What are the management options for a patient with a non-healing ulcer, recurrent anemia, and iron overload, on oral iron and B12 supplements?

Diagnostic Possibilities and Management Approach

This patient most likely has anemia of chronic disease (ACD) with functional iron overload secondary to ongoing inflammation from the non-healing leg ulcer, and oral iron supplementation should be immediately discontinued. 1

Primary Diagnostic Considerations

Anemia of Chronic Disease with Functional Iron Overload

• The combination of severe anemia (Hb 6.4) with elevated ferritin, high transferrin saturation, low TIBC, and raised serum iron is pathognomonic for ACD with iron sequestration. 2
• The non-healing leg ulcer represents a chronic inflammatory state that drives hepcidin upregulation, trapping iron in macrophages and hepatocytes while simultaneously blocking iron utilization for erythropoiesis. 2
• In inflammatory conditions, ferritin behaves as an acute phase reactant rather than a true marker of iron stores, and cut-off levels should be raised to >100 ng/mL to diagnose true iron deficiency. 2
• The paradoxical iron overload state despite severe anemia indicates that iron is present but functionally unavailable for red blood cell production. 1

Secondary Considerations Requiring Evaluation

• Hereditary hemochromatosis (HFE gene mutations) must be excluded, particularly given the iron overload parameters. 1
• Occult gastrointestinal bleeding should be investigated given the recurrent severe anemia, though the iron overload pattern makes this less likely as the sole etiology. 2
• Myelodysplastic syndrome or other bone marrow disorders warrant consideration in a 75-year-old with refractory anemia unresponsive to supplementation. 2
• Chronic kidney disease can contribute to both anemia and altered iron metabolism. 2

Immediate Management Steps

Discontinue Oral Iron Supplementation

• Stop oral iron immediately to prevent further iron accumulation, as continued supplementation in the setting of functional iron overload is contraindicated and potentially harmful. 1, 3
• Oral iron in inflammatory states causes gastrointestinal side effects, generates reactive oxygen species that can worsen tissue damage, and provides no benefit when hepcidin blocks iron utilization. 2

Address the Underlying Inflammatory Source

• Aggressive treatment of the non-healing leg ulcer is the cornerstone of management, as controlling inflammation is essential to normalize iron metabolism and allow effective erythropoiesis. 2
• Evaluate for vascular insufficiency, infection, diabetes, and other factors preventing ulcer healing. 2
• Consider wound care consultation and possible debridement if infection is present. 2

Diagnostic Workup

• Obtain transferrin saturation to better characterize iron status and distinguish between true iron overload versus functional sequestration. 1
• Check C-reactive protein (CRP) to quantify the degree of inflammation. 2
• Perform genetic testing for HFE mutations (C282Y and H63D) to exclude hereditary hemochromatosis. 1
• Evaluate for occult malignancy given age and non-healing ulcer (consider CT imaging if clinically indicated). 1
• Check reticulocyte count and peripheral smear to assess bone marrow response. 2
• Consider bone marrow biopsy if myelodysplastic syndrome is suspected based on other cytopenias or lack of reticulocyte response. 2

Treatment Options Based on Etiology

If Anemia of Chronic Disease is Confirmed

• Intravenous iron may be considered despite elevated ferritin if transferrin saturation is <20% and inflammation is being actively treated, as IV iron can overcome hepcidin-mediated blockade. 2
• However, IV iron should NOT be given during active infection or uncontrolled inflammation. 2
• Erythropoiesis-stimulating agents (ESAs) combined with IV iron may be necessary if anemia persists despite controlling inflammation and optimizing iron availability. 2
• Target hemoglobin of 11-13 g/dL with ESA therapy to avoid thrombotic complications. 2

If True Iron Overload is Confirmed

• Initiate therapeutic phlebotomy if transferrin saturation >50% and ferritin >800 μg/L, with goal of normalizing ferritin levels while maintaining hemoglobin >11 g/dL. 1
• Monitor hemoglobin closely during phlebotomy to prevent worsening anemia. 1
• Limit vitamin C supplementation to ≤500 mg/day as excessive intake enhances iron absorption and may worsen toxicity. 1

Transfusion Considerations

• Blood transfusion should be reserved for hemodynamic instability or severe symptomatic anemia, as it does not address the underlying pathophysiology and carries risks of iron overload, infection, and immunosuppression. 2
• Given Hb 6.4, transfusion may be necessary for symptomatic relief while addressing the underlying cause. 2

Monitoring and Follow-Up

• Recheck ferritin, transferrin saturation, and hemoglobin in 4-6 weeks after discontinuing oral iron to assess response. 1
• Monitor inflammatory markers (CRP) and ulcer healing status every 3 months. 2
• Do not restart iron supplementation without clear evidence of true iron deficiency (ferritin <100 ng/mL AND transferrin saturation <20% in the absence of inflammation). 2, 1

Critical Pitfalls to Avoid

• Never continue oral iron supplementation in the setting of elevated ferritin and ongoing inflammation—this is ineffective and potentially harmful. 2, 1
• Do not assume iron overload parameters indicate adequate iron for erythropoiesis; functional iron deficiency can coexist with elevated ferritin in inflammatory states. 2
• Avoid IV iron administration during active infection or uncontrolled inflammation. 2
• Do not overlook the need for comprehensive evaluation including malignancy screening in elderly patients with unexplained anemia and non-healing ulcers. 1