What is the workup for elevated iron saturation, also known as Hyperferritinemia or Iron Overload?

From the Guidelines

Elevated iron saturation requires a comprehensive workup to identify the underlying cause, which is most commonly hereditary hemochromatosis, and should be managed according to the latest guidelines from the European Association for the Study of the Liver 1. To diagnose hereditary hemochromatosis, begin with confirmatory testing including serum ferritin, total iron binding capacity (TIBC), and transferrin saturation.

• If transferrin saturation exceeds 45% and ferritin is elevated in females (or 50% and ferritin >300 µg/L in males and post-menopausal women), genetic testing for HFE gene mutations should be ordered to diagnose hereditary hemochromatosis 1.
• Additional tests include complete blood count, liver function tests, and blood glucose to assess for end-organ damage.
• Consider liver imaging (ultrasound or MRI) if liver enzymes are abnormal. For confirmed hemochromatosis, treatment involves therapeutic phlebotomy, typically removing one unit of blood weekly until ferritin levels normalize (below 50-100 ng/mL), followed by maintenance phlebotomy every 2-4 months 1. Non-genetic causes of elevated iron saturation include alcoholic liver disease, viral hepatitis, and certain anemias, which require treating the underlying condition. Patients should be advised to avoid iron supplements, vitamin C with meals (enhances iron absorption), and excessive alcohol consumption. Family screening is recommended for first-degree relatives of patients with confirmed hereditary hemochromatosis to enable early intervention before organ damage occurs. It is essential to note that the management of hemochromatosis has evolved, and the latest guidelines should be followed, as outlined in the 2022 EASL clinical practice guidelines on haemochromatosis 1, which supersede previous recommendations 1.

From the Research

Elevated Iron Saturation Workup

• Elevated iron saturation can lead to tissue damage derived from free radical toxicity 2
• Phlebotomy is the treatment of choice for treating iron overload, but iron chelating therapy can be used if phlebotomies are impossible, mainly because of anemia 2, 3
• Iron chelating therapy can be considered if serum ferritin is above 1000μg/L and if liver iron concentration assessing by MRI exceeds 80μmol/g 2
• MRI is a very important mean to monitor cardiac iron load, and if the relaxing parameter T2* is lower than 20ms, a cardiac effective iron chelator agent or an association with deferoxamine should be used 2

Iron Chelation Therapy

• Deferoxamine is the gold standard of iron chelation, but parenteral administration and the burden of a daily infusion pump hinder optimal compliance 2, 3
• Deferiprone is orally active but should be administered three times a day, and it has the advantage of removing toxic iron from myocardium, but agranulocytosis (1 %) can limit its use 2, 3
• Deferasirox is orally active in a single daily dose, is well tolerated but its cardiac effect is limited 2, 3
• Combined subcutaneous (deferoxamine) and oral (deferiprone) treatment seems to hold particular promise 3

Diagnosis and Treatment of Iron Overload

• Iron overload has many different causes, both genetic and environmental, and the two most common iron overload disorders are hereditary haemochromatosis and transfusional siderosis 3
• The two most important treatment options for iron overload are phlebotomy and chelation, and phlebotomy is the initial treatment of choice in haemochromatosis, while chelation is a mainstay in the treatment of transfusional siderosis 3
• Hydroxyurea, when combined with iron chelators such as deferasirox, provides an additional benefit of iron chelation in patients receiving chronic transfusion therapy 4

Identification of Iron Deficiency States

• According to current guidelines, iron deficiency is defined by a serum ferritin level <100 ng/ml or a transferrin saturation (TSAT) <20% if the serum ferritin level is 100-299 μg/L, but these criteria are not supported by any pathophysiological or clinical evidence in patients with heart failure 5
• A low baseline TSAT-but not serum ferritin level-appears to be a reliable indicator of the effect of intravenous iron to reduce major heart failure events 5
• An iron deficiency state in patients with heart failure should be defined by a TSAT <20% (as long as the serum ferritin level is <400 μg/L), and the use of a serum ferritin level <100 μg/L alone as a diagnostic criterion should be discarded 5