What is the differential diagnosis (DDX) for a patient with elevated hemoglobin (Hb), hematocrit (Hct), platelets (plt), hypercalcemia, hyperalbuminemia, and elevated iron levels?

Differential Diagnosis for Elevated Hemoglobin/Hematocrit, Platelets, Calcium, Albumin, and Iron

The constellation of elevated hemoglobin/hematocrit with thrombocytosis, hypercalcemia, hyperalbuminemia, and elevated iron strongly suggests polycythemia vera (PV) as the primary diagnosis, though secondary causes and alternative myeloproliferative neoplasms must be systematically excluded. 1

Primary Myeloproliferative Neoplasm: Polycythemia Vera

Polycythemia vera is the most likely diagnosis when erythrocytosis occurs with thrombocytosis and leukocytosis (trilineage myeloproliferation). 2, 1

• PV is characterized by JAK2-mutated clonal hematopoiesis causing overproduction of red cells, granulocytes, and platelets, with JAK2 mutations present in >95% of cases 3, 4
• Diagnostic thresholds per WHO 2016 criteria: hemoglobin >16.5 g/dL (men) or >16 g/dL (women), and hematocrit >49% (men) or >48% (women) 1, 4
• The presence of thrombocytosis (platelets >400 × 10⁹/L) alongside erythrocytosis is characteristic of PV and distinguishes it from secondary polycythemia 2, 5
• Hypercalcemia can occur in PV due to increased bone turnover from marrow hyperplasia 2

Essential Thrombocythemia

• ET presents with isolated thrombocytosis (platelets >450 × 10⁹/L) but normal hemoglobin/hematocrit, making it less likely when erythrocytosis is present 2
• JAK2 mutations occur in 50-60% of ET cases, with MPL mutations in 3-5% 2

Primary Myelofibrosis

• PMF features megakaryocyte proliferation with atypia, bone marrow fibrosis, leukoerythroblastosis, splenomegaly, and typically anemia rather than erythrocytosis 2
• The presence of elevated hemoglobin/hematocrit makes PMF unlikely as the primary diagnosis 2

Secondary Causes of Erythrocytosis

Secondary erythrocytosis must be excluded before confirming PV, particularly when JAK2 mutation is absent. 1

Hypoxia-Driven Secondary Polycythemia

• Chronic obstructive pulmonary disease (COPD) causes tissue hypoxia stimulating erythropoietin production, but typically presents with isolated erythrocytosis without thrombocytosis 1
• Obstructive sleep apnea produces nocturnal hypoxemia driving compensatory erythrocytosis 1
• Cyanotic congenital heart disease with right-to-left shunting results in arterial hypoxemia and compensatory erythrocytosis to optimize oxygen transport 2, 1
• High-altitude residence causes physiologic erythrocytosis, with hemoglobin increases of 0.2-4.5 g/dL depending on elevation (1000-4500 meters) 1
• Smoking causes "smoker's polycythemia" from chronic carbon monoxide exposure, which resolves with cessation 1

Erythropoietin-Producing Tumors (Non-Hypoxic)

• Renal cell carcinoma, hepatocellular carcinoma, pheochromocytoma, uterine leiomyoma, and meningioma can produce erythropoietin independently 1
• These malignancies may also cause hypercalcemia through parathyroid hormone-related peptide (PTHrP) secretion or bone metastases, explaining the combined findings 2

Relative Polycythemia

• Dehydration, diuretic use, burns, and stress polycythemia (Gaisböck syndrome) cause plasma volume depletion with elevated hematocrit but normal red cell mass 1
• Hyperalbuminemia supports relative polycythemia from hemoconcentration 1

Malignancy-Related Differential

Multiple Myeloma

• MM presents with hypercalcemia, elevated total protein/albumin from monoclonal gammopathy, anemia (not erythrocytosis), and typically thrombocytopenia (not thrombocytosis) 2
• The presence of erythrocytosis and thrombocytosis makes MM unlikely 2

Solid Tumors with Paraneoplastic Syndromes

• Renal cell carcinoma can cause both erythrocytosis (from EPO production) and hypercalcemia (from PTHrP or bone metastases) 1
• Hepatocellular carcinoma may present with elevated albumin (from liver production), erythrocytosis, and hypercalcemia 1

