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.

Historical Perspective

• Sickle cell disease has a significant historical perspective. Many centuries ago, it was noted that people from Africa succumbed to vaso-occlusive pain crises. At this time, the etiology for pain crises was not clear. The pioneering work established by James Herrick nearly a century years ago. James Herrick noted that a dental student from Grenada had abnormally shaped rec blood cells on his peripheral blood smear. In 1936, vaso-occlusion the pulmonary vascular beds was noted on an autopsy. It was not until 1949 that sickle cell disease was associated with an alteration of hemoglobin. Linus Pauling and coworkers noted for the first time that a genetic disease was linked to a mutation of a specific protein.

Classification

• 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 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.

Gross pathology does not play a significant role in diagnosis. 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 can be seen.

• 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.
• There are no other established causes for sickle cell disease.

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

• There are no other risk factors (aside from race) in the development of sickle cell disease. There are, however, risk factors for precipitation of painful vaso-occlusive crises, such as dehydration and poor oxygenation. Risk factors for development of overt renal failure include hypertension, hematuria, nephrotic-range proteinuria, and severe anemia.

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.
• Early clinical features include painful crises, fatigue, and shortness of breath.
• Common complications of sepsis, hypoxia, tissue infarction, and death. Depression is also a common complication.
• Prognosis is generally guarded, and the survival rate at age 18 years rate is approximately 94%, in a Dallas newborn cohort. In Africa, many children are left undiagnosed, so the survival rate is lower.

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 may include the following:

• Bone pain
• Fever
• Infection
• Chest pain
• Blurry vision
• Fatigue
• Shortness of breath

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

• There are some specific laboratory findings associated with sickle cell disease.

Low hemoglobin (anemia) is due to the intrinsic nature of the 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 seen.

• A positive peripheral blood smear showing sickle-shaped cells is characteristic of sickle cell disease.

Imaging Findings

In some cases, plain imaging such as X-rays can be useful. These can show subacute of chronic infarcts of the extremities. Deformities may also be seen on plain radiogrpahs.

• MRI can show avascular necrosis of the leg. It can also show osteomyelitis and marrow hyperplasia.
• CT scan is useful for patients with suspected stroke due to vaso-occlusion.

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. Two mates with sickle cell trait have a 25% chance of producing an offspring with sickle cell disease. For a patient with sickle cell disease who has a baby, the patient's partner should be tested to given insight into the baby's sickle cell status.

Hydroxyurea can prevent sickle cell crises by increasing fetal hemoglobin. Fetal hemoglobin protects against complications of anemia. It protects against end-organ dysfunction, including liver dysfunction.

• Effective measures for the primary prevention of sickle cell disease include screening. Once sickle cell disease is present, preventive measures to avoid sickling and vaso-cclusive crises include hydration and oxygenation.