What is the diagnosis and management for a patient with high iron saturation, normal hemoglobin (Hb) and red blood cell (RBC) count, and high hematocrit (Hct)?

Evaluation and Management of High Iron Saturation with Normal Hemoglobin/RBC and High Hematocrit

Primary Diagnostic Consideration: Hereditary Hemochromatosis

You should immediately test for hereditary hemochromatosis by ordering JAK2 mutation testing and HFE gene mutation analysis (C282Y and H63D), as this presentation of elevated iron saturation with high hematocrit but normal hemoglobin strongly suggests either early hemochromatosis with concurrent iron-restricted erythropoiesis or a myeloproliferative disorder. 1, 2

Key Diagnostic Features

• High transferrin saturation with normal hemoglobin is atypical - in classic hemochromatosis, patients typically have elevated hemoglobin, hematocrit, MCV, MCH, and MCHC due to increased iron uptake and hemoglobin synthesis by immature erythroid cells 3

• The discordance between high iron saturation and normal hemoglobin suggests functional iron deficiency - where iron is present systemically but unavailable for erythropoiesis, commonly seen in inflammatory conditions or myeloproliferative disorders 1, 4

• High hematocrit with normal hemoglobin indicates microcytic erythrocytosis - this pattern occurs when increased RBC production is occurring despite inadequate iron delivery to developing erythrocytes 5, 6

Essential Laboratory Workup

Immediate Testing Required

• Complete iron panel: serum ferritin, transferrin saturation, serum iron, and total iron binding capacity to quantify total body iron stores 1, 2

• Reticulocyte hemoglobin content (CHr): values <28 pg indicate functional iron deficiency at the erythrocyte level, which is more sensitive than ferritin or transferrin saturation for detecting iron-restricted erythropoiesis 7, 4

• C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR): to assess for inflammation that could cause functional iron deficiency despite high iron saturation 1

• Peripheral blood smear review: to assess red cell morphology and identify microcytosis, hypochromia, or abnormal cell populations 2

Genetic Testing

• HFE gene mutation analysis (C282Y and H63D mutations): C282Y homozygosity is found in the majority of hereditary hemochromatosis cases and causes elevated transferrin saturation typically >75% 1

• JAK2 V617F mutation testing: present in up to 97% of polycythemia vera cases, which can present with elevated hematocrit and altered iron metabolism 2

Diagnostic Algorithm

Step 1: Confirm True Erythrocytosis

• Repeat hemoglobin and hematocrit measurements to confirm persistent elevation, as single measurements are unreliable 2

• Calculate mean corpuscular volume (MCV): if MCV is low-normal or reduced with high hematocrit, this confirms microcytic erythrocytosis suggesting iron-restricted red cell production 5, 6

Step 2: Assess Iron Status Comprehensively

• If ferritin <30 μg/L without inflammation: absolute iron deficiency is present despite high transferrin saturation, which can occur in hemochromatosis patients who develop iron deficiency from occult bleeding 1

• If ferritin 30-100 μg/L with elevated CRP/ESR: functional iron deficiency due to inflammation is likely, where hepcidin upregulation traps iron in macrophages despite high serum iron 1

• If ferritin >1000 μg/L: proceed directly to liver biopsy or MRI to assess hepatic iron concentration, as this indicates significant iron overload requiring therapeutic intervention 1

Step 3: Distinguish Primary from Secondary Causes

• If JAK2 mutation positive: diagnose polycythemia vera and refer immediately to hematology for bone marrow biopsy and cytoreductive therapy 2

• If C282Y homozygous with transferrin saturation >75%: diagnose hereditary hemochromatosis and initiate therapeutic phlebotomy weekly targeting ferritin 50-100 μg/L 1

• If both mutations negative: evaluate for secondary causes including chronic hypoxemia (sleep apnea, COPD, cyanotic heart disease), testosterone use, or erythropoietin-producing tumors 2

Critical Clinical Pitfall: Coexisting Iron Deficiency with Erythrocytosis

The most commonly missed diagnosis in this scenario is iron deficiency occurring simultaneously with erythrocytosis - this creates a paradoxical picture where high transferrin saturation reflects the body's attempt to mobilize limited iron stores, while normal hemoglobin masks the severity of both conditions 5, 6

Recognition Features

• Normal hemoglobin with elevated RBC count and hematocrit indicates microcytic red cells being produced in increased numbers to compensate for reduced oxygen-carrying capacity per cell 5

• MCV is unreliable for screening iron deficiency in erythrocytosis - serum ferritin, transferrin saturation, and reticulocyte hemoglobin content are required for accurate diagnosis 5

• This pattern is particularly common in cyanotic congenital heart disease, where chronic hypoxemia drives erythropoiesis while chronic GI blood loss or malabsorption causes iron depletion 1, 5

Management Based on Etiology

If Hereditary Hemochromatosis Confirmed

• Initiate weekly therapeutic phlebotomy (500 mL as tolerated) targeting ferritin 50-100 μg/L and transferrin saturation <50% 1

• Avoid vitamin C supplements and iron supplements during treatment, as vitamin C enhances iron absorption and mobilization 1

• Monitor for reaccumulation after achieving target ferritin, with maintenance phlebotomy every 2-4 months to maintain ferritin 50-100 μg/L 1

• No dietary iron restriction is necessary during active treatment, as phlebotomy removes 200-250 mg iron per session which exceeds dietary intake 1

If Functional Iron Deficiency Identified

• Treat underlying inflammation first before iron supplementation, as hepcidin elevation will prevent iron absorption and utilization 1

• Consider intravenous iron if oral iron fails after 2 weeks (hemoglobin increase <10 g/L predicts treatment failure with 90% sensitivity) or if active inflammatory bowel disease is present 8

• Monitor reticulocyte hemoglobin content which rises within 48-96 hours after IV iron and predicts erythropoietic response more accurately than ferritin or transferrin saturation 4

If Polycythemia Vera Diagnosed

• Maintain hematocrit strictly <45% through therapeutic phlebotomy to reduce thrombotic risk (2.7% vs 9.8% event rate, P=0.007) 2

• Initiate low-dose aspirin (81-100 mg daily) as second cornerstone of therapy for thrombosis prevention 2

• Refer immediately to hematology for bone marrow biopsy confirmation and consideration of cytoreductive therapy if high-risk features present 2

Critical Contraindication

Do NOT perform therapeutic phlebotomy for secondary erythrocytosis unless hematocrit exceeds 65% with documented hyperviscosity symptoms after confirming adequate hydration - routine phlebotomy causes iron depletion, decreased oxygen-carrying capacity, and paradoxically increases stroke risk in compensatory erythrocytosis 1, 2

When to Refer to Hematology

• JAK2 mutation positive - requires bone marrow biopsy and specialized management 2

• Ferritin >1000 μg/L at diagnosis - may indicate advanced hemochromatosis with end-organ damage requiring liver biopsy 1

• Unexplained erythrocytosis after excluding secondary causes - may represent rare genetic disorders of erythropoietin receptor or oxygen-sensing pathways 2

• Concurrent cytopenias or splenomegaly - suggests myeloproliferative or myelodysplastic disorder requiring bone marrow evaluation 1, 2