Sickle Cell Disease: Genetics, signs and symptoms, Treatment

Sickle cell disease (SCD) is a group of hereditary hemoglobin disorder characterized by a transformation of red blood cells into sickle shape on deoxygenation which was first reported in the USA in 1910 by James Herrick

The disease is produced due to a single point mutation.

The abnormal hemoglobin, Hb-S results from the substitution of valine for glutamic acid at the 6th position of the β chain.

The sickle cell disease includes

• Sickle cell anemia (homozygous Hb-S disease)
• Sickle cell/β- thalassemia
• Sickle cell /Hb-C disease

Inheritance

The SCD is inherited in an autosomal co-dominant manner. Homozygotes only produce abnormal beta chains that make hemoglobin S (SS) resulting in the clinical syndrome of sickle­ cell disease.

Heterozygotes produce a mixture of normal and abnormal beta chains that make normal HbA and HbS (AS) resulting in the clinically asymptomatic sickle ­cell trait

Hemoglobin gene

The gene related to sickle cell anemia is the hemoglobin gene (HBB).

Hemoglobin contains iron and transports oxygen from the lungs to the peripheral tissues.

The HBB protein is 146 amino acids long.
The HBB gene is found on chromosome 11.

There are 4 protein subunits of Hemoglobin A

There will be different forms of Hemoglobin when there is a mutation in the beta subunit.

The abnormal beta chain is designated betas and the tetramer of alpha-2betas-2 is designated hemoglobin S.

Sickle cell trait

An S mutation in one copy of the hemoglobin beta gene. Half of the beta subunits are replaced with Beta S.

Sickle cell disease

This results when both copies of the hemoglobin beta gene have an S mutation. All of this person’s beta subunits are replaced by beta S.

Sickle cell hemoglobin C.

This results when one of the beta subunits is replaced with beta C and one is replaced with beta S. The mutation happens because a glutamic acid residue replaces a lysine residue at the 6th position of the beta-globin chain.

Pathophysiology of sickle cell disease

Hemoglobin S is unstable and polymerizes in the setting of stressors leading to the formation of sickled red cells. Sickled cells result in hemolysis and the release of ATP, which is converted to adenosine. Adenosine binds to its receptor (A2B) resulting in the production of 2,3-biphosphoglycerate and the induction of more sickling and to its receptor (A2A) on natural killer cells resulting in pulmonary inflammation.

The free hemoglobin from hemolysis scavenges nitric oxide causing endothelial dysfunction due to the abnormal interaction with the vascular endothelium, vascular injury, and pulmonary hypertension. This process results in anemia, vaso-occlusive episodes, organ damage and increased susceptibility to infection

The rate of sickling is influenced by the intracellular concentration of hemoglobin S and by the presence of other hemoglobins within the cell. Thus, the abnormal hemoglobin C variant participates in the polymerization more readily than hemoglobin A, whereas hemoglobin F strongly inhibits polymerization and its presence markedly retards sickling.

Factors that increase sickling are red blood cell dehydration and factors that lead to the formation of deoxyhemoglobin S (eg, acidosis and hypoxemia) either systemic or local in tissues. The distribution of sickle cell gene parallels that of Falciparum malaria.

Signs and symptoms

The onset of sickle cell disease is during the first year of life when hemoglobin F levels fall.

Clinical features related to hemolytic anemia and vascular occlusion which causes pain, organ dysfunction, and organ failure

Growth failure and psycho-social problems

Splenic infarcts result in auto-splenectomy leading to frequent septicemia.

The patient will present with an aplastic crisis, splenic sequestration crisis, and vascular occlusion. The common sites of acute painful episodes include the spine and long appendicular and thoracic bones. These episodes last hours to days

Cerebral complications due to vaso-occlusion (strokes) are more often seen in children.

Asymptomatic due to the presence of a high amount of Hb-F which interferes with polymerization or co–inheritance of the gene for thalassemia or hereditary persistence of Hb-F

Chronic hemolytic anemia produces jaundice, gallstones, splenomegaly, and poorly healing ulcers over the lower tibia.

