The patient has a markedly elevated serum iron; what is the appropriate management?

Management of Serum Iron 448 µg/dL

You need to immediately obtain a complete iron panel including transferrin saturation (TSAT) and serum ferritin to determine if this represents true iron overload or an isolated laboratory finding, as serum iron alone is insufficient for diagnosis. 1

Initial Diagnostic Workup

Your patient's serum iron of 448 µg/dL is markedly elevated (normal range 60-80 µg/dL), but this single value cannot distinguish between hereditary hemochromatosis, secondary iron overload, or transient elevation. 1

Critical next steps:

• Measure transferrin saturation (TSAT): Calculate as serum iron divided by total iron binding capacity. TSAT ≥45% suggests iron overload and warrants further investigation. 1
• Measure serum ferritin: Values >200 µg/L in women or >300 µg/L in men, combined with elevated TSAT, indicate likely iron overload. 1
• Obtain complete blood count with reticulocytes: Rule out anemia and red cell disorders that could cause secondary iron overload. 1

Interpretation Based on Results

If TSAT ≥45% AND Ferritin Elevated

Proceed with HFE genetic testing for C282Y and H63D mutations to diagnose hereditary hemochromatosis. 1 This is the most common cause of primary iron overload in individuals of European descent.

Key ferritin thresholds for risk stratification:

• Ferritin <1,000 µg/L with normal transaminases and no hepatomegaly: Very low risk of advanced liver fibrosis; can proceed directly to phlebotomy without liver biopsy. 1
• Ferritin >1,000 µg/L with elevated ALT/AST: 80% risk of cirrhosis in C282Y homozygotes; requires non-invasive assessment of liver fibrosis (transient elastography with cutoff <6.4 kPa to rule out advanced fibrosis). 1

If Genetic Testing is Negative

Evaluate for secondary causes of iron overload: 2

• Hematologic disorders: Thalassemia syndromes, myelodysplastic syndrome, myelofibrosis, sideroblastic anemia, sickle cell disease, pyruvate kinase deficiency
• Iatrogenic causes: Chronic transfusion therapy, excessive iron supplementation
• Chronic liver diseases: Alcoholic liver disease, NAFLD, hepatitis C, porphyria cutanea tarda

Treatment Approach

For Confirmed Hereditary Hemochromatosis

Initiate therapeutic phlebotomy immediately - this is the first-line treatment regardless of symptoms. 1, 3

Phlebotomy protocol:

• Remove 450-500 mL of blood weekly or biweekly until ferritin reaches 50-100 µg/L (target range to avoid iron deficiency while depleting excess stores). 1, 3
• Check hematocrit before each session: Do not allow hematocrit to drop >20% from baseline in a single session. 1, 3
• Monitor ferritin every 10-12 phlebotomies (approximately every 3 months) to track progress toward target. 1, 3
• Transition to maintenance phlebotomy once target ferritin achieved: typically 3-4 times yearly for men, 1-2 times yearly for women. 3

Expected outcomes with early treatment: 1

• Improved survival if treated before cirrhosis and diabetes develop
• Improved energy levels and sense of well-being
• Normalization of liver enzymes
• Reversal of hepatic fibrosis in ~30% of cases
• No reversal of established cirrhosis - emphasizing importance of early treatment
• Minimal to no improvement in arthropathy

For Secondary Iron Overload

If ferritin >1,000 ng/mL with transfusion burden ≥2 units/month for >1 year, consider iron chelation therapy with deferoxamine or deferasirox. 1 Phlebotomy is preferred when hemoglobin is adequate and stable. 1

Critical Monitoring and Lifestyle Modifications

During treatment: 3

• Avoid vitamin C supplements: These enhance iron absorption and can worsen overload
• Minimize alcohol consumption: Alcohol increases iron absorption and accelerates liver damage
• Monitor for cardiac involvement if ferritin >1,000 µg/L: Obtain ECG and echocardiography; consider cardiac MRI for iron quantification in severe cases. 1

Family Screening

If hereditary hemochromatosis is confirmed, screen all first-degree relatives with simultaneous HFE genetic testing and iron studies (ferritin and TSAT). 1 Early identification prevents complications through prophylactic phlebotomy before organ damage occurs.

Common Pitfalls to Avoid

• Do not rely on serum iron alone: It fluctuates with meals, inflammation, and time of day. TSAT and ferritin are essential for diagnosis. 1, 4
• Ferritin is an acute phase reactant: Inflammatory conditions (infection, malignancy, chronic disease) can falsely elevate ferritin without true iron overload. 3, 4, 5 If inflammation suspected, measure C-reactive protein and interpret ferritin cautiously.
• Do not over-phlebotomize: Target ferritin of 50-100 µg/L, not iron deficiency, to avoid worsening fatigue. 1, 3
• Cardiac iron overload develops late: By the time cardiomyopathy appears, treatment may no longer be effective, making early screening critical. 1