What does it mean if Mean Corpuscular Hemoglobin (MCH), Mean Corpuscular Volume (MCV), and Mean Corpuscular Hemoglobin Concentration (MCHC) are all elevated?

Elevated MCH, MCV, and MCHC: Clinical Significance and Differential Diagnosis

Elevated MCH, MCV, and MCHC together strongly suggest macrocytosis with increased hemoglobin concentration per cell, most commonly seen in conditions such as polycythemia vera, hemochromatosis, or certain medication effects. 1, 2

Understanding the Red Blood Cell Indices

• MCH (Mean Corpuscular Hemoglobin): Measures the average amount of hemoglobin per red blood cell 1
• MCV (Mean Corpuscular Volume): Measures the average size of red blood cells 1
• MCHC (Mean Corpuscular Hemoglobin Concentration): Measures the concentration of hemoglobin in a given volume of packed red blood cells 3

Primary Causes of Elevated MCH, MCV, and MCHC

Polycythemia Vera and Other Myeloproliferative Disorders

• True polycythemia (increased red cell mass) can present with elevated red cell indices 1
• Clonal proliferation of erythroid precursors leads to larger cells with increased hemoglobin content 1
• Often accompanied by elevated hemoglobin/hematocrit and other clinical features 1

Hemochromatosis and Iron Overload

• Significantly higher MCV, MCH, and MCHC values are seen in patients with hemochromatosis compared to normal controls 2
• Increased iron uptake by immature erythroid cells leads to enhanced hemoglobin synthesis 2
• These parameters may remain elevated even after iron depletion therapy 2

Medication Effects

• Certain medications can cause macrocytosis with elevated red cell indices 4
• Common culprits include:
  • Azathioprine and other thiopurines 5
  • Anticonvulsants 4
  • Methotrexate and other chemotherapeutic agents 4

Other Potential Causes

Laboratory Error/Interference

• Values of MCHC significantly above reference range may not be physiologically possible due to limitations on hemoglobin solubility 3
• Cold agglutination and lipid blood interference can cause falsely elevated MCHC 6
• Critical evaluation of peripheral smear is necessary to confirm true elevation versus laboratory artifact 3, 6

Vitamin B12 or Folate Metabolism Issues

• While B12 deficiency typically causes macrocytosis, normal B12 levels with elevated indices may suggest folate deficiency or metabolic issues 4
• Homocysteine levels can provide additional information on tissue deficiency 4

Chronic Alcohol Use

• Can cause macrocytosis independent of nutritional deficiencies 4
• May present with elevated MCV and sometimes elevated MCH/MCHC 4

Diagnostic Approach

1. Confirm true elevation:

   • Rule out laboratory error by repeating the test and examining peripheral blood smear 3, 6
   • Consider warming samples to 37°C if cold agglutination is suspected 6

2. Assess for iron status:

   • Check serum ferritin, transferrin saturation, and iron studies 1
   • Elevated indices with high ferritin and transferrin saturation suggest iron overload 2
   • Elevated indices with low iron parameters suggest a different etiology 7

3. Evaluate vitamin status:

   • Confirm B12 and folate levels 4
   • Consider homocysteine and methylmalonic acid levels for functional deficiencies 4

4. Review medication history:

   • Identify medications known to cause macrocytosis 4, 5
   • Consider temporal relationship between medication initiation and abnormal indices 5

5. Consider specialized testing:

   • Bone marrow examination may be necessary in cases where the cause remains unclear 1
   • Genetic testing for hemochromatosis (HFE mutations) if iron overload is suspected 2
   • JAK2 mutation testing if polycythemia vera is suspected 1

Clinical Implications

• Elevated MCH, MCV, and MCHC may precede the development of overt disease 2
• These parameters can help distinguish between different types of anemia and polycythemia 1
• Serial monitoring of these indices can help assess response to treatment in conditions like hemochromatosis 2

Important Caveats

• MCHC is particularly susceptible to laboratory error and should be interpreted with caution when significantly elevated 3, 6
• Concurrent conditions may mask expected changes in red cell indices 1
• Interpretation should always be done in the context of complete clinical and laboratory assessment 1