Retinopathy, Hemoglobinopathies 

While many hemoglobinopathies exist, those resulting in proliferative retinopathy are limited to sickle cell disease. Thalassemia major is associated with a nonproliferative pigmentary retinopathy. The pigmentary changes are believed to be secondary to the liberation of free iron as a result of hemolysis of red blood cells that contain the affected hemoglobin. Homozygous sickle cell disease (SS disease), sickle cell C disease (SC disease), and sickle cell-thalassemia disease (S-Thal disease) are common hemoglobinopathies that can present with mild-to-severe proliferative retinal findings.

Sickle cell hemoglobinopathy encompasses a group of inherited genetic disorders, which cause erythrocytes to become sickled and affect multiple organ systems. The rigid sickled erythrocytes lead to vascular occlusion, which results in retinal hypoxia, ischemia, and neovascularization. If this series of events does not stabilize or reverse with recanalization of the occluded retinal vessels, the subsequent end-stage results may be retinal infarction and/or detachment.

Historic milestones

• In 1910, James Herrick, a Chicago physician, first described sickle cell anemia, "The shape of the RBC [red blood cell] was very irregular." What especially attracted attention was the large number of "thin, elongated, sickle-shaped and crescent-shaped forms."
• In 1930, ocular changes associated with sickle cell disease were noted.
• In 1949, Itano and Pauling described the association of sickle cell anemia with abnormal hemoglobin Hb S, which could be differentiated from Hb A by electrophoresis.
• In 1957, Ingram showed that hemoglobin Hb S differed from normal hemoglobin (Hb A) by the single amino acid substitution.
• In 1959, Lieb and coworkers associated angioid streaks with sickle cell disease.
• In 1966, Welch and Goldberg introduced and described much of the modern terminology associated with sickle cell disease with respect to ocular changes.
• In 1971, Goldberg proposed a classification for sickle cell retinopathy.

Hemoglobin molecules are found exclusively in erythrocytes, where their main function is to transport oxygen to tissues. Hb A, the major hemoglobin in adults, is composed of 4 polypeptide chains, 2 alpha chains and 2 beta chains (alpha₂ beta₂) held by noncovalent bonds. The heme and the globin molecules together form hemoglobin, which can bind up to 4 oxygen molecules. The genes coding for alpha and beta globin chains are located on chromosome 16 and chromosome 11, respectively.

The widely accepted pathogenesis for sickle cell retinopathy is vasoocclusion that leads to retinal hypoxia, ischemia, infarction, neovascularization, and fibrovascularization. In sickle cell anemia, the amino acid substitution valine for glutamate occurs on the beta chain at the sixth position. This substitution, combined with conditions that may promote sickling (ie, acidosis, hypoxia), triggers the deoxygenated Hb S to polymerize, making the erythrocyte rigid. This rigidity is partially responsible for the vasoocclusion.

Vasoocclusion also is in part due to the interaction between sickled cells and the vascular endothelium. The adherence of sickled cells to the endothelium triggers an inflammatory process with the release of inflammatory agents. The activated endothelia are procoagulant, thereby inducing further adherence of sickled cells to the endothelium. The activated endothelium and rigid sickled cells bind to von Willebrand factor and thrombospondin, which is secreted by activated platelets. The result of this cascade is vascular stasis, hemolysis, and vasoocclusion of the capillary beds.

Frequency

United States

About 10% of African Americans have an abnormal hemoglobin gene. About 8% of African Americans are heterozygous for Hb S. In the United States, sickle cell anemia primarily occurs in the black population, with approximately 0.2% of African American children afflicted by this disease. The prevalence in adults is lower because of the decrease in life expectancy.

Sickle cell anemia is a homozygous-recessive disorder, that is, the individual receives 2 mutant genes that code for the variant beta globin chain. Sickle cell anemia is most common where the Hb S gene is inherited from both parents, each of whom is a healthy carrier of the gene (HbAS).

Sickle cell C disease is the second most common form. The hemoglobinopathy results from inheriting 1 Hb S gene and 1 Hb C gene, which is common in West African populations.

Sickle cell-thalassemia disease is the third most common hemoglobinopathy.

Different genes within a population determine the frequency of sickle cell disease at birth. The inheritance pattern for hemoglobinopathies is autosomal-recessive (a mendelian pattern). If each parent carries 1 Hb S gene, a 25% chance exists for offspring to have sickle cell disease, a 50% chance for them to have the carrier state, and a 25% chance for them to have normal hemoglobin. The frequency for passing the mutated gene is the same for each pregnancy, regardless of the outcome of the previous pregnancy. With each pregnancy, a 75% chance exists that the newborn will not have sickle cell anemia.

International

See Race.

Mortality/Morbidity

• Sickle cell trait (Hb AS): These patients generally have a normal life expectancy with no systemic or ocular problems. Cases of significant retinopathy are rare. The erythrocytes are likely to sickle and cause splenic infarction only in cases of severe hypoxia, such as with flight in unpressurized aircraft.
• Sickle cell anemia: This disease is not manifested during the neonatal period because the primary hemoglobin molecule circulating at this time is Hb F (fetal hemoglobin). It is characterized by the substitution of the amino acid valine for glutamic acid at the sixth position of the beta globin chain. Systemic disease is more common and more severe than ocular disease.
• Sickle cell-thalassemia disease: This hereditary disorder results from inheriting a sickle cell gene and a beta-thalassemia gene. It can be caused by gene deletions, substitutions, or mutations. Since it results in production of the beta globin chain, most of the synthesized Hb is Hb S. The beta-thalassemias are classified as disorders in which no globin chains are produced or normal globin chains are produced but in diminished quantities. An individual can have 2 types of sickle beta-thalassemia: Hb S beta^o thalassemia, a severe form with no hemoglobin A production, or Hb S beta⁺ thalassemia, a form with some Hb A production and, thus, a milder clinical course. Although systemic manifestations are generally mild when compared to Hb SS, ocular manifestations can be severe.
• Sickle cell C disease: Hemoglobin C is a variant that results from a single amino acid substitution at the sixth position of the beta globin chain, in this case, lysine for glutamic acid. Patients with sickle cell C disease tend to have mild chronic hemolytic anemia, less frequent sickling crisis, and mild systemic findings. Like sickle cell-thalassemia disease, patients with sickle cell C disease tend to have severe ocular pathologies; they are at an increased risk for developing proliferative retinopathy changes.

Race

Although sickle cell disease first was described in a black patient, it is not confined to patients of African ancestry. Sickle cell trait is more common in Central Africa but is infrequent in North and South Africa.

• Of people living in Northern Greece, 20-30% reportedly have Hb S.
• Of Saudi Arabians, especially in the Qatif oasis, 25% have the variant gene.
• Other locations where sickle cell disease occurs include Turkey, Southern Italy, the Mediterranean, and Central India (Orissa, Madhya Pradesh, and Maharastra).
• Theories for this distribution include the protective mechanism of Hb S heterozygosity against falciparum malaria. The gene is most prevalent in Central Africa, particularly in regions where malaria is endemic. The gene is thought to persist because heterozygosity protects slightly against falciparum malaria. Parasitized sickle cell (Hb AS) erythrocytes have a shorter lifespan, so the parasite probably cannot complete its development. Furthermore, the growth of trophozoites is inhibited by low oxygen tension.

Sex

No sexual predilection exists.