What does an isolated elevation of total serum iron with normal ferritin and normal transferrin (total iron‑binding capacity) indicate?

Isolated Elevation of Total Serum Iron with Normal Ferritin and Transferrin

An isolated elevation of serum iron with normal ferritin and normal transferrin (TIBC) most commonly reflects transient physiological variation—particularly recent dietary iron intake, diurnal fluctuation, or acute cellular release—rather than true iron overload or a clinically significant iron disorder. 1

Understanding the Laboratory Pattern

Serum iron is highly variable and should never be interpreted in isolation. 1 The concentration of serum iron increases after each meal, exhibits marked diurnal variation (rising in the morning and falling at night), and shows greater day-to-day variation within individuals than hemoglobin or hematocrit. 1 This inherent instability makes a single elevated serum iron measurement unreliable for diagnosing iron disorders.

Why This Pattern Does NOT Indicate Iron Overload

Transferrin saturation—not serum iron alone—is the primary screening test for iron overload disorders. 2 Transferrin saturation is calculated by dividing serum iron by TIBC and multiplying by 100. 1 A transferrin saturation ≥45% is required to suspect primary iron overload and proceed with genetic testing for hereditary hemochromatosis. 2, 3 When your transferrin saturation is normal (typically <45%), iron overload is excluded with >90% certainty. 2

Normal ferritin further confirms the absence of increased iron stores. 1 Ferritin is the most specific indicator of depleted or elevated iron stores, and normal ferritin essentially rules out iron overload in hemochromatosis, making it an excellent negative predictor. 3 In the general population, iron overload is NOT the most common cause of isolated laboratory abnormalities when transferrin saturation is normal. 2

Common Causes of Isolated Serum Iron Elevation

Transient Physiological Factors

• Recent iron intake: Dietary iron and supplements can acutely elevate serum iron levels within hours of ingestion. 2 This is why iron studies should ideally be performed fasting, in the morning, after avoiding iron-containing supplements and foods for at least 24 hours. 2

• Diurnal variation: Serum iron concentration naturally rises in the morning and falls at night, independent of iron stores. 1

• Day-to-day biological variation: The within-individual variation of serum iron is substantial and greater than that for other iron parameters. 1

Acute Cellular Release

• Hepatocellular injury: Acute hepatitis or other forms of liver cell damage can release stored iron into the circulation, transiently elevating serum iron without affecting ferritin or TIBC. 2

• Muscle necrosis or tissue breakdown: Cell necrosis from any cause releases intracellular iron. 2

• Hemolysis: Active red blood cell destruction releases hemoglobin-bound iron into serum. 3 If hemolysis is suspected, check haptoglobin (which will be markedly low), LDH (elevated), indirect bilirubin (elevated), and reticulocyte count (elevated). 3

Diagnostic Approach

Step 1: Calculate Transferrin Saturation

The single most important next step is to calculate your transferrin saturation. 2, 3 Using your serum iron and TIBC values:

Transferrin saturation (%) = (serum iron ÷ TIBC) × 100 1

• If TS <45%: Iron overload is excluded. 2, 3 No further iron-overload workup is needed. 2
• If TS ≥45%: Suspect primary iron overload and order HFE genetic testing for C282Y and H63D mutations. 2, 3

Step 2: Assess for Transient Causes

• Repeat fasting morning iron studies after avoiding all iron supplements, iron-fortified foods, red meat, and organ meats for 24 hours. 2 This will determine whether the elevation was spurious.

• Check liver enzymes (ALT, AST) to evaluate for hepatocellular injury. 2 Acute hepatitis can cause transient serum iron elevation.

• If hemolysis is suspected (based on clinical context), order haptoglobin, LDH, indirect bilirubin, reticulocyte count, and peripheral blood smear. 3

Step 3: Rule Out Inflammation

Ferritin is an acute-phase reactant that rises during inflammation, infection, and liver disease independent of iron stores. 2, 3 However, in your case, ferritin is normal, which argues strongly against an inflammatory process driving the iron elevation. 1

Critical Pitfalls to Avoid

• Never diagnose iron overload based on serum iron alone without confirming an elevated transferrin saturation. 2, 3 Serum iron must be interpreted in the context of TIBC and ferritin.

• Do not order HFE genetic testing when transferrin saturation is <45%. 2, 3 This leads to unnecessary testing and potential misdiagnosis.

• Recognize that a single abnormal serum iron value often reflects physiological variation rather than disease. 1 Repeat testing under standardized conditions (fasting, morning, no recent iron intake) is essential before pursuing further workup.

Bottom Line

Your pattern—elevated serum iron with normal ferritin and normal transferrin—does not indicate iron overload or a clinically significant iron disorder. 1, 2 The most likely explanation is transient physiological variation from recent dietary intake, diurnal fluctuation, or minor cellular release. Repeat fasting morning iron studies after 24 hours of avoiding iron-rich foods and supplements. 2 If transferrin saturation remains <45% and ferritin remains normal, no further iron-related workup is needed. 2, 3