Priapism.

Sickle cell crisis

Sickle cell crisis is an acute onset of pain, The crises include:

Vaso-occlusive crisis

Many children develop ‘hand-foot’ syndrome. It can also affect chest, abdomen and long bones, especially in the juxta-articular position. This pain may last for 2 to 6 days.

Aplastic crisis

Infections especially parvovirus B19 can lead to a profound drop in hemoglobin by producing red cell aplasia.

Megaloblastic crisis

Due to inadequate folate levels in the body. FA requirement is higher in hemolytic anemia and this factor is responsible for the severity

Splenic sequestration crisis

Usually seen under the age of 2 years. The spleen rapidly enlarges and most of the circulating red cell mass becomes sequestrated

Hemolytic crises may be related to splenic sequestration of sickled cells before the spleen has been infarcted as a result of repeated sickling or with coexistent disorders such as G6PD deficiency

Physical examination

patients are often chronically ill and jaundiced.
There is hepatomegaly, but the spleen is not palpable in adult life.

The heart is enlarged, with a hyperdynamic precordium and systolic murmurs.
Nonhealing ulcers of the lower leg and retinopathy may be present

Laboratory findings

FBC-Chronic hemolytic anemia is present. The hematocrit is usually 20–30%.
a peripheral blood smear is abnormal, with irreversibly sickled cells 5–50% of RBCs
reticulocytosis
Nucleated red blood cells
Howell-Jolly bodies and target cells.
The white blood cell count is elevated to 12,000–15,000/mcL
reactive thrombocytosis
Indirect bilirubin levels are high.
Sickling test

The diagnosis of sickle cell anemia is confirmed by hemoglobin electrophoresis
Hemoglobin S will usually comprise 85–98% of hemoglobin. In homozygous S disease, no hemoglobin A will be present. Hemoglobin F levels are variably increased, and high hemoglobin F levels are associated with a more benign clinical course.

Chest x-ray for acute chest syndrome

Treatment

Treatment to relieve pain, prevention of dehydration, treatment of fever and psycho-social support.

Dietary advice includes adequate calorie intake, adequate folic acid, vitamin-C, vitamin-E and zinc supplement.

Management of complications

Infections: These include prophylactic penicillin, immunization. Pneumococcal vaccination at the age of 18 months followed by boosters every 5 years. Immunization against H. influenza is suggested by the age of 18 months. Hepatitis-B vaccination is also a must.

Transfusions
suppression of Hb-S would lead to decreased vaso-occlusive episodes

Pain
aggressive use of appropriate analgesics,

Fluid supplement and looking for the cause of infection
The most promising agent is hydroxyurea which has the ability to induce fetal hemoglobin synthesis. This has become the standard-of-care today. It decreases the number of vaso-occlusive episodes. The usual dose is 20 mg/kg per day

Bone marrow transplantation 
Gene therapy may become applicable to SCD.
Prenatal diagnosis by chorionic villous biopsy is possible.

Complications

Cardiovascular system
Anemia leading to myocardial ischemia, myocardial infarction restrictive cardiomyopathy

Pulmonary system
due to vaso-occlusion, infections or both..“acute chest syndrome” either due to infection or infarction.

central nervous system
transient ischaemic attacks, strokes and cerebral hemorrhage

Hepato-biliary system
Gall-stones, recurrent abdominal pain due to vaso-occlusive crisis, hepatomegaly and hepatic dysfunction

Reproductive system
Placental infarcts can lead to intrauterine growth retardation and low birth-weight babies. spontaneous abortion is increased.

Urinary system
The kidney is a major target organ. Haematuria, hyposthenuria, abnormal acid load test, increased urinary tract infection hyperuricemia and gout

Ocular complications
Proliferative retinopathy is commonly seen in SCD.

Orthopedic
hand-foot syndrome, avascular necrosis of the hip, Osteomyelitis, Skin ulcers around the ankle