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Secondary Iron Overload

(Secondary Hemochromatosis)


James Peter Adam Hamilton

, MD, Johns Hopkins University School of Medicine

Last full review/revision Sep 2020| Content last modified Sep 2020
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Secondary iron overload results from excess absorption of iron, repeated blood transfusions, or excess oral intake, typically in patients with disorders of erythropoiesis. Consequences can include systemic symptoms, liver disorders, cardiomyopathy, diabetes, erectile dysfunction, and arthropathy. Diagnosis is by elevated serum ferritin, iron, and transferrin saturation levels. Treatment is usually by iron chelation.


Secondary iron overload typically occurs in patients who have

Iron overload results from the following mechanisms:

  • Increased iron absorption

  • Exogenous iron given to treat anemia

  • Repeated blood transfusions (each unit of blood provides about 250 mg of iron; tissue deposition becomes significant when more than about 40 units of blood are transfused)

Increased iron absorption in patients with ineffective erythropoiesis may be partly due to the secretion, by erythroid precursors, of erythroferrone (ERFE), which suppresses hepcidin (an inhibitor of iron absorption).

Patients with hemoglobinopathies and congenital hemolytic anemias now typically live into adulthood, so complications of iron overload are now common and clinically important. In such patients, iron overload involving the heart, the liver, and endocrine organs has become a common cause of death, but survival can be prolonged by iron removal.

Symptoms and Signs

The clinical consequences of iron overload are the same regardless of the etiology and pathophysiology of the overload.

Historically, experts believed that symptoms did not develop until significant organ damage had occurred. However, organ damage is slow and subtle, and fatigue and nonspecific systemic symptoms often occur early.

Glucose intolerance or diabetes mellitus is another common initial manifestation. Some patients present with hypothyroidism. In men, the initial symptoms may be hypogonadism and erectile dysfunction caused by gonadal iron deposition.

Liver disease is the most common complication and may progress to cirrhosis. Patients who develop cirrhosis are at increased risk of hepatocellular carcinoma. The liver disease can present insidiously with nonspecific symptoms and signs, such as fatigue, and with right upper quadrant abdominal pain and hepatomegaly. Laboratory abnormalities of iron overload and hepatitis typically will be present well before clinical symptoms develop. Liver disease is the most common cause of death. Cardiomyopathy with heart failure is the 2nd most common fatal complication. Hyperpigmentation (bronze diabetes) and porphyria cutanea tarda are common, as is symptomatic arthropathy.


  • Measure serum ferritin, iron, and transferrin saturation

Patients with ineffective erythropoiesis should be evaluated for secondary iron overload, which is diagnosed by measuring serum ferritin, serum iron, and transferrin saturation. Serum ferritin measurement is the simplest and most direct initial test. Elevated levels (> 200 ng/mL [> 200 mcg/L] in women or > 250 ng/mL [> 250 mcg/L] in men) are usually present in secondary iron overload but can result from other abnormalities, such as hereditary hemochromatosis, inflammatory liver disorders (eg, chronic viral hepatitis, nonalcoholic fatty liver disease, alcoholic liver disease), cancer, certain systemic inflammatory disorders (eg, rheumatoid arthritis, hemophagocytic lymphohistiocytosis), or obesity.

Further testing is done if ferritin level is abnormal; testing includes fasting serum iron (usually > 300 mg/dL [> 53.7 millimole/L]) and iron binding capacity (transferrin saturation; levels usually > 50%). Hereditary hemochromatosis should be ruled out by history and genetic testing. A transferrin saturation < 45% has a negative predictive value of 97% for iron overload.

Lab Tests for Secondary Iron Overload


  • Usually iron chelation with deferasirox or deferoxamine, or sometimes deferiprone

Some patients can be treated with phlebotomy and given erythropoietin to maintain erythropoiesis. However, because it worsens anemia, phlebotomy is not recommended for many patients (eg, those with hemoglobin level < 10 g/dL [< 100 g/L], those who are transfusion dependent, and those who develop symptoms of anemia after phlebotomy). Treatment in these patients is iron chelation. The goal of treatment is a transferrin saturation of < 50%.

Deferoxamine is the drug traditionally used for iron chelation therapy. It is given by a slow subcutaneous infusion overnight through a portable pump for 5 to 7 nights/week or via 24-hour IV infusion. Dose is 1 to 2 g in adults and 20 to 40 mg/kg in children. However, this therapy is complex to administer and requires an unusual time commitment from patients, resulting in a high rate of nonadherence. Important adverse effects include hypotension, gastrointestinal disturbances, and anaphylaxis (acutely) and vision and hearing loss (with chronic use).

Deferasirox, an oral chelating agent, is an effective and increasingly used alternative to deferoxamine. Deferasirox reduces iron levels and prevents or delays onset of complications of iron overload. Initial dose is 20 mg/kg po once/day. Patients are monitored monthly with dose increases of up to 30 mg/kg once a day. Treatment can be interrupted when serum ferritin is < 500 ng/mL (< 500 mcg/L). Adverse effects (which occur in about 10% of patients) can include nausea, abdominal pain, diarrhea, and rash. Liver and kidney function may become abnormal; liver and kidney blood tests should be done periodically (eg, monthly, sometimes more frequently for high-risk patients).

Deferiprone, another oral iron chelator, is indicated for the treatment of patients with transfusional iron overload due to thalassemia syndromes when chelation therapy with deferasirox or deferoxamine is inadequate. Deferiprone can also be used in combination with deferasirox because they have different mechanisms of action.. Initial dosing is 25 mg/kg orally 3 times a day. The maximum dose is 33 mg/kg orally 3 times a day. Absolute neutrophil counts are obtained weekly to look for neutropenia (precedes agranulocytosis). Serum ferritin is measured every 2 to 3 months; treatment is temporarily interrupted when levels are consistently < 500 ng/mL (< 500 mcg/L).

Diabetes mellitus, cardiomyopathy, erectile dysfunction, and other secondary manifestations are treated as indicated. Patients with advanced fibrosis or cirrhosis due to iron overload should be screened for hepatocellular carcinoma every 6 months with a liver ultrasound.

Patients should follow a balanced diet; it is not necessary to restrict consumption of iron-containing foods (eg, red meat, liver). Alcohol should be consumed only in moderation because it can increase iron absorption and, in high amounts, increases the risk of cirrhosis. Vitamin C supplements should be avoided.

Key Points

  • Secondary iron overload results from excess absorption of iron, repeated blood transfusions, or excess oral intake.

  • The effects of secondary iron overload include liver disease (leading to cirrhosis), skin pigmentation, diabetes, arthropathy, erectile dysfunction, and sometimes heart failure.

  • Diagnose by measuring serum ferritin level; if elevated, confirm by demonstrating elevated serum iron and transferrin saturation.

  • Treat with chelation.

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