What is the appropriate workup for a patient with persistent hyperferritinemia?

From the Guidelines

The appropriate workup for persistent hyperferritinemia should begin with a thorough clinical history and physical examination, followed by targeted laboratory testing to determine the underlying cause, as recommended by the EASL clinical practice guidelines on haemochromatosis 1. The initial step in testing for haemochromatosis is the assessment of serum iron parameters, which should include transferrin saturation and serum ferritin 1. Key considerations in the workup include:

• Complete blood count
• Liver function tests
• Transferrin saturation
• Repeat ferritin level to confirm elevation If transferrin saturation is elevated (>45%), genetic testing for hereditary hemochromatosis (HFE gene mutations) is indicated 1. For patients with normal transferrin saturation, evaluate for inflammatory conditions, metabolic disorders, liver disease, and malignancy with tests such as C-reactive protein, erythrocyte sedimentation rate, hemoglobin A1c, and hepatitis serologies. Imaging studies like liver ultrasound or MRI may be necessary to assess for hepatic iron overload or steatosis. In cases where the diagnosis remains unclear after initial evaluation, consider specialized tests like liver biopsy to quantify iron stores or MRI-based liver iron concentration measurement. Treatment depends on the underlying cause, ranging from phlebotomy for iron overload conditions to addressing the primary disorder in secondary hyperferritinemia, with a target serum ferritin level of 50-100 lg/L during the maintenance phase 1. It is essential to monitor serum haemoglobin and ferritin levels during both induction and maintenance phases to avoid overtreatment and iron deficiency 1. Additionally, periodic checks of plasma folate and plasma cobalamin are advisable, especially in patients who require numerous venesections, with vitamin supplements administered if necessary 1.

From the FDA Drug Label

Deferasirox tablets therapy should only be considered when a patient has evidence of chronic transfusional iron overload. The evidence should include the transfusion of at least 100 mL/kg of packed red blood cells (e.g., at least 20 units of packed red blood cells for a 40 kg person or more in individuals weighing more than 40 kg), and a serum ferritin consistently greater than 1000 mcg/L 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 appropriate workup for a patient with persistent hyperferritinemia includes:

• Evaluating serum ferritin level
• Assessing baseline renal function by:
  • Obtaining serum creatinine in duplicate
  • Calculating estimated glomerular filtration rate (eGFR)
  • Obtaining urinalyses and serum electrolytes to evaluate renal tubular function This information is based on the dosing and administration guidelines for deferasirox tablets 2.

From the Research

Approach to Hyperferritinemia

The workup for a patient with persistent hyperferritinemia involves a comprehensive evaluation to determine the underlying cause of the elevated serum ferritin level.

• The initial step is to confirm the elevation of serum ferritin and rule out any laboratory errors 3.
• A thorough medical history and physical examination are essential to identify any potential causes of hyperferritinemia, such as infections, inflammatory diseases, or malignancies 4, 5.
• Laboratory tests, including complete blood count, liver function tests, renal function tests, and serum transferrin saturation, can help identify the underlying cause of hyperferritinemia 6.
• Imaging studies, such as ultrasound or MRI, may be necessary to evaluate the liver, spleen, or other organs for potential causes of hyperferritinemia 7.

Differential Diagnoses

The differential diagnoses for hyperferritinemia are broad and include:

• Iron overload disorders, such as hemochromatosis 4, 6
• Inflammatory diseases, such as rheumatoid arthritis or adult-onset Still's disease 5
• Infections, such as sepsis or abscesses 7
• Malignancies, such as hematological or solid tumors 4, 7
• Liver or renal disease, such as cirrhosis or nephrotic syndrome 4, 6
• Metabolic syndrome 6

Evaluation Strategy

The evaluation strategy for hyperferritinemia should be tailored to the individual patient's presentation and medical history.

• For patients with mild elevations in serum ferritin, a thorough medical history and physical examination, along with basic laboratory tests, may be sufficient to identify the underlying cause 3.
• For patients with more significant elevations in serum ferritin or those with concerning symptoms, such as fever or weight loss, a more comprehensive evaluation, including imaging studies and specialty consultations, may be necessary 5, 7.