemosiderins. Copper stasis was unlikely in noncirrhotic patients. The enhanced induction of cuproproteins by excess iron may contribute to copper accumulation in hemosiderins. In conclusion, we have demonstrated that copper accumulates in hemosiderins in iron overload conditions, perhaps due to alterations in copper metabolism.
