What is the appropriate workup and management for a patient with elevated ferritin (iron storage protein) levels?

From the Guidelines

The workup for elevated ferritin begins with a thorough history and physical examination, followed by additional laboratory testing to determine the underlying cause, and management depends on the identified cause, with therapeutic phlebotomy being the mainstay of treatment for hereditary hemochromatosis, as recommended by the American Association for the Study of Liver Diseases 1. The initial tests should include complete blood count, liver function tests, iron studies (serum iron, total iron binding capacity, transferrin saturation), hemoglobin A1C, and renal function tests.

• If transferrin saturation is greater than 45%, genetic testing for hereditary hemochromatosis (HFE gene mutations) should be performed, as suggested by the European Association for the Study of the Liver 1.
• For hereditary hemochromatosis, therapeutic phlebotomy is the mainstay of treatment, typically removing 500mL of blood (approximately 200-250mg of iron) weekly until ferritin levels normalize (below 50-100 ng/mL), then maintenance phlebotomy every 2-4 months, as recommended by the American College of Physicians 1.
• For inflammation-related hyperferritinemia, treating the underlying condition is essential, and in metabolic syndrome or non-alcoholic fatty liver disease, lifestyle modifications including weight loss, exercise, and reducing alcohol consumption are recommended, as suggested by the American Association for the Study of Liver Diseases 1.
• For alcohol-related liver disease, complete alcohol cessation is crucial, and patients with severe iron overload may require iron chelation therapy with medications like deferasirox (starting at 20mg/kg/day orally) or deferoxamine (20-40mg/kg/day subcutaneously), as recommended by the American Association for the Study of Liver Diseases 1. Regular monitoring of ferritin levels every 3-6 months is important to assess treatment response, and elevated ferritin requires attention because chronic iron overload can lead to serious complications including liver cirrhosis, diabetes, cardiomyopathy, and arthropathy, as highlighted by the European Association for the Study of the Liver 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). 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 Serum transaminases and bilirubin Baseline auditory and ophthalmic examinations

The appropriate workup for a patient with elevated ferritin levels includes:

• Evaluating serum ferritin levels
• Assessing baseline renal function through serum creatinine, estimated glomerular filtration rate (eGFR), urinalyses, and serum electrolytes
• Checking serum transaminases and bilirubin
• Conducting baseline auditory and ophthalmic examinations The management of elevated ferritin levels involves using the minimum effective dose of deferasirox to achieve a trend of decreasing ferritin, with dose adjustments made based on serum ferritin trends, and monitoring for potential adverse effects such as renal and hepatic impairment, and auditory and ocular abnormalities 2.

From the Research

Elevated Ferritin Workup

Elevated ferritin levels can be caused by various conditions, including iron overload, inflammation, and malignancy. The appropriate workup and management for a patient with elevated ferritin levels involve a step-by-step approach to identify the underlying cause.

Possible Causes of Elevated Ferritin

• Iron overload syndromes, such as hemochromatosis 3, 4
• Inflammatory conditions, such as adult-onset Still's disease, systemic juvenile idiopathic arthritis, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome 3
• Malignancy, which is the most frequent condition associated with markedly elevated ferritin levels 3
• Anemia of chronic inflammation 3
• Liver diseases, such as hepatitis B or C, alcohol abuse, and non-alcoholic fatty liver disease 5
• Hemolytic anemia 5

Diagnostic Approach

• Measure serum ferritin levels and assess for iron overload using total iron binding capacity saturation (TS) 6
• Evaluate for inflammatory and malignant conditions using clinical data and laboratory tests 3, 7
• Consider genetic testing for hemochromatosis and other iron overload disorders 4, 5
• Use a practical algorithm to guide the diagnosis and management of hyperferritinemia 7, 5

Management

• Iron chelation therapy, such as deferasirox, may be effective in reducing ferritin levels in patients with iron overload syndromes 4
• Treatment of underlying inflammatory or malignant conditions may also help to reduce ferritin levels 3
• Phlebotomy or liver biopsy may be necessary to confirm iron overload and guide management 6