Management of Elevated Ferritin with Normal Iron Saturation
In a patient with ferritin 300 ng/mL and iron saturation 38% who is not on iron supplementation, the next step is to investigate for secondary causes of hyperferritinemia—specifically chronic alcohol consumption, inflammatory conditions, hepatocellular injury, metabolic syndrome, and malignancy—before considering iron overload disorders. 1, 2
Initial Diagnostic Approach
Assess for Common Causes of Hyperferritinemia
The iron saturation of 38% is below the threshold typically associated with iron overload (≥45-50%), making secondary hyperferritinemia more likely than primary iron overload. 1
Evaluate for the following conditions that account for >90% of hyperferritinemia cases: 2
- Chronic alcohol consumption - Obtain detailed alcohol history 2
- Inflammatory conditions - Check C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) 1, 2
- Hepatocellular injury - Measure AST, ALT, and consider checking creatine kinase (CK) for muscle injury 2
- Metabolic syndrome components - Assess blood pressure, BMI, waist circumference, fasting glucose, cholesterol, and triglycerides 1
- Malignancy - Consider age-appropriate cancer screening if clinically indicated 2
Key Distinction: Ferritin as an Acute Phase Reactant
Ferritin is an acute phase reactant that can be elevated in the absence of increased iron stores in patients with necroinflammatory liver disease (alcoholic liver disease, chronic hepatitis B and C, nonalcoholic fatty liver disease), lymphomas, and other chronic inflammatory conditions. 1 In the general population, iron overload is not the most common cause of elevated ferritin. 1
When to Consider Iron Overload
Transferrin Saturation Thresholds
Consider genetic hemochromatosis testing only if transferrin saturation is ≥45% (some guidelines use ≥50% for men). 1 Your patient's saturation of 38% does not meet this threshold, making hereditary hemochromatosis unlikely. 1
HFE Genetic Testing Indications
HFE testing for C282Y and H63D mutations should be performed only when both transferrin saturation is increased (≥45%) AND serum ferritin is elevated. 1 Since your patient has normal transferrin saturation, genetic testing is not indicated at this time. 1
Context-Specific Considerations
If Patient Has Chronic Kidney Disease
In CKD patients on dialysis, ferritin levels between 300-800 ng/mL have been common and there has been no evidence that such levels are associated with adverse iron-mediated effects. 1 However, your patient is not on iron supplementation, making this context less relevant unless CKD is present. 1
If Patient Has Heart Failure
In heart failure patients, when transferrin saturation is low (<20%) and ferritin is high (>300 ng/mL), anemia of inflammation is generally considered. 1 Your patient's saturation of 38% suggests adequate iron availability for erythropoiesis. 1
Recommended Diagnostic Workup
Order the following tests to identify the cause: 1, 2
- Complete metabolic panel (liver enzymes: AST, ALT)
- Inflammatory markers (CRP, ESR)
- Complete blood count to assess for anemia or cytosis
- Fasting glucose and lipid panel
- Hepatitis B and C serologies if liver disease suspected
- Consider abdominal imaging if hepatomegaly or other concerning features present
When Advanced Imaging Is Needed
MRI assessment of hepatic iron content should be considered if: 1, 3
- Ferritin continues to rise despite addressing secondary causes
- Ferritin exceeds 1000 μg/L with unclear etiology 1
- Clinical suspicion for iron overload persists despite normal transferrin saturation
- Multiple etiologies are identified and contribution of iron overload remains uncertain 2
Common Pitfalls to Avoid
Do not initiate phlebotomy or chelation therapy based solely on ferritin 300 ng/mL with normal transferrin saturation. 1 This level does not indicate iron overload requiring treatment, and the normal saturation argues against significant iron accumulation. 1
Do not order HFE genetic testing without elevated transferrin saturation (≥45%). 1 This wastes resources and may lead to unnecessary anxiety about a diagnosis that is highly unlikely with normal iron saturation. 1
Recognize that ferritin has wide variability when measured serially, making single measurements less reliable for clinical decision-making. 1 If monitoring is needed, repeat measurements should be obtained under similar conditions. 1
Special Population: Dysmetabolic Iron Overload Syndrome
If metabolic syndrome criteria are present with mild hepatic iron content increase on MRI, this represents dysmetabolic iron overload syndrome—the most common iron overload disease. 3 In this condition, bloodlettings are often poorly tolerated without clear benefit. 3 Management should focus on treating the underlying metabolic abnormalities rather than iron removal. 3