HbC disease

**Genetics/Pathophysiology:** Missense mutation at position 6 of the β-globin chain substitutes lysine (positive charge) for glutamic acid (negative charge). Sickle Hb (HbS) has valine at the same position (Glu→Val). HbC has reduced solubility and crystallizes within RBCs, especially when dehydrated (via increased K-Cl cotransport and Gardos channel activity causing cell dehydration). This increases MCHC and decreases RBC deformability, so the spleen removes the cells (extravascular hemolysis). Autosomal recessive inheritance (codominant expression: AC = trait, CC = disease).

**Epidemiology:** Highest prevalence in West Africa (Burkina Faso, northern Ghana); about 2-3% of African Americans carry HbC trait. Heterozygosity appears to confer relative protection against severe *Plasmodium falciparum* malaria (impaired cytoadherence from altered PfEMP-1 display on the RBC surface), which explains the allele's frequency.

**Clinical features:** - HbCC: mild to moderate chronic extravascular hemolytic anemia, splenomegaly (unlike HbSS adults, who autosplenectomize), mild jaundice, and pigment gallstones (bilirubin). Patients are often asymptomatic or have mild abdominal discomfort or arthralgias. There are no vaso-occlusive crises as in sickle cell disease. - HbAC trait: asymptomatic, normal or near-normal blood counts, with occasional target cells. - HbSC disease (compound heterozygote): clinically important. It is a milder sickling disorder than HbSS but can cause vaso-occlusive pain, avascular necrosis of the femoral head, proliferative retinopathy (more common than in HbSS), splenic infarction or sequestration (the spleen may persist into adulthood), hematuria/papillary necrosis, and pregnancy complications.

**Diagnosis:** - Peripheral smear: many target cells (codocytes), microspherocytes in CC, and occasional intraerythrocytic HbC crystals, rod-shaped or hexagonal ("bar of gold"). In HbSC the crystals are more irregular. Often normocytic or microcytic anemia with elevated MCHC. - Hemoglobin electrophoresis (alkaline): HbC migrates with HbA2, HbE, and HbO-Arab; so confirm with acid agar or HPLC. HbCC shows about 90-100% HbC with no HbA. Trait shows about 40% HbC and about 60% HbA. - Labs of hemolysis: elevated LDH and indirect bilirubin, low haptoglobin, increased reticulocytes. - Sickle solubility test is negative in HbC alone.

**Management:** Usually none. Give folic acid supplementation if hemolysis is significant. Splenectomy is rarely needed, and cholecystectomy is done for symptomatic gallstones. For HbSC, use sickle-cell care (hydroxyurea in selected patients, ophthalmologic screening, vaccination and hydration).

**Board pearls:** - Glu→Lys (HbC) vs Glu→Val (HbS) at β-6. - Target cells + mild hemolysis + splenomegaly in an African American patient = HbC. - HbC trait is protective against malaria. - HbC crystals on smear are classic. - Other target cell causes: HbC disease, thalassemia, liver disease, asplenia, iron deficiency (mnemonic HALT: HbC disease, Asplenia, Liver disease, Thalassemia). - Don't confuse with HbSC, which has a more severe course and more retinopathy.