Iron Overload Ferritin Thresholds
Iron overload is indicated by ferritin levels above 250 μg/L in men and above 200 μg/L in women when accompanied by transferrin saturation ≥45% in women or ≥50% in men. 1
Sex-Specific Diagnostic Thresholds
The 2022 EASL guidelines establish clear biochemical criteria for iron overload that differ by sex 1:
- Women: Ferritin >200 μg/L AND transferrin saturation >45% 1
- Men: Ferritin >300 μg/L AND transferrin saturation >50% 1
Both criteria must be met simultaneously to indicate true iron overload. 1, 2 The upper limit of normal ferritin reference ranges are 250 μg/L for men and 200 μg/L for women, but these values alone do not confirm iron overload without elevated transferrin saturation. 1
Critical Diagnostic Algorithm
Step 1: Measure Transferrin Saturation Simultaneously
Never interpret ferritin in isolation. 1, 2 Ferritin is an acute-phase reactant that rises during inflammation, infection, liver disease, malignancy, and tissue necrosis independent of actual iron stores. 1, 2
- If transferrin saturation ≥45%: Suspect primary iron overload and proceed immediately to HFE genetic testing for C282Y and H63D mutations 1, 2
- **If transferrin saturation <45%**: Iron overload is excluded with >90% certainty; the elevated ferritin represents secondary causes (inflammation, liver disease, metabolic syndrome, alcohol, malignancy) 1, 2
Step 2: Confirm Genetic Diagnosis When Indicated
C282Y homozygosity or C282Y/H63D compound heterozygosity confirms HFE-related hereditary hemochromatosis when transferrin saturation is elevated. 1, 2 This genotype is present in >80% of patients with clinically overt hemochromatosis. 1
Risk Stratification by Ferritin Level
Even when iron overload is confirmed, ferritin level predicts organ damage risk 2:
| Ferritin Level | Clinical Significance | Action Required |
|---|---|---|
| <1,000 μg/L | Low risk of organ damage; 94% negative predictive value for advanced fibrosis [1,2] | Therapeutic phlebotomy can begin without liver biopsy if age <40 years and normal liver enzymes [1,2] |
| 1,000–10,000 μg/L | Higher risk of cirrhosis if iron overload present; in C282Y homozygotes with elevated ALT and platelets <200,000/μL, predicts cirrhosis in ~80% of cases [1,2] | Consider liver biopsy to assess fibrosis [1,2] |
| >10,000 μg/L | Rarely represents simple iron overload; suggests life-threatening conditions (hemophagocytic lymphohistiocytosis, severe inflammation, malignancy) [2,3] | Urgent specialist referral required [2] |
Common Clinical Pitfalls
Do not diagnose iron overload based on ferritin alone. 1, 2 Over 90% of elevated ferritin cases in the general population are caused by chronic alcohol consumption, inflammation, cell necrosis, tumors, and metabolic syndrome/NAFLD—not iron overload. 2
Do not order HFE genetic testing when transferrin saturation <45%. 1, 2 This leads to false-positive diagnoses and unnecessary phlebotomy. In a large screening study, only 2.1% of men and 3.6% of women with ferritin 200–1,000 μg/L were C282Y homozygotes. 4
Do not overlook liver biopsy in patients with ferritin >1,000 μg/L and abnormal liver tests. 1, 2 This combination warrants histologic assessment for cirrhosis, as ferritin >1,000 μg/L has 100% sensitivity but only 70% specificity for cirrhosis in hemochromatosis patients. 2
Context-Specific Interpretation
In Inflammatory Conditions
Ferritin rises acutely during inflammation while transferrin saturation often drops, creating a pattern of elevated ferritin with low transferrin saturation that does not indicate iron overload. 1, 2 In adult-onset Still's disease, ferritin can reach 4,000–30,000 ng/mL with glycosylated ferritin fraction <20%, but this reflects disease activity rather than iron stores. 2
In Liver Disease
In NAFLD or alcoholic liver disease with transferrin saturation <45%, elevated ferritin reflects hepatocellular injury and insulin resistance rather than iron overload. 2 Treatment should target the underlying liver disease, not the ferritin level itself. 2
In Chronic Kidney Disease
Functional iron deficiency can occur with ferritin 100–700 ng/mL and transferrin saturation <20% in patients on erythropoiesis-stimulating agents, where IV iron may still be beneficial despite elevated ferritin. 2 This represents sequestered iron unavailable for erythropoiesis, not true overload. 2