At what transferrin saturation level is a patient considered at risk for iron overload?

Transferrin Saturation Threshold for Iron Overload Risk

A transferrin saturation ≥50% in men or ≥45% in women indicates risk for iron overload and mandates immediate HFE genetic testing for hereditary hemochromatosis. 1, 2

Evidence-Based Thresholds

The most authoritative guidelines establish clear sex-specific cutoffs:

• Men: Transferrin saturation >50% combined with ferritin >300 µg/L indicates biochemical iron overload 2
• Women: Transferrin saturation >45% combined with ferritin >200 µg/L indicates biochemical iron overload 2

The 45% threshold provides 84% sensitivity in men and 73% sensitivity in women for detecting C282Y homozygosity, making it the optimal screening cutoff despite some biological variability 2, 3

Why Transferrin Saturation Matters More Than Ferritin

Transferrin saturation is the primary screening test because it detects iron overload earlier than ferritin 1. Normal transferrin is not more than 50% saturated with iron; when saturation exceeds this physiologic limit, free iron becomes available and tissue deposition begins 1.

Ferritin alone cannot diagnose iron overload because it rises as an acute-phase reactant in inflammation, liver disease, malignancy, and tissue necrosis independent of actual iron stores 1, 2. In contrast, transferrin saturation ≥45% specifically indicates true iron overload requiring genetic evaluation 2.

Clinical Algorithm When Transferrin Saturation is Elevated

Step 1: Confirm the Pattern

• If TS ≥45% (women) or ≥50% (men): Suspect primary iron overload 2
• Measure ferritin simultaneously—the combination provides optimal diagnostic accuracy 1, 2
• **If TS <45% with elevated ferritin:** Iron overload is excluded with >90% certainty; evaluate secondary causes (alcohol, inflammation, NAFLD, malignancy) 1, 2

Step 2: Order HFE Genetic Testing

Immediately test for C282Y and H63D mutations when TS meets threshold 1, 2, 4. C282Y homozygosity confirms HFE-related hereditary hemochromatosis in 85-90% of clinically affected patients 4, 5.

Step 3: Assess for Organ Damage

Check these markers to stratify cirrhosis risk:

• Liver enzymes (ALT, AST) 1, 2, 5
• Platelet count 1, 2, 5
• The combination of ferritin >1,000 µg/L, elevated transaminases, and platelet count <200,000/µL predicts cirrhosis in 80% of C282Y homozygotes 1, 2, 4, 5

Liver biopsy is indicated when: ferritin >1,000 µg/L with elevated liver enzymes, hepatomegaly, age >40 years, or platelet count <200,000/µL 1, 2, 4, 5

Upper Safety Limit: When Does Overload Become Dangerous?

Transferrin saturation >80% is associated with transfusional hemosiderosis and documented organ damage 1. Patients with thalassemia who developed severe iron overload had TSAT levels >88% with ferritin >7,500 ng/mL and experienced liver cell damage 1.

There is no known risk associated with TSAT ≤50% 1. The guidelines explicitly state there is no physiologic rationale for maintaining TSAT >50%, but values between 20-50% are considered safe during iron therapy 1, 6.

Critical Pitfalls to Avoid

Never diagnose iron overload based on ferritin alone without confirming TS ≥45% 1, 2. Over 90% of elevated ferritin cases are caused by inflammation, chronic alcohol consumption, cell necrosis, tumors, or metabolic syndrome—not iron overload 1, 2.

Do not order HFE genetic testing when TS <45%, as this leads to false-positive diagnoses and unnecessary phlebotomy 2, 4. The threshold was specifically chosen to balance sensitivity and specificity 2.

Recognize that up to 33% of C282Y homozygotes may have a normal TS on a single measurement due to biological variability 3. If clinical suspicion is high (family history, suggestive symptoms), repeat testing is warranted 4, 3.

Special Context: Chronic Kidney Disease Exception

In CKD patients on erythropoiesis-stimulating agents, functional iron deficiency can occur despite elevated ferritin when TS <20% 1, 7. This represents iron sequestration by inflammation (hepcidin-mediated), not true overload 2, 7. These patients may benefit from IV iron therapy even with ferritin 100-700 ng/mL if TS remains <20% 1, 2, 7.

Bottom Line for Clinical Practice

Transferrin saturation ≥45% (women) or ≥50% (men) is the evidence-based threshold that signals iron overload risk and triggers the diagnostic cascade for hereditary hemochromatosis. 2 Values below these cutoffs exclude primary iron overload with >90% certainty when ferritin is also within normal limits 2. The upper safety limit is approximately 50%, with documented organ damage occurring at levels >80% 1.