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Sickle Cell Disease:
Epidemiology and Pathophysiology

Epidemiology of Sickle Cell Disease

The sickle hemoglobin (HbS) mutation confers a genetic advantage against malaria so carrier frequency is highest in areas where malaria is (or was) endemic, including (Figure):1-4

  • Africa
  • Mediterranean Europe
  • The Middle East
  • Some regions of India
  • The Caribbean
  • South and Central America

Sickle Cell Epidemiology: Global Distribution

Figure. Global distribution of pathological Hb disorders, 1996.4


Predicting Stroke Risk in SCD

Transcranial Doppler ultrasonography is used to measure abnormal blood flow velocity in large intracranial arteries, which can predict stroke risk.

Learn more >

In these regions, the HbS gene frequency is 10-30%1. In Africa, about 200,000 new cases of sickle cell disease (SCD) occur each year.2 The incidence of SCD in other parts of the world is increasing due to population migration.

In the USA, SCD affects > 70,000 African-Americans and 1 in 375 newborns.5 In the UK, it affects 1 in 2,400 live births across ethnic groups, and > 12,000 individuals are living with SCD. This makes SCD the most common and fastest-growing genetic disorder in the UK.1

Did You Know...?

Sickle cell disease is increasingly detected in neonatal screening programs. However, the disease can be diagnosed at any age.

Pathophysiology of Sickle Cell Disease

Infants who receive 2 copies of the HbS mutation are homozygous (HbSS) and have the most severe disease phenotype. Heterozygous carriers (HbAS) have a mostly benign condition without clinical disability known as "sickle cell trait".

Although SCD is due to a single mutation, the disorders show considerable heterogeneity due to genetic and environmental factors (Table).

Table. Genotypes and phenotypes associated with the HbS mutation

Disease name β genotype Hb electrophoresis Phenotype
Sickle cell trait (HbAS) βA/βS HbS
HbA2
Rest HbA
~ 40%
Normal
Heterozygous "sickle cell trait"
  • Clinically asymptomatic
SCD (HbSS βS/βS HbS
HbF
HbA
HbA2
~ 80-98%
0-20%
None
Normal
Homozygous condition
  • Most severe genotype
SCD (HbSC) βS/βC HbS
HbC
Minimal HbA2
50%
50%
Heterozygous for HbS and HbC with intermediate phenotypical severity
  • Less severe than HbSS but retinopathy more common
SCD (S/βº-thalassemia) βS/βº HbA
HbA2
Rest HbS
None
4-6%
0-25%
Heterozygous for HbS and thalassemia
  • As severe as HbSS
SCD (βS/+-thalassemia) βS/β+ HbA
HbA2
HbF
Rest HbS
≤ 35%
4-6%
0-20%
≥ 50%
Mild-to-moderate phenotype

HbA = adult hemoglobin; HbA2 = hemoglobin A2; HbAS = heterozygous HbS mutation; HbC = hemoglobin C; HbF = fetal hemoglobin; HbS = sickle hemoglobin; HbSC = sickle hemoglobin C; HbSS = homozygous HbS mutation; SCD = sickle cell disease.

Genetic and Environmental Modulators of SCD Phenotype

Genetic modulators of SCD phenotype include co-inheritance of thalassemia and genetic factors involved in the regulation of:6

  • Vascular hemodynamics
  • Endothelial cell function
  • Red blood cell (RBC) membrane proteins
  • Cytokine response

Environmental factors include infection, climate, nutrition, socioeconomic status, and access to medical care.

Learn about clinical manifestations of SCD >

References

  1. Sickle Cell Society. Standards for the Clinical Care of Adults with Sickle Cell Disease in the UK 2008. Available from : http://www.sicklecellsociety.org/app/webroot/files/files/CareBook.pdf. Accessed February 2009.
  2. Weatherall DJ, Clegg JB. Bull World Health Organ. 2001;79:704-12.
  3. Modell B, Darlison M. Bull World Health Organ. 2008;86:480-7.
  4. WHO. WHO Technical Report Series 865. 1996. WHO, Geneva, Switzerland.
  5. The Agency for Health Care Policy and Research (AHCPR). Clinical Practice Guideline number 6. 1993; Publication 93-0562.
  6. Steinberg MH, Adewoye AH. Curr Opin Hematol. 2006;13:131-6.

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