Hematology
Hemoglobinopathies
Hemoglobin C disease

Editorial Board Member: Patricia Tsang, M.D., M.B.A.
Deputy Editor-in-Chief: Genevieve M. Crane, M.D., Ph.D.

Topic Completed: 12 November 2020

Minor changes: 12 November 2020

Copyright: 2020, PathologyOutlines.com, Inc.

PubMed Search: Hemoglobin C disease [title] pathology

Page views in 2020 to date: 189
Cite this page: Mais DD. Hemoglobin C disease. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/hematologyhemoglobinCdisease.html. Accessed November 25th, 2020.
Definition / general
  • Homozygosity for C (βC) allele of hemoglobin beta chain (HBB) gene
Essential features
  • Mild chronic hemolysis
  • Characteristic blood smear morphology
  • Relative protection against severe Plasmodium falciparum malaria
  • Diagnosed by electrophoresis or high performance liquid chromatography (HPLC)
Terminology
  • HbC disease, HbCC
ICD coding
  • ICD-10: D58.2 - other hemoglobinopathies
Epidemiology
Sites
  • Bone marrow, spleen
Pathophysiology
  • HbC has lysine (AAG) substituted for glutamate (GAG) at position 6 of the beta chain
  • Has poor solubility, leading to precipitation in red blood cells
  • Activation of potassium / chloride channels leads to cellular dehydration
  • Slightly shortened red blood cell survival (hemolytic anemia)
Etiology
  • Inherited genetic mutation
Clinical features
  • Mild chronic hemolysis, usually well compensated and asymptomatic
  • Some patients have mild anemia, splenomegaly or gallstones (Hemoglobin 2013;37:16)
  • Protects against severe Plasmodium falciparum malaria (Sci Rep 2017;7:14267)
  • Note that heterozygous C train (HbAC) is clinically asymptomatic, manifesting only as target cells in the peripheral blood smear but does confer some protection against severe P. falciparum malaria
Diagnosis
  • Hemoglobin electrophoresis or HPLC shows about 95% HbC with no HbA and less than 5% HbA2 and HbF
  • Molecular genetic testing important in some cases; beta gene sequencing currently best method
Laboratory
  • Normal to mildly decreased hemoglobin (Hemoglobin 2013;37:16)
  • Normal to slightly increased reticulocytes (Hemoglobin 2013;37:16)
  • Normal to slightly increased bilirubin and lactate dehydrogenase (LDH)
  • Decreased mean corpuscular volume (microcytosis), on average about 55 fL
  • Normal to increased mean corpuscular hemoglobin concentration (MCHC)
  • Normal to slightly increased red cell distribution width (RDW)
  • Relative reduction in glycated HbA1C (Clin Chim Acta 2012;413:819)
Prognostic factors
  • Overall prognosis good; no known reduction in overall life expectancy
Case reports
Treatment
  • No treatment required
  • Genetic counseling may be indicated to address risk of compound heterozygosity in offspring
Microscopic (histologic) description
  • Bone marrow is hypercellular with relative erythroid hyperplasia
  • Irregular nuclear contours and other dyspoietic changes may be seen
Peripheral smear description
  • Microcytosis
  • Numerous target cells
  • Irregularly contracted cells
  • Occasional rhomboid crystals, more numerous postsplenectomy
Peripheral smear images

Contributed by Daniel D. Mais, M.D.

Peripheral blood smear (Wright stain)

Hemoglobin electrophoresis

Molecular / cytogenetics description
  • Beta globin (HBB) gene located at 11p15.5
  • Point mutation in sixth codon, GAG > AAG
  • Lysine encoded instead of glutamate at sixth amino acid (β6 glu→lys)
  • Same amino acid position affected in HbS (β6 glu→val)
Sample pathology report
  • Hemoglobin electrophoresis:
    • Consistent with hemoglobin C disease (see comment)
    • Comment: Blood smear demonstrates microcytic red cells, frequent target cells, boat cells and occasional blunt ended hemoglobin crystals. Electrophoresis shows 96.7% HbC.
Differential diagnosis
  • On cellulose acetate electrophoresis at alkaline pH, migrates with:
    • HbE
    • HbO Arab
    • HbC Harlem
    • HbA2
    • Distinguished on citrate agar
  • On HPLC, migrates very close to:
    • HbA2
    • Hb Lepore
    • Distinguished by electrophoresis
  • Rarely, transient acquired HbC after exchange transfusion (Ann Clin Lab Sci 2015;45:627)
Board review style question #1
Which of the following is true regarding HbC disease?

  1. Affected patients are more prone to severe malaria
  2. Affected patients are usually transfusion dependent
  3. Affected patients may have falsely low glycated HbA1c
  4. HbC comigrates with HbE and HbO Arab on citrate agar
  5. It is clinically more severe than sickle cell disease
Board review answer #1
C. Affected patients may have falsely low glycated HbA1c

Comment Here

Reference: Hemoglobin C disease
Board review style question #2

In the image shown above of an alkaline electrophoretic gel, what other hemoglobin variant comigrates with the abnormal band in the left panel?

  1. HbCS
  2. HbD
  3. HbF
  4. HbO
  5. HbS
Board review answer #2
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