From the Guidelines
Elevated ferritin levels with concurrent iron deficiency can be caused by several conditions that trigger inflammation in the body, including chronic inflammatory conditions, liver disease, malignancies, chronic kidney disease, obesity, and certain medications. This seemingly paradoxical situation occurs because ferritin is an acute phase reactant that increases during inflammatory states, even when actual iron stores are low.
Common Causes
- Chronic inflammatory conditions like rheumatoid arthritis, inflammatory bowel disease, and chronic infections, where inflammatory cytokines stimulate ferritin production independently of iron status 1
- Liver disease, particularly alcoholic liver disease and non-alcoholic fatty liver disease, can elevate ferritin due to hepatocyte damage releasing stored ferritin while impairing iron metabolism 1
- Malignancies, especially hematologic cancers, can raise ferritin through tumor-related inflammation 1
- Chronic kidney disease affects iron metabolism and increases ferritin while reducing iron availability 1
- Obesity creates a chronic inflammatory state that elevates ferritin while promoting hepcidin production, which blocks iron absorption 1
- Certain medications like non-steroidal anti-inflammatory drugs can cause both gastrointestinal blood loss (leading to iron deficiency) and inflammation (raising ferritin) 1
Diagnosis
This condition requires careful diagnosis with additional iron studies including transferrin saturation, total iron binding capacity, and serum iron to distinguish between true iron overload and inflammatory-driven ferritin elevation 1. In patients with chronic inflammation, ferritin levels may not accurately reflect iron stores, and other markers of inflammation such as C-reactive protein or measures of iron status such as total iron binding capacity should be considered 1.
From the Research
Causes of Elevated Ferritin and Low Iron
Elevated ferritin levels with concurrent iron deficiency can be caused by various factors, including:
- Inflammatory conditions such as adult-onset Still's disease, systemic juvenile idiopathic arthritis, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome 2
- Malignancy, which was found to be the most frequent condition associated with elevated ferritin levels in a study of 627 patients 2
- Iron-overload syndromes, which were the second most common condition associated with elevated ferritin levels in the same study 2
- Anemia of chronic inflammation, which can lead to elevated ferritin levels despite low iron availability 3
- Chronic inflammatory conditions such as inflammatory bowel disease (IBD), chronic heart failure (CHF), and chronic kidney disease (CKD), which can cause elevated ferritin levels due to inflammation 3, 4
Diagnostic Challenges
Diagnosing iron deficiency in patients with inflammatory conditions can be challenging due to the elevation of ferritin levels caused by inflammation 5, 3. In such cases, transferrin saturation (TSAT) can be used as a marker of iron availability to confirm iron deficiency 3. A serum ferritin threshold of <100 μg/L or TSAT < 20% can be considered diagnostic for iron deficiency in CHF, CKD, and IBD 3.
Correction for Inflammation
To remove the effects of subclinical inflammation on plasma ferritin concentrations, correction factors can be used 6. A study found that inflammation increased ferritin by approximately 30% and was associated with a 14% underestimation of iron deficiency 6. Measures of both acute-phase proteins (APP) and C-reactive protein (CRP) are needed to estimate the full effect of inflammation and can be used to correct ferritin concentrations 6.