Introduction
Background
Sickle cell disease (SCD) is a chronic hemoglobinopathy of clinical relevance because of its significant morbidity and mortality, particularly in people of African and Mediterranean ancestry. Carriers of the sickle cell trait (HbAS, heterozygotes) have some resistance to the often-fatal malaria caused by Plasmodium falciparum.1,2,3
Skeletal sickle cell anemia. Hand-foot syndrome. Soft tissue swelling with periosteal new-bone formation and a moth-eaten lytic process at the proximal aspect of the fourth phalanx.
Skeletal sickle cell anemia. Expanded medullary cavity. The diploic space is markedly widened due to marrow hyperplasia. Trabeculae are oriented perpendicular to the inner table, giving a hair-on-end appearance.
Skeletal sickle cell anemia. Osteomyelitis. Coronal T1-weighted MRI shows marrow edema in the shortened third metacarpal, which appears dark. Note the loss of cortex along the radial aspect of the metacarpal.
Ever since carriers of the mutated gene survived the deadly malaria epidemics that were thought to occur thousands of years ago, the gene has continued to survive in malaria-endemic areas. However, in areas such as the US, where malaria is not a problem, the trait no longer provides a survival advantage and instead poses the threat of sickle cell disease if the carrier's children inherit the sickle cell gene from both parents (ie, HbSS). Although carriers of sickle cell trait do not suffer from the disease, individuals with one copy of HbS and one copy of a different beta-globin gene variant such as HbC or Hb beta-thalassemia have a less severe form of the disease.
Although the disease is most frequently found in sub-Saharan Africa, it is also found in some parts of Sicily, Greece, southern Turkey, and India, all of which have areas in which malaria is endemic.
For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Sickle Cell Crisis.
Pathophysiology
Sickle cell disease is a genetically transmitted autosomal recessive disorder, resulting from an amino acid substitution of valine for glutamic acid at the sixth position on the beta chain of the hemoglobin molecule in red blood cells. This substitution creates instability of the hemoglobin molecule in the deoxygenated state, during which HbS polymerizes and causes red blood cells to change from the usual biconcave disc shape to an irregular sickled shape.
The abnormal shape of these red blood cells and their propensity to adhere to the walls of blood vessels can occlude the vessels, preventing normal blood flow and decreasing the delivery of oxygen to organs and tissues, a condition known as crisis. The sickled cells are also extremely susceptible to hemolysis, causing individuals with sickle cell disease to have chronic anemia.
Predisposing causes of sickle cell crises
Vaso-occlusive episodes are associated with dehydration, acidosis, and fever. Cold and systemic illnesses (eg, infections) commonly precipitate sickle cell crises. Sudden changes in altitude and travel in nonpressurized aircraft sometimes precede onset of a vaso-occlusive crisis.
Manifestations of sickle cell disease
The skeletal manifestations of sickle cell disease are the result of changes in bone and bone marrow caused by the chronic tissue hypoxia that is exacerbated by episodic occlusion of the microcirculation by the abnormal sickle cells. The main processes that lead to bone and joint destruction in sickle cell disease are infarction of bone and bone marrow, compensatory bone marrow hyperplasia, secondary osteomyelitis, and secondary growth defects.
When the rigid erythrocytes jam in the arterial and venous sinusoids of skeletal tissue, the resultant effect is intravascular thrombosis, which leads to infarction of bone and bone marrow. Repeated episodes of these crises eventually lead to irreversible bone infarcts and osteonecrosis, especially in weight-bearing areas. These areas of osteonecrosis (avascular necrosis/aseptic necrosis) become radiographically visible as sclerosis of bone with secondary reparative reaction and eventually result in degenerative bone and joint destruction.
Infarction of bone and bone marrow in patients with sickle cell disease can lead to the following changes: osteolysis (in acute infarction), osteonecrosis (avascular necrosis/aseptic necrosis), articular disintegration, myelosclerosis, periosteal reaction (unusual in the adult), H vertebrae (steplike endplate depression also known as the Reynold sign or codfish vertebrae) (see Image 1), dystrophic medullary calcification (see Image 10), and bone-within-bone appearance (see Image 11).
