What are the causes of a decreased Mean Corpuscular Hemoglobin Concentration (MCHC)?

Causes of Decreased MCHC

Decreased MCHC (hypochromia) is most commonly caused by iron deficiency, which occurs when insufficient iron is available for hemoglobin synthesis in developing red blood cells. 1

Primary Causes

Iron Deficiency (Most Common)

• Iron deficiency is the predominant cause of reduced MCHC, occurring when inadequate iron is available for hemoglobin synthesis in erythroid precursors 1
• MCHC decreases in both absolute iron deficiency (depleted iron stores) and functional iron deficiency (adequate stores but impaired mobilization) 1
• Iron deficiency progresses through three stages: first, anisocytosis and microcytosis appear with normal hemoglobin; second, MCV and MCH decline with mild anemia; finally, MCHC drops below normal only in advanced iron deficiency with hemoglobin typically below 9 g/dL 2
• MCHC is a more reliable marker than MCV because it is less dependent on storage conditions and counting equipment 1, 3

Thalassemia

• Thalassemia (particularly alpha and beta thalassemia trait) causes microcytosis and hypochromia with low MCHC 1
• In thalassemia, MCV is typically reduced out of proportion to the level of anemia, which helps distinguish it from iron deficiency 1
• Mean MCHC values are significantly lower in iron deficiency compared to thalassemia and other causes of microcytic anemia 4

Chronic Inflammatory Conditions

• Chronic inflammatory states can cause reduced MCHC, though this is less common than iron deficiency 1
• Inflammation can cause iron sequestration, leading to functional iron deficiency with hypochromic red cells 5

Sideroblastic Anemia

• Sideroblastic anemia can present with microcytosis and hypochromia, resulting in low MCHC 1
• This represents a defect in heme synthesis despite adequate iron availability 6

Iron Deficiency in Cyanotic Heart Disease

• In cyanotic congenital heart disease, iron deficiency exacerbates polycythemia-related complications 6
• Iron deficiency results in microcytic hypochromic red cells with decreased oxygen-carrying capacity due to reduced mean hemoglobin levels 6
• These iron-deficient red cells become relatively rigid microspheres that are less deformable in the microcirculation 6

Diagnostic Approach to Low MCHC

Initial Laboratory Assessment

• Serum ferritin is the single most useful marker for iron deficiency, with levels <15 μg/L indicating absent iron stores and <30 μg/L indicating low body iron stores 1
• Transferrin saturation provides insight into circulating iron available for erythropoiesis 1
• Combined assessment of ferritin and transferrin saturation is useful for diagnosing absolute versus functional iron deficiency 1

Distinguishing Iron Deficiency from Thalassemia

• Low MCV with RDW >14.0% suggests iron deficiency, while low MCV with RDW ≤14.0% suggests thalassemia minor 1
• The difference between calculated MCHC and directly measured MCHC is significantly greater in iron deficiency than in other causes of microcytic anemia 4

When Iron Studies Are Normal

• Normal iron studies with microcytosis and hypochromia warrant hemoglobin electrophoresis, particularly in patients with appropriate ethnic background for thalassemia 1
• Consider genetic disorders of iron metabolism or heme synthesis when ferritin and/or transferrin saturation are elevated despite microcytic anemia 6

Critical Pitfalls to Avoid

Inflammatory Conditions Masking Iron Deficiency

• Serum ferritin is an acute phase protein and can be falsely normal or elevated in inflammatory conditions despite true iron deficiency 1, 3
• Ferritin >150 μg/L is unlikely to occur with absolute iron deficiency even with inflammation 1
• Consider dual pathology and do not rely solely on ferritin in patients with known inflammatory conditions 3

Combined Deficiencies

• In patients with combined deficiencies (iron plus B12/folate), MCV may appear normal while MCHC remains low 1
• This can mask the presence of iron deficiency if only MCV is evaluated 1

Mandatory Investigation of Underlying Cause

• In adult men and post-menopausal women with iron deficiency, gastrointestinal evaluation is mandatory as GI blood loss is the most common cause 1, 3
• Even mild reductions in MCHC should be investigated as they may indicate serious underlying pathology 3

Clinical Significance Beyond Anemia

• Low MCHC (relative hypochromia) independently predicts increased mortality risk in heart failure patients, even with normal hemoglobin levels 7
• Persistently low MCHC reflects left atrial overload and left ventricular hypertrophy and may predict nonatherosclerotic cardiovascular disease 5, 7