Importance Of Iron
- Iron is an essential metal for hemoglobin synthesis of erythrocytes, oxidation– reduction reactions, and cellular proliferation
- Most iron is within red blood cells, the remainder is stored in ferritin, while only 1–2 mg of iron are absorbed in the intestinal tract and circulated in the blood
- Average daily dietary iron intake is 8-18 mg, daily iron derived from red blood cell turnover is 20mg
Issues With Excess Iron
- Toxicity of iron related to generation of reactive oxygen species (ROS) via the Fenton reaction è damage to liver, heart, brain, pancreas, pituitary
- The hydroxyl radical is the most toxic fraction and it targets carbohydrate, protein, and nucleic acids
- Excess iron also promotes atherosclerosis, carcinogenesis, and diabetes
- No mechanism to actively excrete iron, therefore regulating absorption is crucial
Hepcidin And Iron Homeostasis
- Hepcidin is a 25 amino acid peptide hormone that inhibits iron entry into the plasma compartment from the three main sources of iron: dietary absorption in the duodenum, the release of recycled iron from macrophages and the release of stored iron from hepatocytes
- When iron is deficient, hepatocytes produce less or no hepcidin, allowing more iron to enter plasma
Type 1 (i.e. classic)Hereditary Hemochromatosis
- A mutation in the HFE gene (regulates hepcidin transcription) causes increased absorption of iron despite a normal dietary iron The most common HFE variants are C282Y, H63D, and S65C. The detection of C282Y variation confirms the diagnosis of type 1 HH. Individuals with H63D and S65C variants, in the absence of C282Y, are not at risk of iron overload
- Common autosomal recessive disorder in white men, variable Approximately 28% of men and 1% of women develop HH which is influenced by other lifestyle factors (e.g. liver disease, alcohol intake, iron intake)
- Men are affected around 2-3 times as often as The estimated ratio between men and women is 1.8:1 to 3:1. Women with hemochromatosis become symptomatic later in life than men due to the blood loss and consequent iron excretion associated with menstruation.
- Excess iron is deposited in the cells as This eventually leads to cell death and replacement of these cells by a fibrous deposition that causes destruction or impairment of organ function.
HH Workup From JAMA Article
Summary
- Iron homeostasis is critical for adequate oxygen delivery and redox balance, however too much causes tissue/organ damage via reactive oxygen species (i.e. -OH)
- Disorders of iron overload are common and should be considered, if left untreated can lead to significant disease states later in life
- HFE mutations are not deterministic in terms of developing hemochromatosis, risk of iron overload can potentially be mitigated via lifestyle interventions
HFE: human homeostatic iron regulator protein Found in liver and intestinal cells
Regulates hepcidin transcription
Iron uptake is normally tightly controlled We only absorb 5-35% of our ingested iron
Low hepcidin: dysregulation of iron uptake/storage: ir overload
The most common HFE variants are C282Y, H63D, and S65C. The detection of C282Y variation confirms the diagnosis of type 1 HH. Individuals with H63D and S65C variants, in the absence of C282Y, are not at risk of iron overload
HFE C282Y
Incomplete penetrance of homozygous carriers 28% of men and 1% of women develop HH Influenced by other lifestyle factors (liver disease intake, iron intake)
Heterozygotes have increased risk when paired w More mild form of hereditary hemochromatosis Heterozygotes without H63D
Approx. population risk of iron overload
