What is the cause of elevated hemoglobin, hematocrit, and iron levels in a male?

Elevated Hemoglobin, Hematocrit, and Iron in Males: Diagnostic Approach

The most likely causes of simultaneously elevated hemoglobin, hematocrit, and iron in a male are polycythemia vera (a myeloproliferative neoplasm), secondary polycythemia from chronic hypoxia, or less commonly, hereditary hemochromatosis with concurrent polycythemia. This constellation requires systematic evaluation starting with transferrin saturation and serum erythropoietin levels to distinguish primary from secondary causes 1, 2.

Initial Diagnostic Framework

The simultaneous elevation of all three parameters (hemoglobin, hematocrit, and iron) is unusual and requires a structured approach:

Step 1: Confirm True Polycythemia

• Hemoglobin threshold for males: ≥18.5 g/dL or documented sustained increase of ≥2 g/dL from baseline 1
• Hematocrit threshold: >60% strongly suggests increased red cell mass without requiring formal measurement 1
• Rule out spurious elevation from hemoconcentration (dehydration, diuretic use) 1

Step 2: Measure Transferrin Saturation

This is the single most critical test to interpret the elevated iron. 2

• If transferrin saturation ≥45%: Suspect true iron overload (hereditary hemochromatosis or iron loading from chronic transfusions) and proceed with HFE genetic testing for C282Y and H63D mutations 1, 2, 3
• If transferrin saturation <45%: The elevated iron likely reflects inflammation, liver disease, or metabolic syndrome rather than true iron overload 2, 3

Step 3: Measure Serum Erythropoietin (EPO)

EPO level distinguishes polycythemia vera from secondary causes: 1

• Low EPO (<70% sensitivity but >90% specificity): Highly suggestive of polycythemia vera 1
• Normal EPO: Polycythemia vera remains possible; proceed to bone marrow examination 1
• Elevated EPO: Indicates secondary polycythemia from hypoxia, renal disease, or EPO-secreting tumors 1

Primary Differential Diagnosis

Polycythemia Vera (Most Likely if EPO Low)

Diagnostic criteria require: 1

• Hemoglobin ≥18.5 g/dL in men AND
• Presence of JAK2 V617F mutation (or JAK2 exon 12 mutation) AND
• One minor criterion: bone marrow hypercellularity with trilineage growth, low serum EPO, or endogenous erythroid colony formation

Bone marrow examination shows: 1

• Hypercellularity with increased megakaryocytes in clusters
• Giant megakaryocytes with pleomorphic morphology
• Decreased bone marrow iron stores (despite elevated serum iron)
• Mild reticulin fibrosis in 12% of cases

Critical pitfall: Iron deficiency commonly coexists with polycythemia vera due to chronic phlebotomy or occult bleeding, which can mask the diagnosis by lowering hemoglobin below diagnostic thresholds 1. In such cases, formal diagnosis requires demonstrating WHO criteria after iron replacement 1.

Secondary Polycythemia with Concurrent Iron Overload

Consider when EPO is elevated or normal: 1

• Chronic hypoxia: Cyanotic congenital heart disease, chronic lung disease, high altitude residence, sleep apnea 4, 5
• Renal causes: Renal cell carcinoma, polycystic kidney disease, renal artery stenosis
• EPO-secreting tumors: Hepatocellular carcinoma, cerebellar hemangioblastoma

The combination of severe polycythemia with iron overload is rare but documented: In chronic hypoxia, patients may develop hematocrit levels approaching 70-80% while simultaneously having iron deficiency (low ferritin) or, paradoxically, iron loading from repeated transfusions 4, 5.

