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Diagnosis

Because the accumulation of iron is a gradual process that can occur over a number of decades, even in homozygous hemochromatosis, iron overload is often diagnosed late in the course of the disease after significant tissue injury has already taken place. Clinical symptoms develop insidiously, and organ damage develops slowly and variably, making early detection difficult. Asymptomatic testing is possible (e.g. by genotyping or blood testing) but is not a standard procedure in the absence of actual symptoms. Iron overload in patients with HH can be diagnosed in several ways:

• Diagnostic blood tests, including increased serum ferritin (>200 ng/mL) and elevated serum iron (>300 ng/mL). Elevated serum transferrin saturation (>50%) is a sensitive marker for excess iron; transferrin saturation of ≥60% for men and ≥50% for women on at least two occasions (without any other known cause for the elevation) is considered to be an indicator of hemochromatosis [18].
• Quantitative phlebotomy can be used to accurately assess the amount of free iron. A strict weekly schedule of phlebotomy is carried out and the serum ferritin levels monitored. When iron deficiency develops, the original iron quantity can be established based on the cumulative amount of iron removed. This is an accurate method used to confirm cases of suspected hemochromatosis.
• Magnetic resonance imaging may detect hepatic iron stores.
• Urinary iron excretion >2 mg/24 hours induced by deferoxamine (Desferal^®) can be used as a diagnostic test when the diagnosis is uncertain.
• Liver biopsy remains the reference standard method for determining iron overload.
• Presence of the C282Y gene can be determined by polymerase chain reaction genotyping analysis [19].

Treatment

Given that most patients with HH have unimpaired erythropoiesis, phlebotomy is the simplest method of removing excess iron in most of these patients. This method of treatment is effective in improving survival if the course of treatment is started before cirrhosis develops [20]. Phlebotomy can alleviate some liver symptoms and endocrine damage, however it cannot reverse liver fibrosis [21]. Weekly phlebotomies removing 450-500 mL of blood and, therefore, about 200-250 mg of iron, are performed until serum iron levels are normal (≤50 ng/mL) and transferrin saturation is ≤50%. When these tests are normal, further phlebotomies can be performed at longer intervals to maintain transferrin saturation at <10%. Among patients who do not have anemia, side effects of phlebotomy are uncommon, although fatigue may result. For patients who cannot (or choose not to) be phlebotomized, iron chelation therapy is an alternative.

One important aspect of treatment is dietary management. Foods containing large concentrations of bioavailable iron (e.g. red meat) should be avoided. Alcohol intake should be restricted as it can increase absorption of iron [22;23], in particular enhancing hepatic injury due to iron overload [24]. Vitamin C also increases the rate of intestinal iron absorption and hence should be limited to approximately 500 mg/day [25].

Secondary manifestations such as diabetes mellitus, cardiac abnormalities and impotency are treated as indicated.

HYPOTRANSFERRINEMIA

In hypotransferrinemia/atransferrinemia, impaired transferrin production (or production of abnormal transferrin) may lead to reduced transport of iron to the bone marrow and therefore impaired erythropoiesis. Iron, therefore, remains in storage sites such as the liver, leading to iron overload.

ACERULOPLASMINEMIA

In aceruloplasminemia, a deficiency in ceruloplasmin (also known as ferroxidase) prevents adequate oxidization of Fe²⁺ to Fe³⁺. As transferrin only binds iron in the ferric state, this inhibits the binding of iron by transferrin [26;27]. The movement of iron from intracellular stores into plasma is therefore impaired, which leads to secondary iron overload.

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References
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Learn how the distribution of iron differs in hereditary and transfusional iron overload.