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

From the Guidelines

The workup for elevated 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, such as fatigue, joint pain, and liver disease.

• Key laboratory tests should include:
  • Complete blood count
  • Comprehensive metabolic panel
  • Iron studies (serum iron, total iron binding capacity, transferrin saturation)
  • Hemoglobin A1c
  • Lipid panel
  • Hepatitis serologies
• If transferrin saturation is elevated, genetic testing for hereditary hemochromatosis (HFE gene mutations) should be performed, as recommended by the EASL guidelines 1.
• For patients with normal transferrin saturation, consider inflammatory conditions, metabolic syndrome, liver disease, or alcohol use as potential causes, and additional testing may include C-reactive protein, erythrocyte sedimentation rate, and liver imaging if liver enzymes are abnormal.
• In cases where ferritin exceeds 1,000 ng/mL with unexplained elevation, consider liver biopsy to assess for iron overload, although this is not explicitly recommended by the EASL guidelines 1. Treatment depends on the underlying cause, with phlebotomy being the recommended treatment for hemochromatosis, aiming to maintain ferritin levels between 50-100 lg/L 1. Ferritin levels should be monitored regularly after initiating treatment to prevent complications such as liver cirrhosis, diabetes, and cardiac dysfunction from iron overload.

From the FDA Drug Label

Prior to starting therapy, or increasing dose, evaluate: Serum ferritin level Baseline renal function: Obtain serum creatinine in duplicate (due to variations in measurements) Calculate the estimated glomerular filtration rate (eGFR). Use a prediction equation appropriate for adult patients (e.g., CKD-EPI, MDRD method) and in pediatric patients (e.g., Schwartz equations). Obtain urinalyses and serum electrolytes to evaluate renal tubular function

The workup for elevated ferritin includes evaluating serum ferritin levels and baseline renal function, which consists of obtaining serum creatinine in duplicate, calculating the estimated glomerular filtration rate (eGFR), and evaluating renal tubular function through urinalyses and serum electrolytes 2.

Key components of the workup include:

• Serum ferritin level
• Baseline renal function
• Serum creatinine
• Estimated glomerular filtration rate (eGFR)
• Urinalyses
• Serum electrolytes

It is essential to note that the workup may vary depending on the individual patient's condition and the underlying cause of the elevated ferritin levels. However, the above-mentioned components are the primary focus as per the provided drug label information 2.

From the Research

Diagnostic Approach for Elevated Ferritin

• The discovery of hyperferritinemia is often fortuitous, revealed in results from a laboratory screening or follow-up test 3.
• The aim of the diagnostic procedure is to identify the cause of hyperferritinemia and to identify or rule out hepatic iron overload, in a three-stage process 3.
• In the first step, clinical findings and several simple laboratory tests are sufficient to detect four of the most frequent causes of high ferritin concentrations: alcoholism, inflammatory syndrome, cytolysis, and metabolic syndrome 3.

Common Causes of Hyperferritinemia

• Only 10% of cases are related to an iron overload, whilst the rest is seen as a result of acute phase reactions and reactive increases in ferritin due to underlying conditions 4.
• The most common form of haemochromatosis is due to homozygous mutations (specifically, the C282Y mutation) in HFE, which encodes hereditary haemochromatosis protein 5.
• Non-HFE forms of haemochromatosis due to mutations in HAMP, HJV or TFR2 are much rarer 5.

Diagnostic Tests

• Hepatic MRI to assess its iron concentration is the principal examination to guide diagnosis and treatment 3.
• Transferrin saturation is used to detect hepatic iron overload, with a high saturation (> 50%) indicating potential hereditary hemochromatosis 3.
• Serum ferritin concentration is used to monitor iron depletion and maintenance therapy in patients with hemochromatosis 6.

Treatment Options

• Phlebotomy is the mainstay therapy for haemochromatosis, although iron chelation can be used in some patients 5.
• Deferasirox has been shown to be effective in reducing iron burden in patients with hereditary hemochromatosis and could be a safe alternative to phlebotomy in selected patients 7.