Secondary Iron Overload

How to Cite This Chapter: Agarwal A, Verhovsek M, Mach T. Secondary Iron Overload. McMaster Textbook of Internal Medicine. Kraków: Medycyna Praktyczna. Accessed April 23, 2024.
Last Updated: September 5, 2022
Last Reviewed: September 5, 2022
Chapter Information

Definition, Etiology, PathogenesisTop

Secondary iron overload encompasses the following etiologies:

1) Ineffective erythropoiesis states affecting iron absorption or distribution, including thalassemias, sickle cell disease, sideroblastic anemias, chronic hemolytic anemia, pyruvate kinase deficiency, dehydrated hereditary stomatocytosis.

2) Iron overload secondary to excessive intake, including chronic or frequent red blood cell (RBC) transfusions and inappropriate iron therapy (oral or IV).

3) Miscellaneous causes: Porphyria cutanea tarda, aceruloplasminemia, congenital atransferrinemia.

Clinical Features and Natural HistoryTop

Clinical features are similar to primary hemochromatosis.

Natural history is specific to the etiology of secondary iron overload and will not be explored in detail in this chapter.


As in primary hemochromatosis, serum ferritin is a useful screening test for iron overload. Magnetic resonance imaging (MRI) or liver biopsy (or both) may be useful in specific situations.

1. Blood tests: Complete blood count (CBC) as well as liver enzyme and iron studies should be conducted. A general cutoff point of ferritin level >1000 microg/L can be applied for most cases of secondary iron overload, although it is increasingly recognized that in non–transfusion-dependent thalassemias (NTDTs) (eg, beta thalassemia intermedia and hemoglobin H disease) and other inherited hemolytic anemias iron overload can be present at ferritin levels ≥300 microg/L in men and >200 microg/L in women. Transferrin saturation is useful in confirming the presence of iron overload.

2. MRI: Specialized MRI imaging provides noninvasive quantification of hepatic iron overload in individuals with clearly documented iron overload or in cases with diagnostic uncertainty, where clear establishment or exclusion of increased iron deposition into peripheral tissues may be valuable. Selected patients may also require specialized MRI-based iron quantification in other organs (eg, heart, pancreas, pituitary).

3. Liver biopsy: Quantification of hepatic iron concentration and histopathologic iron staining based on biopsy may be used to evaluate peripheral tissue iron stores and evidence of fibrosis. Biopsies are typically reserved for cases where histologic examination and clear iron deposition quantification may change management, or where clarity regarding the underlying etiology of end-organ sequelae may be obtained. Noninvasive MRI may be used preferentially to biopsy, when available, given procedural risks and potential for inaccurate estimation of the total hepatic iron content when hepatic iron distribution is patchy.


Treatment should be focused on the underlying condition whenever possible.

Phlebotomy is useful for certain types of secondary iron overload. It is clearly indicated in porphyria cutanea tarda (reduction in skin manifestations), and small volume phlebotomy (“miniphlebotomy”) can often be safely and successfully used in patients with NTDTs with normal or near-normal baseline hemoglobin levels.

In patients who are ineligible for phlebotomy, including all who are transfusion-dependent, pharmacologic iron chelation strategies are used. Deferoxamine is a parenteral therapy that can be administered via a continuous subcutaneous or IV infusion 8 to 24 hours per day at a total daily dose of 20 to 60 mg/kg/d. Options of oral iron chelation include deferasirox (dispersible tablets 10 to 40 mg/kg/d; film-coated tablets or granules 14-28 mg/kg/d) or deferiprone 75 to 100 mg/kg/d (total daily dose divided into tid dosing). Selection of iron chelation regimens depends on coexisting comorbidities, medication availability, and patient preference for administration route and frequency, as well as organs affected by iron overload and severity of iron loading. In our experience, iron chelation is typically managed by specialized medical teams. Possible retinal or auditory toxicity (deferoxamine), agranulocytosis (deferiprone), and liver or renal toxicity (deferasirox) should be considered when initiating therapy.


Patients with iron overload require ferritin monitoring at regular intervals (eg, every 1-4 months). Selected patients, as outlined (see Diagnosis, above), also benefit from MRI monitoring of hepatic iron concentrations. Specialized liver MRI will often be completed annually to monitor therapeutic effects.


Previously, when the availability of iron chelation agents was limited, complications of organ iron overload were one of the main causes of early mortality in patients with transfusion-dependent thalassemia. With the advent and growing availability of a variety of iron chelation drugs, it is expected that patients with these conditions will now have dramatically improved life expectancies.

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