Etiology

Hereditary Hemochromatosis

• HFE-Related
  • C282Y Homozygosity
  • C282Y/H63D Compound Heterozygosity
  • Other Mutations of HFE
• Non-HFE-Related
  • Juvenile Hemochromatosis
  • Autosomal Dominant Hemochromatosis (Solomon Islands)

Secondary Iron Overload

• Iron-Loading Anemias +/- Transfusion
  • Alpha/Beta Thalassemia Major (see Thalassemias, [[Thalassemias]]): ineffective erythropiesis -> increased iron absorption
    • Note: enhancement in iron absorption is much more pronounced with ineffective erythropoiesis (eg, thalassemia, MDS) than with increased effective erythropoiesis (eg, hereditary spherocytosis, sickle cell anemia)
  • Hereditary Sideroblastic Anemias: ineffective erythropiesis -> increased iron absorption
  • Myelodysplastic syndrome (MDS) variants such as refractory anemia with ringed sideroblasts (RARS) (see Myelodysplastic Syndrome, [[Myelodysplastic Syndrome]]): ineffective erythropiesis -> increased iron absorption
  • Chronic Hemolytic Anemias: xxx
• Dietary Iron Overload
• Parenteral Iron (Infusional) Overload
  • Frequent Parenteral Iron Infusion in Chronic Hemodialysis Patient (see Chronic Kidney Disease, [[Chronic Kidney Disease]])
  • Frequent Intravenous Hematin (Hemin) Use in Acute Porphyria (see Acute Porphyria, [[Acute Porphyria]])
    • Hematin molecule contains 8.56 percent iron by weight, a single 4 mg/kg dose delivers 24 mg of iron to a 70 kg person
• Transfusional Iron Overload: Each unit of transfused red cells introduces 200 to 250 mg of elemental iron into the body.
  • Sickle cell anemia
  • Refractory aplastic anemia
  • Myelodysplastic Syndrome (MDS) (see Myelodysplastic Syndrome, [[Myelodysplastic Syndrome]])
  • Leukemias
• Chronic Liver Disease
  • Hepatitis B
  • Hepatitis C
  • Alcoholic Liver Disease
  • Porphyria Cutanea Tarda
  • Non-Alcoholic Fatty Liver Disease (NAFLD) (see Non-Alcoholic Fatty Liver Disease, [[Non-Alcoholic Fatty Liver Disease]])

Other

• African Iron Overload: The iron overload in patients with African iron overload was initially thought to result from ingestion of enormous amounts of dietary iron in the form of a traditional beer fermented in steel drums [18]. This beer has an iron content of 80 mg/L and beer drinkers commonly consume several liters on weekends. Thus, iron intake in such subjects is markedly greater than the 10 to 20 mg per day in the normal Western diet. However, iron overload occurs in only a small number of these beer drinkers, suggesting that a genetic factor might be superimposed on an environmental factor.
• Neonatal/Perinatal Iron Overload
• Aceruloplasminemia
• Congenital Atransferinemia
• Insulin Resistance: association between otherwise unexplained hepatic iron overload and the insulin resistance syndrome has been described. It has been hypothesized that insulin may have a role in hepatic iron overload by stimulating cellular iron uptake through increased transferrin receptor externalization
  • Physiology: normal transferrin saturation

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EXTREMELY HIGH FERRITIN LEVELS — Extremely high ferritin levels (ie, >10,000 ng/mL) in the absence of genetic or transfusional iron overload may be found in a number of conditions, such as juvenile idiopathic arthritis, systemic lupus erythematosus, and hemophagocytic lymphohistiocytosis (HLH). It is important that HLH be considered in this context, as this condition can be fatal if not diagnosed and treated in an urgent manner. (See “Pathophysiology and diagnosis of iron overload syndromes”, section on ‘High levels of ferritin in the absence of iron overload’ and “Clinical features and diagnosis of hemophagocytic lymphohistiocytosis”, section on ‘Serum ferritin levels’.)

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## Physiology

In normal subjects there is no mechanism to regulate iron loss from the body, which averages about 1 mg/day in adult men from sweat, shed skin cells, and gastrointestinal losses. Premenopausal adult women lose an additional 0.5 to 1.0 mg/day because of menses. Therefore, to insure normal stores of iron within the body, iron absorption must be tightly regulated. A simple calculation will make this clear. If iron absorption is increased in an individual by as little as 1.5 mg/day above the amount needed to achieve homeostasis, this will result in the accumulation of 5.5 grams of iron every decade, 16 grams in 30 years and 33 grams in 60 years. This latter figure corresponds to the amount of iron (30 to 40 g) usually found in patients with clinically detected hereditary hemochromatosis (HH) and explains both the delayed time for the clinical appearance of this disease in men and its rarity in premenopausal women. (See “Regulation of iron balance”.)

As a result of the inability to increase iron loss, iron overload is an inevitable response to increased iron entry into the body. This can occur by one of three mechanisms (table 1):

●A massive increase in iron intake

●An increase in iron absorption when iron intake is normal

●The parenteral administration of iron, as with transfusional overload

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References

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