Skeletal sickle cell anemia. H vertebrae. Lateral view of the spine shows angular depression of the central portion of each upper and lower endplate.
Skeletal sickle cell anemia. Chronic infarcts and secondary osteoarthritis. Image shows advanced changes of irregular sclerosis and lucency on both sides of the knee joint reflecting numerous prior infarcts. The joint surfaces are irregular and the cartilages are narrowed due to secondary osteoarthritis.
Skeletal sickle cell anemia. Bone-within-bone appearance. Following multiple infarctions of the long bones, sclerosis may assume the appearance of a bone within a bone, reflecting the old cortex within the new cortex.
The shortened survival time of the erythrocytes in sickle cell (10-20 days) leads to a compensatory marrow hyperplasia throughout the skeleton. The bone marrow hyperplasia has the resultant effect of weakening the skeletal tissue by widening the medullary cavities, replacing trabecular bone and thinning cortices.
Deossification due to marrow hyperplasia can bring about the following changes in bone: decreased density of skull, decreased thickness of outer table of skull due to widening of diploe, hair on-end striations of the calvaria (see Images 4-5), and osteoporosis sometimes leading to biconcave vertebrae, coarsening of trabeculae in long and flat bones, and pathologic fractures.
Skeletal sickle cell anemia. Expanded medullary cavity. The diploic space is markedly widened due to marrow hyperplasia. Trabeculae are oriented perpendicular to the inner table, giving a hair-on-end appearance.
Skeletal sickle cell anemia. Detailed view of the expanded medullary cavity in the same patient as in Image above.
Skeletal sickle cell anemia. Bone deformity. Image shows shortening of the second and third metacarpals and phalanges with partial or complete early fusion of the growth plates due to osteonecrosis in infancy. Osteomyelitis is now superimposed the third metacarpal.
Patients with sickle cell disease can have a variety of growth defects due to the abnormal maturation of bone. The following growth defects are often seen in sickle cell disease: bone shortening (premature epiphyseal fusion) (see Image 17), epiphyseal deformity with cupped metaphysis, peg-in-hole defect of distal femur, and decreased height of vertebrae (short stature and kyphoscoliosis).
Frequency
United States
The following statistics are available from the Centers for Disease Control and Prevention and the National Institutes of Health4,5 :
- Sickle cell anemia is the most common inherited blood disorder in the US
- More than 70,000 people have sickle cell disease
- Sickle cell disease occurs in 1 in every 500 African Americans
- About 8% of African Americans are carriers of sickle cell disease
- Two million people have sickle cell trait
- Approximately 1 in 12 African Americans has sickle cell trait
International
The disease is most frequently found in sub-Saharan Africa. It is also found in some parts of Sicily, Greece, southern Turkey, and India, all of which have areas in which malaria is endemic.
Mortality/Morbidity
The morbidity and mortality associated with sickle disease are primarily due to recurrent vaso-occlusion. These have been classified into separate clinical syndromes based on the dominant pathophysiology and affected organ system.
- The disease is marked by a chronic anemic state with intermittent painful crises, impaired growth and development, increased susceptibility to infection, and a predilection for acute attacks on specific organ systems from microinfarction. After age 10 years, painful crises decrease but complications increase.
- Most patients live to early- or mid-adult years, and most die before age 50 years. The usual causes of death are thrombosis, pulmonary embolus, infection, or renal failure. Deaths at younger age tend to occur from cerebrovascular accidents or sepsis.
- See also Morbidity and associated conditions in the Clinical Details section, below.
Race
Sickle cell disease is seen primarily in blacks and, to a lesser extent, in people who live around the Mediterranean Sea. In the United States, sickle cell disease is rare in other races.
Age
- After age 10 years, rates of painful crises decrease, but rates of complications increase.
- Most patients live to early- or mid-adult years, and most die before age 50 years.
Anatomy
Infarction tends to occur in the diaphyses of small tubular bones in children and in the metaphyses and subchondrium of long bones in adults.
Because of the anatomic distribution of the blood vessels supplying the vertebrae, infarction affecting the central part of the vertebrae (fed by a spinal artery branch) results in the characteristic H vertebrae of sickle cell disease (see Image 1). The outer portions of the plates are spared because of the numerous apophyseal arteries.
