What is the differential diagnosis for a patient with elevated hemoglobin (Hb), hematocrit (Hct), mean corpuscular volume (MCV), and mean corpuscular hemoglobin concentration (MCHC)?

Differential Diagnosis of Elevated Hemoglobin, Hematocrit, MCV, and MCHC

Critical Note on MCHC Elevation

Elevated MCHC is extremely rare and should prompt immediate consideration of laboratory artifact, hereditary spherocytosis, or cold agglutinins rather than true polycythemia. 1 True elevation of all four parameters simultaneously (Hb, Hct, MCV, and MCHC) is physiologically unusual and warrants verification of laboratory values before proceeding with extensive workup.

Primary Differential Considerations

Laboratory Error or Artifact (Most Likely)

• Cold agglutinins can falsely elevate MCHC by causing RBC clumping, leading to artificially low RBC counts and falsely elevated MCV and MCHC. 1
• Hyperglycemia can falsely elevate MCV and calculated hematocrit but does not affect hemoglobin measurement. 1
• Sample storage issues can alter hematocrit by 2-4% due to MCV changes, while hemoglobin remains stable. 1
• Repeat the CBC with a fresh sample, ensuring proper handling and warming to 37°C if cold agglutinins are suspected. 1

Hereditary Spherocytosis

• The only true pathologic condition that consistently produces elevated MCHC (typically >36 g/dL). 1
• Associated with spherical RBCs that have decreased surface area-to-volume ratio, concentrating hemoglobin. 1
• Look for family history of anemia, jaundice, splenomegaly, and gallstones. 1
• Confirm with peripheral blood smear showing spherocytes and osmotic fragility testing. 1

True Polycythemia with Concurrent Conditions

If laboratory values are confirmed accurate and MCHC elevation is mild or borderline:

Polycythemia Vera with Unique Features

• PV typically presents with elevated Hb (>18.5 g/dL in men, >16.5 g/dL in women) and Hct (>55% in men, >49.5% in women). 1
• Iron deficiency commonly coexists with PV due to chronic phlebotomy or occult bleeding, which typically lowers MCV and MCHC, not raises them. 2, 3
• Test for JAK2 V617F mutation (exon 14) and JAK2 exon 12 mutations to confirm PV. 1
• Elevated MCHC would be atypical for PV unless there is a concurrent hemoglobinopathy. 4

Secondary Polycythemia (Hypoxia-Driven)

• Chronic hypoxia from COPD, sleep apnea, high altitude, or smoking stimulates erythropoietin production. 1
• Smoker's polycythemia results from carbon monoxide exposure and resolves with smoking cessation. 4, 1
• Measure serum erythropoietin levels: elevated in secondary causes, low-normal in PV. 4, 1
• Consider sleep study if nocturnal hypoxemia suspected. 1

Secondary Polycythemia (Hypoxia-Independent)

• Renal cell carcinoma, hepatocellular carcinoma, pheochromocytoma, uterine leiomyoma, and meningioma can produce erythropoietin autonomously. 4, 1
• Post-renal transplant erythrocytosis occurs in some patients. 4
• Erythropoietin receptor mutations cause familial polycythemia with low EPO levels. 4, 1
• Chuvash polycythemia (von Hippel-Lindau gene mutation) causes abnormal oxygen sensing. 4, 1

Relative Polycythemia (Plasma Volume Depletion)

• Dehydration, diuretic use, severe burns, diarrhea, vomiting, and capillary leak syndrome cause plasma volume contraction with normal red cell mass. 4, 1
• Gaisböck syndrome (relative polycythemia with hypertension) and stress polycythemia are poorly understood and controversial entities. 4
• Recheck CBC after ensuring adequate hydration; if values normalize, no further workup needed. 5, 1

Diagnostic Algorithm

Step 1: Verify Laboratory Values

• Repeat CBC with fresh sample, warming to 37°C if cold agglutinins suspected. 1
• Review peripheral blood smear for spherocytes, RBC morphology, and agglutination. 1
• If MCHC >36 g/dL persists, strongly consider hereditary spherocytosis. 1

Step 2: Assess Hydration Status

• Evaluate for clinical signs of dehydration: orthostatic hypotension, decreased skin turgor, dry mucous membranes. 4, 5
• Review medications (diuretics), recent fluid losses (vomiting, diarrhea, burns). 4
• If dehydration present, rehydrate and recheck CBC before proceeding. 5

Step 3: Distinguish Primary from Secondary Polycythemia

• Measure serum erythropoietin level: low-normal suggests PV, elevated suggests secondary causes. 4, 1
• Order JAK2 V617F mutation testing; if negative, test JAK2 exon 12 mutations. 1
• Check serum ferritin and transferrin saturation to assess iron status. 1, 2
• Obtain arterial blood gas or pulse oximetry to evaluate for hypoxemia. 1

Step 4: Evaluate for Secondary Causes

• Obtain detailed smoking history and quantify pack-years; measure carboxyhemoglobin if actively smoking. 4, 1
• Consider sleep study if symptoms of sleep apnea (snoring, daytime somnolence, witnessed apneas). 1
• Review medication list for exogenous erythropoietin, testosterone, or anabolic steroids. 4, 1
• Image kidneys and liver if EPO elevated without clear hypoxic cause to exclude EPO-secreting tumors. 4, 1

Step 5: Specialized Testing if Diagnosis Unclear

• Refer to hematology for bone marrow biopsy if JAK2 mutations negative but PV still suspected. 1
• Consider hemoglobin electrophoresis to exclude high-oxygen-affinity hemoglobin variants. 1
• Genetic testing for EPOR mutations in familial cases with low EPO. 4

Common Pitfalls to Avoid

• Do not proceed with extensive polycythemia workup without first excluding laboratory artifact, especially with elevated MCHC. 1
• Do not perform therapeutic phlebotomy unless Hb >20 g/dL and Hct >65% with hyperviscosity symptoms. 1
• Avoid repeated phlebotomies without monitoring iron status, as this causes iron depletion and paradoxically decreases oxygen-carrying capacity. 1
• Do not overlook coexisting iron deficiency in polycythemia patients, which typically lowers (not raises) MCV and MCHC. 2, 3
• In patients with confirmed PV, maintain Hct strictly <45% to reduce thrombotic risk. 4

Management Considerations

If Hereditary Spherocytosis Confirmed

• Refer to hematology for consideration of splenectomy in severe cases. 1
• Monitor for complications: gallstones, hemolytic crises, aplastic crises. 1
• Provide folate supplementation due to increased RBC turnover. 1

If Polycythemia Vera Confirmed

• Initiate therapeutic phlebotomy to maintain Hct <45% in all patients. 4
• Start low-dose aspirin (81-100 mg daily) unless contraindicated to reduce thrombotic risk. 4
• Consider hydroxyurea for high-risk patients (age >60 or prior thrombosis). 4
• Monitor for progression to myelofibrosis or acute leukemia. 4

If Secondary Polycythemia Identified

• Treat underlying cause: optimize COPD management, initiate CPAP for sleep apnea, smoking cessation counseling. 1
• Discontinue exogenous erythropoietin or testosterone if causative. 1
• Surgical resection of EPO-secreting tumors when feasible. 4