From the Guidelines
For isolated elevated ferritin with normal iron studies, CBC, and CMP, the initial workup should focus on identifying common causes beyond iron overload, starting with repeating the ferritin measurement to confirm the elevation, and then ordering additional tests including hemoglobin A1C, hepatitis panel, alcohol use assessment, and inflammatory markers (CRP, ESR) as recommended by recent guidelines 1. The approach to diagnosing the cause of elevated ferritin levels should consider the patient's symptoms, physical findings, and family history, as outlined in the 2011 practice guideline by the American Association for the Study of Liver Diseases 1. Key points to consider in the workup include:
- Repeating the ferritin measurement to confirm the elevation
- Ordering additional tests including hemoglobin A1C, hepatitis panel, alcohol use assessment, and inflammatory markers (CRP, ESR)
- Considering testing for hereditary hemochromatosis with genetic testing for HFE mutations, especially if ferritin is significantly elevated (>1000 ng/mL) or there's family history, as suggested by the EASL clinical practice guidelines for HFE hemochromatosis 1
- Ultrasound of the liver may be warranted to assess for fatty liver disease
- Remembering that ferritin is an acute phase reactant that increases with inflammation, infection, malignancy, and metabolic conditions like obesity, diabetes, and alcohol use - these are often more common causes than iron overload
- If initial workup is unrevealing and ferritin remains persistently elevated, considering referral to hematology or hepatology for further evaluation, and lifestyle modifications including weight loss, diabetes management, and alcohol reduction may help reduce ferritin levels in metabolic causes, as supported by the expert consensus guidelines on intravenous iron uses, formulations, administration, and management of reactions 1.
From the Research
Approach to Elevated Ferritin
- Elevated serum ferritin concentrations can be caused by various conditions, including iron overload, inflammation, and liver disease 2
- A diagnostic approach to hyperferritinemia should include patient history, transferrin saturation, serum concentrations of alanine and aspartate aminotransferases (ALT, AST), testing for HFE mutations, liver imaging, liver biopsy, and liver iron concentration 2
Hyperferritinemic Syndromes
- Hyperferritinemic syndromes, such as Adult-Onset Still's Disease (AOSD), macrophage activation syndrome, catastrophic antiphospholipid syndrome, and septic shock, can present with elevated ferritin levels and fever of unknown origin (FUO) 3
- These syndromes are potentially life-threatening and require early diagnosis and prompt treatment 3
Unexplained Isolated Hyperferritinemia
- Unexplained isolated hyperferritinemia without iron overload can be caused by mutations in the L-ferritin IRE or in A helix of L-ferritin gene, but some cases remain unsolved 4
- Subjects with unexplained isolated hyperferritinemia may have a previously undescribed form of hyperferritinemia possibly attributable to increased cellular ferritin secretion and/or decreased serum ferritin clearance 4
Markers of Acute Versus Chronic Medical Conditions
- Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are frequently requested investigations that aid in diagnosing and following complicated disease conditions 5
- Elevated ESR was seen more frequently in acute medical conditions as compared to CRP, but both CRP and ESR have positive association with acute as well as chronic medical conditions 5
Serum Ferritin/C-Reactive Protein Ratio
- The serum ferritin/C-reactive protein ratio is a simple and effective biomarker for diagnosing iron deficiency in the context of systemic inflammation 6
- A threshold of ≤6 demonstrated the highest Youden index for predicting iron deficiency, and this ratio could potentially replace the complex set of criteria currently recommended by learned societies 6