What are the recommendations for a patient with normal ferritin, high (Hyperferremia) serum iron, and normal Total Iron Binding Capacity (TIBC)?

Evaluation and Management of High Serum Iron with Normal Ferritin and TIBC

Calculate the transferrin saturation (TSAT) immediately, as this is the critical missing value that will guide your entire diagnostic and management approach. 1

Immediate Next Step: Calculate Transferrin Saturation

The transferrin saturation is calculated as: (serum iron ÷ TIBC) × 100 1

This single calculation determines whether you're dealing with potential hemochromatosis, a transient elevation, or another iron disorder.

Diagnostic Algorithm Based on TSAT Results

If TSAT >45%: Suspect Hemochromatosis

Proceed immediately to HFE genetic testing for hemochromatosis, as transferrin saturation >45% is the primary screening threshold regardless of ferritin level. 1

• The 2022 EASL guidelines specify that TSAT >45% warrants genetic evaluation even when ferritin appears normal 1
• Normal ferritin does NOT exclude hemochromatosis, particularly in early disease or in patients without significant iron accumulation yet 1
• Order HFE gene testing for C282Y and H63D mutations 1
• For patients of non-European ancestry, consider direct sequencing of a broader gene panel (HFE, HJV, TFR2, CP, SLC40A1) 1

Key clinical actions if TSAT >45%:

• Obtain complete blood count with reticulocytes to exclude hemolytic disorders 1
• Check liver transaminases (AST, ALT) 1
• Assess for hepatomegaly clinically 1
• If ferritin is <1,000 μg/L with normal transaminases and no hepatomegaly, the risk of advanced liver fibrosis is very low, but genetic testing remains indicated 1

If TSAT <45%: Consider Alternative Causes

With normal TSAT (<45%), high serum iron with normal ferritin and TIBC suggests a transient elevation or dysmetabolic hyperferritinemia rather than true iron overload. 2

Common causes to investigate:

• Timing of blood draw: Serum iron has significant diurnal variation (rises in morning, falls at night) and increases after meals 1
• Recent iron ingestion: Oral iron supplements or iron-rich meals can transiently elevate serum iron 1
• Acute phase reaction: While ferritin is normal, check inflammatory markers (CRP, ESR) as inflammation can affect iron parameters 1
• Liver disease: Check hepatic function panel, as liver disease can cause abnormal iron handling 2, 3
• Metabolic syndrome: Dysmetabolic hyperferritinemia can present with elevated iron indices without true iron overload 2

Critical Pitfalls to Avoid

Do not dismiss elevated serum iron simply because ferritin is normal. Early hemochromatosis can present with elevated TSAT before ferritin rises significantly 1, 2

Do not repeat iron studies on the same day or within 24 hours. The marked diurnal and day-to-day variation in serum iron makes serial same-day measurements unreliable 1

If repeating studies, obtain fasting morning samples to minimize variability from meals and diurnal fluctuation 1

When Genetic Testing is Positive for Hemochromatosis

If HFE C282Y homozygosity or compound heterozygosity is confirmed:

• Initiate therapeutic phlebotomy when ferritin rises above the normal range, even if currently normal 1
• Monitor ferritin every 3 months initially; increase frequency as levels approach normal range 1
• Target ferritin <50 μg/L during initial depletion phase 1
• Maintain ferritin at 50-100 μg/L with maintenance phlebotomy every 3-6 months 1
• Screen first-degree relatives with iron studies and genetic testing 1

Monitoring Strategy if No Hemochromatosis Found

Repeat fasting morning iron panel in 3-6 months to determine if elevation persists 1

• If persistently elevated with TSAT <45%, investigate for secondary causes (liver disease, metabolic syndrome, chronic inflammation) 2, 3
• If normalized on repeat testing, the initial elevation was likely transient and requires no specific intervention 1