Iron is an essential element, but in excess it can result in cell injury (Table 3.1). When storage mechanisms are overwhelmed, iron in low molecular weight forms can play a catalytic role in the initiation of free radical reactions. The resulting oxyradicals have the potential to damage cellular lipids, nucleic acids, proteins, and carbohydrates, resulting in wide-ranging impairment in cellular function and integrity. The rate of free radical production must overwhelm the cytoprotective defenses of cells before injury occurs.

In HFE hemochromatosis, there can be a pathologic expansion of body iron stores due to an increase in the absorption of dietary iron. Transferrin saturation is increased and non-transferrin-bound iron (which is redox-active) may be present. The excess iron is preferentially deposited in the cytoplasm of parenchymal cells of various organs and tissues including the liver, pancreas, heart, endocrine glands, skin, and joints. Damage can result in micronodular cirrhosis of the liver and atrophy of the pancreas (primarily islets). Hepatocellular carcinoma, usually in the presence of cirrhosis, is another consequence of excess iron deposition in the liver. Symptoms are related to damage of involved organs and include liver failure (from cirrhosis), diabetes mellitus, arthritis, cardiac dysfunction (arrhythmias and failure), and hypogonadotrophic hypogonadism. Important co-factors of iron-induced liver injury include chronic hepatitis C and excess alcohol consumption. Although cadmium and lead may also be transported by divalent metal transporter-1, the major apical iron transporter in enterocytes, excess iron is considered to be the major cause of toxicity in hemochromatosis.