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.

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 erythematosis

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

• Patients of all age groups may develop sickle cell disease.

Gender

• [Disease name] affects men and women equally.

• [Gender 1] are more commonly affected with [disease name] than [gender 2].
• The [gender 1] to [Gender 2] ratio is approximately [number > 1] to 1.

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, shortness of breath, and infection.
• Common complications of [disease name] include [complication 1], [complication 2], and [complication 3].
• 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 [disease name] may include the following:

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

Physical Examination

• Patients with [disease name] usually appear [general appearance].
• Physical examination may be remarkable for:

• hypotension
• tachycardia
• dehydration
• scleral icterus
• pallor (conjunctival 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 Xrays 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.
• On [imaging study 1], [disease name] is characterized by [finding 1], [finding 2], and [finding 3].
• [Imaging study 2] may demonstrate [finding 1], [finding 2], and [finding 3].

Other Diagnostic Studies

• [Disease name] may also be diagnosed using [diagnostic study name].
• Findings on [diagnostic study name] include [finding 1], [finding 2], and [finding 3].

Treatment

Medical Therapy

• There is no treatment for [disease name]; the mainstay of therapy is supportive care.

• The mainstay of therapy for [disease name] is [medical therapy 1] and [medical therapy 2].
• [Medical therapy 1] acts by [mechanism of action 1].
• Response to [medical therapy 1] can be monitored with [test/physical finding/imaging] every [frequency/duration].

Surgery

• Surgery is the mainstay of therapy for [disease name].
• [Surgical procedure] in conjunction with [chemotherapy/radiation] is the most common approach to the treatment of [disease name].
• [Surgical procedure] can only be performed for patients with [disease stage] [disease name].

Prevention

• There are no primary preventive measures available for [disease name].

• Effective measures for the primary prevention of [disease name] include [measure1], [measure2], and [measure3].

• Once diagnosed and successfully treated, patients with [disease name] are followed-up every [duration]. Follow-up testing includes [test 1], [test 2], and [test 3].