What is the management for a patient with hyperferritinemia, normal serum iron, and low transferrin saturation?

Management of Hyperferritinemia with Normal Iron and Low Transferrin Saturation

This presentation of elevated ferritin (525 ng/mL) with low transferrin saturation (28%) and normal serum iron (33 µg/dL) indicates inflammation or metabolic dysfunction rather than true iron overload, and iron supplementation is contraindicated while the underlying cause must be identified. 1

Immediate Assessment Required

Do not treat with iron supplementation or phlebotomy at this time. 1 The dissociation between high ferritin and low TSAT is the key diagnostic feature distinguishing this from hereditary hemochromatosis or true iron overload states. 2

Critical Diagnostic Steps

• Check inflammatory markers immediately - obtain CRP, ESR, and liver function tests, as ferritin is an acute-phase reactant and this pattern strongly suggests inflammation, infection, malignancy, or metabolic syndrome rather than iron overload. 1

• Assess for metabolic syndrome - evaluate for obesity, diabetes, hypertension, and fatty liver disease, as dysmetabolic hyperferritinemia commonly presents with this exact pattern (elevated ferritin, normal-to-low TSAT). 2

• Screen for alcohol use - obtain detailed alcohol history and consider GGT, AST/ALT ratio, as alcoholic liver disease disrupts iron metabolism causing severely elevated ferritin with variable TSAT, mimicking iron overload disorders. 3

• Rule out chronic kidney disease - check creatinine and eGFR, as CKD patients commonly show this pattern and have specific iron management considerations. 4

Why This is NOT Iron Overload

**Transferrin saturation <45% effectively excludes hereditary hemochromatosis and primary iron overload disorders.** 1 The EASL guidelines specify that elevated TSAT (>45%) is the hallmark of hemochromatosis, not ferritin alone. 1

• Low TSAT (28%) indicates functional iron deficiency or inflammation - not iron excess, as true iron overload states present with TSAT >45% along with elevated ferritin. 1, 5

• Ferritin 525 ng/mL alone does not indicate tissue iron accumulation - ferritin rises with inflammation independent of body iron stores, and all common iron status markers are influenced by inflammation. 1

• MRI quantification would show normal hepatic iron concentration - studies demonstrate that hyperferritinemic subjects without elevated TSAT and without HFE mutations have normal hepatic iron content (36-39 µmol/g vs. 123 µmol/g in true hemochromatosis). 5

Management Algorithm

Step 1: Identify the Underlying Cause

• If inflammatory markers elevated - treat the underlying inflammatory condition (infection, autoimmune disease, malignancy) and recheck ferritin after inflammation resolves. 1

• If metabolic syndrome present - recommend weight loss through dietary modification and increased physical activity, as this is the primary treatment for dysmetabolic hyperferritinemia. 1, 2

• If alcohol-related - counsel on alcohol cessation and manage alcoholic hepatitis appropriately; ferritin will normalize with abstinence without need for phlebotomy. 3

• If CKD-related - do NOT give IV iron when ferritin >500 ng/mL per National Kidney Foundation guidelines, even if TSAT is low, due to insufficient safety evidence. 6

Step 2: What NOT to Do

Iron supplementation is contraindicated and potentially harmful when ferritin is normal or elevated, regardless of TSAT. 1 The ESPEN guidelines explicitly state that iron supplementation with normal or high ferritin values is not recommended. 1

• Do not perform therapeutic phlebotomy - this is reserved for confirmed iron overload with TSAT >45% and appropriate genetic testing or secondary causes. 1

• Do not order HFE genetic testing - the low TSAT makes hereditary hemochromatosis extremely unlikely, and testing would not change management. 1, 5

• Avoid vitamin C supplementation - this accelerates iron mobilization and should be avoided during any evaluation of iron disorders. 6

Step 3: Monitoring

• Recheck iron panel in 8-10 weeks after addressing underlying cause - not earlier, as ferritin levels remain falsely elevated for weeks after inflammatory resolution. 1

• Monitor for development of anemia - the low TSAT suggests potential for functional iron deficiency if inflammation persists, though iron supplementation remains contraindicated with ferritin >500 ng/mL. 1, 6

Common Pitfalls to Avoid

The most critical error is treating elevated ferritin as iron overload without considering TSAT. 2 This pattern (high ferritin, low TSAT) represents the opposite problem - inflammation with functional iron restriction, not iron excess. 1, 4

• Do not rely on ferritin alone - it is insufficient to diagnose iron overload and must be interpreted with TSAT, as ferritin >800 ng/mL with TSAT <20% is increasingly common in inflammatory states. 4

• Recognize that both markers are affected by inflammation - serum iron, hemoglobin, MCV, transferrin, TSAT, TIBC, hepcidin, and ferritin are all influenced by inflammation, making interpretation challenging. 1

• Consider hepcidin measurement if available - in critically ill or inflammatory states, hepcidin is a more reliable indicator of true iron deficiency than TSAT when ferritin is elevated. 1