Hereditary Hemochromatosis with Reactive Polycythemia

Rare but possible scenario: 1, 2

• C282Y homozygosity causes progressive iron accumulation
• Elevated hemoglobin/hematocrit may reflect hepatic dysfunction or secondary causes
• Transferrin saturation ≥45% with elevated ferritin confirms iron overload
• Requires HFE genetic testing for definitive diagnosis

Algorithmic Diagnostic Approach

Follow this sequence: 1, 2

1. Confirm polycythemia: Hemoglobin ≥18.5 g/dL or hematocrit >60% in males
2. Measure transferrin saturation and serum ferritin simultaneously
   • TS ≥45%: Order HFE genetic testing (C282Y, H63D)
   • TS <45%: Iron elevation likely secondary to inflammation or liver disease
3. Measure serum erythropoietin level
   • Low: Strongly suggests polycythemia vera → proceed to JAK2 mutation testing
   • Normal: PV still possible → bone marrow examination
   • Elevated: Secondary polycythemia → evaluate for hypoxia, renal disease, tumors
4. If JAK2 V617F positive with low EPO: Diagnosis of polycythemia vera confirmed
5. If JAK2 negative: Bone marrow biopsy with cytogenetics to evaluate for PV or other myeloproliferative neoplasms
6. If C282Y homozygote with TS ≥45%: Hereditary hemochromatosis confirmed; evaluate for secondary causes of polycythemia

Special Considerations and Pitfalls

Iron Status Interpretation in Polycythemia

Never assume normal iron stores based on elevated serum iron alone. 2, 3

• Serum ferritin is the most powerful test for iron deficiency (ferritin <12 μg/dL diagnostic) 1
• Ferritin can be falsely elevated by inflammation, liver disease, or malignancy even with true iron deficiency 1, 2
• In polycythemia vera, bone marrow iron stores are typically decreased despite normal or elevated serum iron 1

Microcytic Polycythemia

This paradoxical finding indicates iron deficiency despite elevated red cell mass: 5

• Mean corpuscular volume (MCV) <80 fL with hematocrit >60%
• Occurs in chronic hypoxia when iron is withheld to prevent dangerous hyperviscosity
• Management requires careful phlebotomy with concurrent iron supplementation to maintain stable hematocrit while correcting microcytosis 5

Hyperviscosity Risk

Hematocrit approaching 70% creates vascular sludging risk regardless of cause: 5

• Symptoms include headache, dizziness, visual disturbances, thrombosis
• Therapeutic phlebotomy indicated when hematocrit >60% with symptoms
• Target hematocrit <45% in polycythemia vera to reduce thrombotic risk

When Liver Disease Confounds the Picture

Elevated ferritin with normal transferrin saturation suggests: 2, 3

• Non-alcoholic fatty liver disease (NAFLD) accounts for >90% of hyperferritinemia cases when combined with metabolic syndrome 2, 3
• Chronic alcohol consumption increases both iron absorption and hepatocellular injury 3
• Acute hepatitis or cirrhosis releases ferritin from damaged hepatocytes 2
• Management: Treat underlying liver disease, not the elevated ferritin itself 3

Risk Stratification by Ferritin Level

Even with elevated iron parameters, ferritin level predicts organ damage risk: 2

• Ferritin <1,000 μg/L: Low risk of cirrhosis (94% negative predictive value in hemochromatosis) 2
• Ferritin 1,000-10,000 μg/L: Higher risk of advanced fibrosis if iron overload present; consider liver biopsy if ALT elevated or age >40 2
• Ferritin >10,000 μg/L: Rarely represents simple iron overload; evaluate urgently for hemophagocytic lymphohistiocytosis, adult-onset Still's disease, or malignancy 2

Additional Testing to Consider

• Complete blood count with differential: Evaluate for leukocytosis, thrombocytosis (suggests PV) 1
• Comprehensive metabolic panel: Assess liver enzymes (ALT, AST) for hepatocellular injury 2, 3
• Oxygen saturation: Rule out hypoxia as secondary cause 1
• Abdominal ultrasound: Evaluate for splenomegaly (PV), hepatomegaly, renal masses 1
• Bone marrow biopsy with cytogenetics: Required when JAK2 negative or diagnosis equivocal 1

The key to diagnosis is never relying on a single parameter but integrating transferrin saturation, EPO level, and JAK2 mutation status to distinguish primary myeloproliferative disease from secondary polycythemia with or without concurrent iron overload. 1, 2