What is the workup for elevated ferritin (iron) levels?

From the Guidelines

The workup of high ferritin should begin with the assessment of serum iron parameters, including transferrin saturation and serum ferritin, as recommended by the EASL clinical practice guidelines on haemochromatosis 1. The initial evaluation should include a thorough history and physical examination to identify potential causes of elevated ferritin levels, such as fatigue, joint pain, and liver disease.

• Key laboratory tests should include:
  • Serum iron parameters: transferrin saturation and serum ferritin
  • Liver function tests: to assess for liver damage or disease
  • Inflammatory markers: such as C-reactive protein to evaluate for underlying inflammatory conditions
• If transferrin saturation is elevated (>45%), genetic testing for hereditary hemochromatosis should be performed, specifically looking for HFE gene mutations, as recommended by the EASL guidelines 1.
• For patients with normal transferrin saturation, evaluation should focus on other causes of elevated ferritin, such as:
  • Inflammatory conditions
  • Liver disease
  • Malignancy
  • Metabolic syndrome
• Additional tests may include hepatitis serology, alcohol use assessment, hemoglobin A1c, and lipid panel, as these conditions can also contribute to elevated ferritin levels 1.
• In cases of significant hyperferritinemia (>1000 ng/mL) without obvious cause, consider rare conditions like hemophagocytic lymphohistiocytosis or Still's disease, and imaging studies such as liver ultrasound or MRI may be necessary to assess for iron overload or liver pathology. The importance of this systematic approach lies in distinguishing between true iron overload conditions requiring specific interventions like phlebotomy versus reactive hyperferritinemia where treating the underlying condition is paramount, as highlighted by the EASL guidelines 1.

From the FDA Drug Label

For patients with transfusional iron overload, measure serum ferritin monthly to assess for possible overchelation of iron. If the serum ferritin falls below 1000 mcg/L at 2 consecutive visits, consider dose reduction, especially if the deferasirox tablets dose is greater than 17.5 mg/kg/day. If the serum ferritin falls below 500 mcg/L, interrupt therapy with deferasirox tablets and continue monthly monitoring.

The workup of high ferritin involves monitoring serum ferritin levels monthly in patients with transfusional iron overload to assess for possible overchelation of iron.

• Dose reduction should be considered if serum ferritin falls below 1000 mcg/L at 2 consecutive visits, especially if the deferasirox tablets dose is greater than 17.5 mg/kg/day.
• Therapy interruption should be considered if serum ferritin falls below 500 mcg/L, with continued monthly monitoring 2.

From the Research

Workup of High Ferritin

The workup of high ferritin involves several steps to determine the underlying cause of elevated serum ferritin levels.

• The first step is to exclude hereditary hemochromatosis, a genetic disorder that can cause iron overload, by performing genetic testing for the HFE mutation 3.
• If hereditary hemochromatosis is excluded, the next step is to identify other potential causes of elevated serum ferritin, such as:
  • Alcohol consumption
  • Metabolic syndrome
  • Obesity
  • Diabetes
  • Liver disease
  • Malignancy
  • Infection or inflammation 3
• Laboratory tests, including serum ferritin and transferrin saturation, can help diagnose hereditary hemochromatosis and monitor iron overload 4.
• In some cases, referral to a specialist, such as a gastroenterologist, hematologist, or physician with an interest in iron overload, may be necessary to further evaluate and manage elevated serum ferritin levels 3.
• It is essential to note that elevated serum ferritin can be caused by various non-iron overload conditions, and venesection therapy may not be the treatment of choice in these cases 3.

Evaluation of Elevated Serum Ferritin

The evaluation of elevated serum ferritin involves a step-by-step approach to determine the underlying cause.

• The Australian Red Cross Blood Service Therapeutic Venesection program can provide guidance on the interpretation of iron studies and the role of venesection therapy 3.
• A serum ferritin level above 1000 µg/L or an unclear cause of elevated serum ferritin may require referral to a specialist for further evaluation and management 3.
• The diagnosis and management of hereditary hemochromatosis involve laboratory testing, genetic testing, and treatment with phlebotomy to remove excess iron stores 4.
• Studies have shown that deferasirox, an oral iron chelator, can be effective in reducing iron burden in patients with hereditary hemochromatosis 5, 6.