Iron Overload Syndromes

• Hereditary hemochromatosis causes elevated serum iron and ferritin with normal hemoglobin/hematocrit initially, though secondary erythrocytosis can develop 2
• The combination with thrombocytosis makes primary hemochromatosis less likely as the sole diagnosis 2

Diagnostic Algorithm

Immediate laboratory evaluation should include JAK2 mutation testing (exon 14 V617F and exon 12), complete blood count with differential, peripheral blood smear, serum erythropoietin level, comprehensive metabolic panel, serum protein electrophoresis, and iron studies (ferritin, transferrin saturation). 1, 3

First-Tier Testing

• Confirm true polycythemia by repeating hemoglobin/hematocrit measurements, as single values are unreliable 1
• JAK2 V617F mutation testing is positive in >95% of PV cases and distinguishes primary from secondary causes 1, 3
• Serum erythropoietin levels are low or inappropriately normal in PV, elevated in secondary hypoxic causes 1
• Peripheral blood smear may show leukocytosis, thrombocytosis, and basophilia in PV 3

Second-Tier Testing (If JAK2 Negative)

• JAK2 exon 12 mutations occur in 2-3% of PV cases with isolated erythrocytosis 1
• Bone marrow biopsy showing hypercellularity with trilineage growth (panmyelosis) confirms PV diagnosis 2, 1
• Evaluate secondary causes: chest imaging and pulmonary function tests for COPD, sleep study for obstructive sleep apnea, renal/abdominal imaging for EPO-producing tumors 1
• Serum calcium and PTH to distinguish primary hyperparathyroidism from malignancy-related hypercalcemia 2

Third-Tier Testing

• Bone marrow biopsy with cytogenetics if diagnosis remains unclear after initial workup 1
• Abnormal karyotype occurs in 15-20% of PV patients, most frequently +9, -Y, +8, and 20q- 5
• Molecular testing for SRSF2, IDH2, RUNX1, U2AF1 mutations (prognostically adverse, combined incidence 5-10%) 5

Critical Diagnostic Pitfalls

• "Masked PV" presents with normal hemoglobin/hematocrit due to concurrent iron deficiency or blood loss, but JAK2 mutation and bone marrow findings confirm diagnosis 4, 6
• Iron deficiency can coexist with erythrocytosis, causing microcytic polycythemia with elevated RBC count but reduced hemoglobin; mean corpuscular volume (MCV) is unreliable for screening, requiring serum ferritin and transferrin saturation 2, 1
• Hemoglobin is more reliable than hematocrit for diagnosis, as hematocrit falsely increases 2-4% with sample storage and is affected by hyperglycemia 1
• Testosterone therapy (prescribed or unprescribed) causes erythrocytosis and should be considered in younger adults 1
• Altitude-adjusted thresholds must be used for high-altitude residents to avoid misdiagnosis 1

Management Implications Based on Diagnosis

If Polycythemia Vera Confirmed

• Maintain hematocrit strictly <45% through therapeutic phlebotomy to reduce thrombotic risk (CYTO-PV trial: 2.7% vs 9.8% event rate, P=0.007) 1, 5
• Initiate low-dose aspirin (81-100 mg daily) immediately unless contraindications exist 3, 5
• High-risk patients (age ≥60 years, prior thrombosis, WBC ≥10 × 10⁹/L) require cytoreductive therapy with hydroxyurea or pegylated interferon-α 2, 3, 5

If Secondary Erythrocytosis

• Treat underlying condition: smoking cessation, CPAP for sleep apnea, management of COPD 1
• Therapeutic phlebotomy is indicated ONLY if hematocrit >65% with hyperviscosity symptoms after excluding dehydration 2, 1
• Repeated routine phlebotomies are contraindicated due to iron depletion, decreased oxygen-carrying capacity, and paradoxically increased stroke risk 2, 1

If Malignancy-Related

• Renal imaging (ultrasound or CT) to exclude renal cell carcinoma if EPO-producing tumor suspected 1
• Serum protein electrophoresis and bone marrow biopsy if multiple myeloma suspected (though erythrocytosis makes this unlikely) 2