What is the appropriate management for a patient with hyperferremia (elevated serum iron) and leukocytosis (high White Blood Cell (WBC) count)?

Management of Elevated Serum Iron and High WBC Count

The immediate priority is to measure transferrin saturation (TSAT) to distinguish true iron overload from an acute inflammatory response causing both hyperferremia and leukocytosis, as TSAT >45% indicates genuine iron overload requiring urgent evaluation for hemochromatosis, while normal/low TSAT suggests the elevated iron is secondary to inflammation or infection driving the leukocytosis. 1

Initial Diagnostic Algorithm

Step 1: Measure Transferrin Saturation and Assess Clinical Context

• Obtain fasting TSAT and serum ferritin simultaneously with the elevated serum iron level, as these parameters together determine whether iron overload is present or if hyperferremia reflects acute phase reactivity 1
• Evaluate for infectious or inflammatory causes of leukocytosis including checking C-reactive protein (CRP), complete metabolic panel with liver enzymes (AST/ALT), and assessing for fever, signs of infection, or systemic inflammation 1, 2
• Review medication history particularly for NSAIDs and assess alcohol consumption, as these commonly elevate ferritin without true iron overload 1

Step 2: Interpretation Based on TSAT Results

Scenario A: TSAT ≥45% with Elevated Ferritin

• This indicates true iron overload (hemochromatosis) requiring immediate HFE genetic testing for C282Y and H63D mutations 1
• If ferritin >1000 μg/L with elevated aminotransferases and platelet count <200,000/μL, there is an 80% probability of cirrhosis in C282Y homozygotes, necessitating urgent hepatology referral 1
• Liver biopsy should be considered in C282Y homozygotes with ferritin >1000 μg/L, elevated AST/ALT, hepatomegaly, or age >40 years to assess for cirrhosis 1
• Initiate therapeutic phlebotomy once hemochromatosis is confirmed, removing 400-500 mL blood weekly or biweekly until ferritin reaches 50-100 μg/L 1

Scenario B: TSAT <20-45% with Elevated Ferritin and Leukocytosis

• This pattern indicates hyperferritinemia secondary to inflammation, infection, or malignancy rather than iron overload 1, 3, 2
• Investigate underlying causes systematically: In a study of 627 patients with ferritin >1000 μg/L, malignancy was most common (24%), followed by iron overload syndromes (22%), with inflammatory conditions accounting for significant cases 2
• Screen for occult malignancy including hematologic malignancies (16% of extreme hyperferritinemia cases) and solid tumors, particularly if constitutional symptoms present 2, 4
• Evaluate for hemophagocytic lymphohistiocytosis (HLH) if ferritin is extremely elevated (>10,000 ng/mL) with persistent fever, cytopenias, hepatosplenomegaly, or progressive clinical deterioration, though HLH represents only a minority of hyperferritinemic cases 2, 4
• Consider adult-onset Still's disease if ferritin >5000 μg/L with quotidian fevers, salmon-pink rash, arthritis, and leukocytosis with neutrophil predominance 2

Critical Pitfalls to Avoid

• Do not rely on total iron-binding capacity (TIBC) for clinical decision-making, as TIBC measurements have poor reproducibility (mean coefficient of variation 16%) and can be artificially elevated in iron poisoning 5
• Do not assume protective iron stores based on elevated ferritin alone when TSAT is low, as ferritin primarily reflects inflammation rather than iron availability in this context 3, 2
• Do not perform faecal occult blood testing as it is insensitive and non-specific for evaluating iron status 1
• Do not initiate iron chelation therapy without confirming true iron overload via TSAT >45% and genetic testing or liver biopsy, as inappropriate chelation in inflammatory hyperferritinemia provides no benefit 1

Monitoring Strategy

• If hemochromatosis confirmed: Monitor hemoglobin/hematocrit before each phlebotomy to avoid reducing hematocrit to <80% of baseline, and check ferritin every 10-12 phlebotomies (approximately every 3 months) 1
• If inflammatory hyperferritinemia: Recheck ferritin, TSAT, CRP, and complete blood count every 3 months while treating underlying condition 6
• Screen for hemochromatosis complications including diabetes mellitus, arthropathy (particularly metacarpophalangeal joints), cardiac dysfunction, hypogonadism, and hypothyroidism if iron overload confirmed 1

Additional Considerations for Specific Populations

• In patients with concurrent liver disease: Hepatitis A and B vaccination should be administered while iron overloaded to minimize risk of additional hepatic complications 1
• In patients requiring ongoing evaluation: Liver MRI with T2* sequences can non-invasively quantify hepatic iron concentration and assess extrahepatic organ involvement (pancreas, heart) when diagnosis remains uncertain 1