Sickle-cell disease overview

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2], Shyam Patel [3]

Overview

Sickle-cell disease is a group of genetic disorders of the red blood cell caused by a mutation in the β-globin chain gene of hemoglobin at the 6th position replacing glutamic acid to valine. HbS polymerizes reversibly when deoxygenated to form a network of fibrous hemoglobin polymers that stiffens the RBC membrane, giving it a sickle shape. These sickled cells loose the pliability to cross thin capillaries and possess a sticky membrane, giving it a property to adhere to the endothelium of blood vessels, thereby causing vaso-occlusion. It causes significant morbidity and mortality, particularly in people in the Mediterranean and African region. The treatment includes measures to avoid vaso-occlusion, such as avoidance of dehydration, low oxygen conditions, or cold weather. Hydroxyurea has been used to increase fetal hemoglobin production.

Historical Perspective

Sickle-cell disease was first discovered by James Herrick, an American cardiologist and professor of medicine, in 1910 following presentation by his intern Ernest Irons. In 1922, the phrase, "sickle-cell anemia," was first used by Verne Mason, M.D. at Johns Hopkins University to describe the shape of the red blood cells.

Classification

Sickle-cell disease may be classified according to the number and type of the two alleles of beta-globin. Sickle-cell disease may also be classified as an autosomal recessive genetic disorder. Sickle cell disease does not have a traditional classification method, as is true for other hemoglobinopathies. However, there are a few particular subtypes. Each subtype is based on the number and type of hemoglobin allele(s). The letter S denotes an allele with the sickle cell mutation. The subtypes (and the associated disease in parentheses below) are as follows:

• HbSS (sickle cell anemia)
• HbSC (milder form of sickle cell anemia)
• HbAS (sickle cell trait)
• HbSB+thal (beta-thalassemia anemia)
• HbSB0thal (beta-thalassemia anemia)

• Other variants of sickle cell disease include HbSD, HbSE, or HbSO (one sickle cell gene and one other gene).

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Pathophysiology

The pathophysiology of sickle cell disease is based on a mutation in the beta-globin chain of hemoglobin, which leads to red blood cell sickling and vaso-occlusive crises. The pathogenesis of sickle cell disease is characterized by an amino acid substitution on the beta-globin chain on chromosome 11, resulting in red blood cell sickling and vaso-occlusive episodes in various organs. A mutation in beta-globin, namely a a point mutation in exon 1 that substitutes valine for glutamic acid, has been associated with the development of sickle cell disease, involving the hemoglobin synthesis pathway. On microscopic analysis, a peripheral blood smear will show sickle-shaped red blood cells, which are the characteristic findings of sickle cell disease. In some cases, hemoglobin C crystals may be observed. The point mutation causes cells to sickle, resulting in decreased deformability and decreased passage of red blood cells through the vasculature.

Causes

Sickle cell disease is caused by a mutation in the beta-globin gene on chromosome 11.

Differentiating Sickle Cell Disease from other Diseases

• Sickle cell disease must be differentiated from other diseases that cause fatigue, infection, bone pain, such as:

• Thalassemia
• Acute leukemia
• Autoimmune hemolytic anemia
• HbSC disease
• HbS-beta-thalassemia
• Septic arthritis
• Polycythemia vera
• Systemic lupus erythematosus

Epidemiology and Demographics

• The prevalence of sickle cell disease is approximately 160 per 100,000 individuals worldwide at birth. The actual prevalence, however, is less given that people die from the disease at an early time point.
• Approximately 1 in 12 persons of African descent have sickle cell trait.
• Approximately 100,000 persons are living with sickle cell disease in the United States.

Age

• Age is not a risk factor for sickle cell disease since this disease is inherited at birth. Unlike other diseases that increase with age, persons with sickle cell disease are born with the condition.

Gender

• Sickle cell disease affects men and women equally. It is not an X-linked disease.

Race

• There is a racial predilection for sickle cell disease.
  • Sickle cell disease usually affects individuals of the black race.
  • Sickle cell disease also affects persons of eastern Mediterranean descent and Middle Eastern descent.

Risk Factors

The most potent risk factor in the development of sickle-cell disease is race, which include Africans, African Americans, Indians, and persons of Mediterranean descent. An additional risk factor is geographic location, with these locations containing the greatest occurrences of disease.

Screening

Sickle cell disease is currently a disease for which newborn screening is available, mandated, and routinely performed in the United States.

Natural History, Complications and Prognosis

• The majority of patients with sickle cell disease remain asymptomatic until the second half of the first year of life. This is the time when fetal hemoglobin production declines such that sickled hemoglobin manifests clinically.
• If left untreated, sickle-cell disease can result in death.
• Early clinical features include painful crises, fatigue, and shortness of breath.
• Common complications include sepsis, hypoxia, tissue infarction, depression, and death.
• Prognosis is generally guarded in the United States and poor in developing nations.

Diagnosis

Diagnostic Criteria

• The diagnosis of sickle cell disease is made when a person has:

• The characteristic genetic mutation (glutamic acid to valine) in beta-globin
• Symptoms characteristic of sickle cell disease

Symptoms

• Sickle cell disease is usually symptomatic.

Symptoms of sickle-cell disease include:

• Pain and/or bone pain
• Dactylitis
• Blurry vision
• Persistent and painful erection
• Numbness
• Tingling
• Motor skill loss
• Speech deficits
• Gait disturbance
• Leg ulceration
• Jaundice

Physical Examination

• Patients with sickle cell disease usually appear ill during times of acute exacerbation of painful crises. If patients are well controlled on their medications, they can appear clinically well.
• Physical examination may be remarkable for:

• Hypotension
• Tachycardia
• Dehydration
• Scleral icterus
• Pallor (conjunctival, mucosal, and/or skin)
• Fever
• Otitis/sinusitis
• Splenomegaly (due to extramedullary hematopoiesis)
• Heart failure
• Frontal and parietal bone bossing (due to extramedullary hematopoiesis)

Laboratory Findings

The most important laboratory test for sickle cell anemia is a complete blood count (CBC), specifically hemoglobin and hematocrit. Low hemoglobin (anemia) is due to the intrinsic nature of the disease. A positive peripheral blood smear showing sickle-shaped cells is characteristic of sickle cell disease. High total bilirubin with predominantly indirect bilirubin may suggest hemolysis, since bilirubin is a breakdown production of hemoglobin. High lactate dehydrogenase (LDH) may also be seen if there is hemolysis. High reticulocyte count may be seen if the bone marrow is attempting to compensate for the anemia. Low oxygen content on arterial blood gas (ABG) may be observed.

Imaging Findings

• In some cases, plain imaging such as x ray can be useful, which may reveal subacute or chronic infarcts of the extremities or deformities.
• CT scan is useful for patients with suspected stroke due to vaso-occlusion.
• MRI can show avascular necrosis of the leg. It can also show osteomyelitis and marrow hyperplasia.

Other Diagnostic Studies

• Sickle cell disease does not require any additional diagnostic tests. Newborn screening accurately identifies patients with sickle cell disease.

Treatment

Medical Therapy

• The mainstay of therapy for sickle cell disease is supportive care. Supportive care includes pain control, transfusions, antibiotics if there is infection, hydration, and oxygenation.

Specific therapies include hydroxyuea, which increases fetal hemoglobin production, exchange transfusions, and stem cell transplant.

Surgery

• Surgery has no significant role in sickle cell disease.

Prevention

• There are no primary preventive measures available for sickle cell disease. However, genetic counseling is an option.

Hydroxyurea can prevent sickle cell crises by increasing fetal hemoglobin. Fetal hemoglobin protects against complications of anemia.

References