Hemochromatosis is a disorder associated with deposits of an excess of iron that causes multiple organ dysfunctions. Normally, iron absorption is tightly regulated because the body is incapable of excreting excess iron. Hemochromatosis occurs when there are high pathologic levels of iron accumulation in the body. Hemochromatosis has been called “bronze diabetes” due to the discoloration of the skin and associated disease of the pancreas.
Retained iron is primarily deposited in the parenchymal cells in hereditary hemochromatosis, whereas with transfusional hemochromatosis it is primarily deposited in the reticuloendothelial cells. The excess iron is deposited in the cells as hemosiderin. This eventually leads to cell death and replacement of these cells by a fibrous deposition that causes destruction and/or impairment of organ function.
Organs affected by hemochromatosis include the liver, pancreas, heart, thyroid, joints, skin, gonads, and pituitary. Excessive alcohol intake and viral hepatitis accelerate the pathology associated with hemochromatosis, especially with respect to liver and pancreatic toxicity.
Iron overload of macrophages can cause impaired phagocytosis and lead to decreased immunity, resulting in increased risk of infection from Listeria, Yersinia enterocolitica, and Vibrio vulnificus. Patients with hemochromatosis should not handle or eat raw shellfish due to the increased risk of sepsis from Vibrio vulnificus.
The most common cause of hemochromatosis is an inherited autosomal recessive condition with variable penetrance. This condition is classified as primary hemochromatosis. Hereditary hemochromatosis occurs in homozygotes with a mutation of the HFE protein. A mutation in the HFE gene causes increased absorption of iron despite a normal dietary iron intake. The HFE protein regulates the production of hepcidin, the iron regulatory hormone. Hepcidin is produced by the liver, and it determines how much iron is absorbed from the diet and released from storage sites in the body. The normal function of HFE appears to be the control of iron uptake by cells through its interaction with transferrin receptor. Two mutations of the HFE gene are responsible for 90% of the cases of hereditary hemochromatosis in people of Northern European descent. Heterozygotes may have abnormalities in clinical markers of iron metabolism but do acquire iron overload. Heterozygotes do have an increased risk of diabetes over the general population due to unknown mechanisms.
Causes of secondary hemochromatosis include erythropoietic hemochromatosis, a condition that results from absorption of excess iron because the patient is producing excessive amounts of red blood cells. This often occurs as a result of an underlying disease of the red blood cells that causes them to be more fragile, and therefore, to have a shortened lifespan. When the cells are destroyed, the iron from them is deposited in the body tissues. The same mechanism is in effect in patients who receive multiple, usually chronic, transfusions of red blood cells. Other less common conditions, such as porphyria cutanea tarda, can also cause iron overload. Erythropoietic hemochromatosis follows the prevalence of the underlying disease (i.e., thalassemia, spherocytosis) and is found in a wider range of races than the hereditary form of the disorder.
Finally, excessive iron consumption also can cause hemochromatosis. Historically, this has resulted from drinking beer prepared in steel drums. Accidental and intentional overdoses of iron can result from the consumption of some over-the-counter dietary supplements.
Clinical signs of the condition depend on the organ system most affected. Patients usually are asymptomatic until adulthood, and often a diagnosis will not be made until multiple systems are affected. Symptoms are related to the organ affected, but almost all patients complain of severe fatigue. Patients are typically symptomatic for up to ten years before diagnosis. A high index of suspicion combined with a thorough family history is required to diagnose this condition. Women with hemochromatosis become symptomatic later in life than men due to the blood loss and consequent iron excretion associated with menstruation.
The investigation should start with the measurement of serum transferrin saturation or serum ferritin concentration. It should be noted that transferrin saturation testing in erythropoietic hemochromatosis may not be as effective to test for iron overload in these patients. The ferritin specificity can be affected by inflammatory conditions. If a ferritin level above 200 mcg/L in women or 300 mcg/L in men, or a transferrin saturation more than 40% in women or 50% in men should lead to further testing. In the United States, where the HFE mutation is prevalent, further genetic testing for the mutations C282Y and H63D should be obtained.
The conventional therapy for primary hemochromatosis is phlebotomy. By drawing off red blood cells, the major mobilizer of iron in the body, iron toxicity can be minimized. Patients may require 50 to 100 phlebotomies of 500 mL each to reduce iron levels to normal. Phlebotomy is usually performed once or twice a week. Once iron levels have normalized, lifelong, but less frequent, phlebotomy (typically 3-4 times a year) is required. The objective is to obtain a ferritin level of less than 50 mcg/L. Alcohol should be strictly prohibited with this condition because it can accelerate liver and pancreatic toxicity. Preexisting end-organ damage is rarely reversed by phlebotomy. Treatment for associated end-organ dysfunction, such as insulin for pancreatic dysfunction, is indicated. If hemochromatosis is detected early, treatment prevents end-organ dysfunction, and there is little mortality or morbidity associated with it. However, patients rarely live more than 2 years after the diagnosis if severe end-organ damage has occurred.
Although chelation is not as effective in hereditary hemochromatosis, it is of more benefit in erythropoietic hemochromatosis where phlebotomy is not typically an option. Deferoxamine is an intravenous iron-chelating agent. Deferiprone and deferasirox are oral iron chelators. They are all equivalent in efficacy in mobilization and excretion of iron.
Erythropoietin in combination with phlebotomy is sometimes employed to maintain the hemoglobin concentration while forcing iron mobilization.