Skeletal sickle cell anemia. H vertebrae. Lateral view of the spine shows angular depression of the central portion of each upper and lower endplate.
Skeletal sickle cell anemia. Osteonecrosis. Image shows flattening of the femoral heads with a mixture of sclerosis and lucency characteristic of osteonecrosis.
Skeletal sickle cell anemia. Osteonecrosis. Detail of the right hip.
Skeletal sickle cell anemia. Osteonecrosis. Detail of the left hip.
Osteonecrosis of the epiphysis of the femoral head (see Images 6-8) is often bilateral and eventually progresses to collapse of the femoral heads. This same phenomenon is also seen in the humeral head, distal femur, and tibial condyles.
Presentation
Physical examination
The characteristic appearance in children with sickle cell disease includes frontal and parietal bossing and prominent maxilla due to marrow hyperplasia expanding the bone. The extremities may appear proportionately longer than normal because there is often flattening of the vertebrae.
The physical findings of acute infarction seen in sickle cell disease include local effects from swelling of the affected bone, such as that due to proptosis or ophthalmoplegia from orbital bone infarction. Also present is pain, swelling, and warmth of the involved extremity, such on the dorsa of the hands and feet in patients with dactylitis.
The physical findings seen in sickle cell disease as sequelae of chronic infarction include structural and functional orthopedic abnormalities. Examples include an immobile or nonfunctional shoulder joint, abnormal hip growth and deformity, secondary osteoarthritis, shortened fingers and toes, and kyphoscoliosis.
Morbidity and associated conditions
Hand-foot syndrome, or aseptic dactylitis, (see Image 3) is a common presentation of sickle cell disease. This condition is caused by infarction of bone marrow and cortical bone in the metacarpals, metatarsals, and proximal phalanges. Hand-foot syndrome is usually one of the earliest manifestations of the disease. Other pertinent findings of hand-foot syndrome include a presentation with exquisite pain and soft tissue swelling of the hands and feet, a sudden appearance and lasting 1-2 weeks, and an occurrence between age 6 months and 3 years. This syndrome is not seen after age 5 years because hematopoiesis in the small bones of the hands and feet ceases at this age. Osteomyelitis is the major differential diagnosis.
Skeletal sickle cell anemia. Advanced dactylitis. Lytic processes are present at the first and fifth metacarpals, along with periostitis, which is most prominent in the third metacarpal.
Acute bone pain crises are caused by bone marrow ischemia or infarction. These usually start after age 2-3 years and occur as gnawing, progressive pain most commonly in the humerus, tibia, and femur and less commonly in the facial bones. Periarticular pain and joint effusion, often associated with a sickle cell crisis, are considered a result of ischemia and infarction of the synovium and adjacent bone and bone marrow.
Patients with acute bone pain crises usually present with fever, leukocytosis, and warmth and tenderness around the affected joints. This process tends to affect the knees and elbows, mimicking rheumatic fever and septic arthritis. In adolescence and adulthood, the most prominent complication is osteonecrosis of 1 or more epiphyses, usually of the femoral or humeral heads. Chronic pain is often associated with later stages of osteonecrosis, particularly in the femoral head. Pain due to avascular necrosis is most notable with weight bearing on the joint. Patients often have pain associated with functional limitation of the affected joint.
Skeletal sickle cell anemia. Osteomyelitis. CT scan in a soft tissue window demonstrates a large abscess in the left thigh encircling the femur, with hypoattenuating pus surrounded by a rim of vivid enhancement.
Skeletal sickle cell anemia. Bone deformity. Image shows shortening of the second and third metacarpals and phalanges with partial or complete early fusion of the growth plates due to osteonecrosis in infancy. Osteomyelitis is now superimposed the third metacarpal.
Skeletal sickle cell anemia. Osteomyelitis. Coronal T1-weighted MRI shows marrow edema in the shortened third metacarpal, which appears dark. Note the loss of cortex along the radial aspect of the metacarpal.
