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
  • Hepatitis serologies
• If transferrin saturation is elevated, genetic testing for hereditary hemochromatosis (HFE gene mutations) should be considered, as recommended by the EASL guidelines 1.
• For patients with normal transferrin saturation, consider inflammatory conditions such as alcoholic liver disease, non-alcoholic fatty liver disease, chronic infections, autoimmune disorders, or malignancies.
• Additional testing may include liver function tests, inflammatory markers (CRP, ESR), and imaging studies of the liver.
• In cases where the cause remains unclear, consider less common conditions like ferroportin disease or aceruloplasminemia. The management of elevated ferritin depends on the underlying cause, ranging from phlebotomy for hemochromatosis to treating the primary condition for secondary causes, as outlined in the American Association for the Study of Liver Diseases practice guideline 1.
• Phlebotomy is recommended for patients with hemochromatosis and iron overload, with a target ferritin level of 50-100 lg/L 1.

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). Obtain urinalyses and serum electrolytes to evaluate renal tubular function Serum transaminases and bilirubin Baseline auditory and ophthalmic examinations

The workup for elevated ferritin includes evaluating serum ferritin level, baseline renal function (including serum creatinine, estimated glomerular filtration rate, urinalyses, and serum electrolytes), serum transaminases and bilirubin, and baseline auditory and ophthalmic examinations 2.

From the Research

Causes of Elevated Ferritin

• The most frequent cause of hyperferritinemia was non-human immunodeficiency virus infection, followed by solid tumor, liver dysfunction, renal failure, and hematological malignancy 3
• Sepsis or septic shock, liver disease (except hepatitis), and hematological malignancy are important differential diagnoses in hyperferritinemic adult critically ill patients without hemophagocytic lymphohistiocytosis (HLH) 4
• Hyperferritinemia can also be caused by acute phase reactions and reactive increases in ferritin due to underlying conditions, with only 10% of cases related to an iron overload 5

Diagnostic Workup

• The diagnostic procedure for hyperferritinemia involves a three-stage process:
  1. Clinical findings and simple laboratory tests to detect frequent causes such as alcoholism, inflammatory syndrome, cytolysis, and metabolic syndrome 6
  2. Investigation of rarer diseases, including chronic hematologic diseases and excessive iron intake or infusions 6
  3. Verification of hepatic iron concentration using hepatic MRI to rule out overload, especially if the ferritin concentration is very high or continues to rise 6

Management

• Differentiation of the presence or absence of an associated iron overload upon hyperferritinemia is essential, although often proves to be complex 5
• An algorithm for the diagnostic workup and management of hyperferritinemia is proposed, including general principles regarding the treatment of iron overload 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