Skeletal sickle cell anemia. Bone infarction in an infant. Image shows a curvilinear area of sclerosis with central lucency in the metaphysis of the femur representing a bone infarct.
Patients with sickle cell disease are prone to infection of the bone and bone marrow, or osteomyelitis, (see Images 15-22) in areas of infarction and necrosis. Although Staphylococcus aureus is the most common cause of osteomyelitis in the general population, studies have shown that in patients with sickle cell disease, the relative incidence of Salmonella osteomyelitis is twice that of staphylococcal infection.
Preferred Examination
MRI is the best method for detecting early signs of osteonecrosis (see Images 13-14) in patients with sickle cell disease and for identifying episodes of osteomyelitis (see Images 19-21).
Skeletal sickle cell anemia. Osteonecrosis. Coronal T1-weighted MRI shows a slightly flattened femoral head with a serpentine margin of low signal intensity around an area of ischemic marrow with signal intensity similar to that of fat.
Skeletal sickle cell anemia. Osteonecrosis in the same patient as in Image above. Coronal T2-weighted MRI shows a serpentine area of low signal intensity and additional focal areas of abnormal low signal intensity in the femoral head; these findings reflect collapse of bone and sclerosis.
Nuclear medicine scanning can also be used to detect early osteonecrosis (see Image 23). This modality also plays a role in detecting osteomyelitis. Likewise, indium leukocyte scanning has an important role in diagnosing osteomyelitis.
Skeletal sickle cell anemia. Bone infarct in the same patient as in Image 22 in Multimedia. Bone scan shows an area of increased uptake in the distal femoral metaphysis corresponding to the infarct demonstrated on the previous plain radiograph.
Skeletal sickle cell anemia. Chronic infarcts and secondary osteoarthritis. Image shows advanced changes of irregular sclerosis and lucency on both sides of the knee joint reflecting numerous prior infarcts. The joint surfaces are irregular and the cartilages are narrowed due to secondary osteoarthritis.
Skeletal sickle cell anemia. Medullary sclerosis. Image shows patchy sclerosis of the proximal tibia due to old infarctions. In other cases, sclerosis may be diffuse rather than patchy.
Plain radiography of the extremities is useful in evaluating subacute and chronic infarction and in assessing the number and severity of prior episodes of infarction (see Images 10-12). Plain radiographs are also excellent for evaluating deformities and other complications of bone infarction.
Limitations of Techniques
Osteonecrosis is visible on plain images only in the later stages after the affected bone is substantially damaged.
Differential Diagnoses
Legg-Calve-Perthes Disease
Rheumatoid Arthritis, Hands
Septic Arthritis
Other Problems to Be Considered
Gaucher disease also expands the marrow cavity and causes bone marrow infarction. Unlike sickle cell disease, which causes splenic infarction, Gaucher disease causes splenomegaly.
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References
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Ashley-Koch A, Yang Q, Olney S. Sickle Hemoglobin (HbS) Allele and Sickle Cell Disease. Aug 5 1998;Available at: www.cdc.gov/genomics/hugenet/reviews/sickle.htm#At-A-Glance. [Full Text].
Burnett MW, Bass JW, Cook BA. Etiology of osteomyelitis complicating sickle cell disease. Pediatrics. Feb 1998;101(2):296-7. [Medline].
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Further Reading
Related eMedicine topics
Sickle Cell Anemia (from Hematology)
Sickle Cell Disease (from Ophthalmology)
Anemia, Sickle Cell (from Emergency Medicine)
Pediatrics, Sickle Cell Disease
Sickle Cell Anemia (from Pediatrics, General Medicine)
Guidelines
Screening for Sickle Cell Disease in Newborns: U.S. Preventive Services Task Force
Recommendation Statement
Clinical studies
Evaluation of Hydroxyurea Plus L-Arginine or Sildenafil to Treat Sickle Cell Anemia
Effects of Nitric Oxide and Nitroglycerin in Patients With Sickle Cell Anemia
Keywords
sickle cell anemia, SCD, sickle cell disease, hemoglobin S disease, hemoglobin A, Hb S disease, sickle cell trait, hemoglobinopathy, Plasmodium falciparum, HbAS, HbSS
