AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Nuclear Medicine
• Intervention
• Multimedia
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Nuclear Medicine
• Intervention
• Multimedia
• References

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.

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 vasoocclusive 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), bone-within-bone appearance (see Image 11).

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), osteoporosis, sometimes leading to biconcave vertebrae, coarsening of trabeculae in long and flat bones, and pathologic fractures.

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 prevalence of sickle cell disease (HbSS) is 0.2% among African Americans and 0.1% among Hispanic Americans.

The prevalence of sickle cell trait (HbAS) is 10% among African Americans.

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 vasoocclusion. 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.

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.

Clinical Details

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.

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.

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).

Nuclear scanning (see Image 23) can also be used to detect early avascular necrosis. This modality also plays a role in detecting osteomyelitis. Likewise, indium leukocyte scanning has an important role in diagnosing osteomyelitis.

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.

DIFFERENTIALS

Section 3 of 10  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Nuclear Medicine
• Intervention
• Multimedia
• References

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.

RADIOGRAPH

Section 4 of 10  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Nuclear Medicine
• Intervention
• Multimedia
• References

Findings

The early plain radiographic findings of dactylitis consist of soft tissue swelling. Periosteal new-bone formation can be seen on radiographs 7-10 days later. Additionally, medullary expansion, cortical thinning, trabecular resorption, and resultant focal lucency may be seen 2-3 weeks after the onset of symptoms, but these findings usually resolve within weeks (see Images 2-3).

Osteonecrosis can affect the articular portions of the long bones. Collapse of the bone surfaces that are affected by osteonecrosis usually result in degenerative joint destruction. Radiographs of the affected joint may show patchy sclerosis initially, followed by flattening of bone (see Images 7-8).

Widened medullary cavities may be noted. In the calvaria, the major trabecular spicules in the widened diploic space are aligned perpendicular to the inner table, giving the skull the characteristic hair-on-end appearance (see Images 4-5).

Thickened bone can be observed. In the extremities, the medullary cavities are widened and the cortices are thinned, with loss of the normal modeling of the bone due to marrow hyperplasia.

Infarction of the central portion of the vertebral endplates results in the characteristic H deformity (angular depression) of vertebral bodies. When present in multiple vertebrae, this finding is virtually pathognomonic for sickle cell disease (see Image 1).

Shortening of bone may be depicted. Epiphyseal infarction may produce cone-shaped epiphysis or premature fusion of the epiphysis resulting in abnormal shortening of the involved bone (see Image 17).

After 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 (see Image 11).

Regarding myelosclerosis, the cumulative effects from repeated chronic small episodes of infarction result in a mottled, strandlike increased opacity in the medullary region (see Image 10).

Although radiography is not as sensitive as other studies for osteomyelitis in the first 1-2 weeks, plain images subsequently show cortical destruction, periosteal new bone, and (with time) sinus tracts and sequestra (see Images 17-18).

CT SCAN

Section 5 of 10  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Nuclear Medicine
• Intervention
• Multimedia
• References

Findings

Although CT is not an initial study in most patients, CT scans can show findings of osteonecrosis, including sclerosis, collapse of bone (especially femoral heads), and a bone-within-bone appearance (see Image 16).

CT may also demonstrate findings in osteomyelitis, including abscesses, cloacae (sinus tracts), and sequestra or dead bone (see Images 15-16).

Degree of Confidence

CT is not the test of choice for evaluation of acute osteomyelitis.

MRI

Section 6 of 10  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Nuclear Medicine
• Intervention
• Multimedia
• References

Findings

MRI allows the early detection of changes in bone marrow due to acute and chronic bone marrow infarction, marrow hyperplasia, osteomyelitis, and osteonecrosis.

Acute infarction is characterized by diffuse decreased signal intensity on T1-weighted MRIs and increased signal intensity on T2-weighted images. This change results from bone marrow edema. With time, the process becomes more focal, and T1-weighted images show a serpiginous line of low signal intensity surrounding hyperintense marrow (see Image 13). A double line of low signal intensity surrounding inner high signal intensity is sometimes seen on T2-weighted MRIs.

Chronic bone infarcts, or old infarction and fibrosis, appears as focal areas of decreased signal intensity on both T1- and T2-weighted images.

Bone marrow hyperplasia presents as diffuse areas of decreased signal intensity on T1-weighted images in patients with sickle cell disease. This effect is due to the replacement of fatty marrow by hematopoietic marrow.

With osteomyelitis, areas of edema have decreased signal intensity that replaces the usual high signal intensity of fatty marrow on T1-weighted images. This appears as areas of increased signal intensity on T2-weighted images and results from bone marrow edema and/or joint effusions.

Sequestra, sinus tracts, and subperiosteal abscesses are also clearly identified when present.

Degree of Confidence

As with plain radiography, the sine qua non of diagnosing osteomyelitis on MRI is the identification of cortical destruction for which MRI is exquisitely sensitive.

MRI has a specificity of 98% and a sensitivity of 85-97% for identifying bone marrow infarcts.

NUCLEAR MEDICINE

Section 7 of 10  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Nuclear Medicine
• Intervention
• Multimedia
• References

Findings

Bone scanning can be used to detect early stages of osteonecrosis, and it is not as costly as MRI. Osteonecrosis can be detected on bone scans, appearing mostly as focal areas of increased activity. Occasionally, areas of decreased uptake can be seen; this is usually seen in early disease. Bone marrow scans demonstrate areas of decreased activity in marrow infarction.

The combination of an indium In 111 white blood cell scanning and technetium Tc 99m bone marrow scanning is useful to diagnose osteomyelitis. Osteomyelitis appears as an area of increased activity on the white blood cell scan that is not matched on the marrow scan.

INTERVENTION

Section 8 of 10  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Nuclear Medicine
• Intervention
• Multimedia
• References

Interventional radiologists may play a role in obtaining a sample to identify the infecting organism in osteomyelitis. Subperiosteal and soft tissue abscesses may also be drained.

MULTIMEDIA

Section 9 of 10  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Nuclear Medicine
• Intervention
• Multimedia
• References

Media file 1:  Skeletal sickle cell anemia. H vertebrae. Lateral view of the spine shows angular depression of the central portion of each upper and lower endplate.
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Media file 2:  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.
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Media file 3:  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.
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Media file 4:  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.
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Media file 5:  Skeletal sickle cell anemia. Detailed view of the expanded medullary cavity in the same patient as in Image 4.
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Media file 6:  Skeletal sickle cell anemia. Osteonecrosis. Image shows flattening of the femoral heads with a mixture of sclerosis and lucency characteristic ofosteonecrosis.
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Media file 7:  Skeletal sickle cell anemia. Osteonecrosis. Detail of the right hip.
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Media file 8:  Skeletal sickle cell anemia. Osteonecrosis. Detail of the left hip.
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Media file 9:  Skeletal sickle cell anemia. Bone infarct. Image shows patchy sclerosis of the humeral head and shaft representing multiple prior bone infarcts.
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Media file 10:  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.
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Media file 11:  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.
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Media file 12:  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.
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Media file 13:  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.
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Media file 14:  Skeletal sickle cell anemia. Osteonecrosis in the same patient as in Image 13. 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.
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Media file 15:  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.
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Media file 16:  Skeletal sickle cell anemia. Osteomyelitis and bone-within-bone. Bone-window CT scan in the same patient as in Image 15 shows a bone-within-bone appearance (concentric rings of cortical bone) in the right femur. On the left, a sinus tract (cloaca) traverses the lateral aspect of the femoral cortex, and a small, shardlike sequestrum is present deep to the sinus tract.
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Media type:  CT

Media file 17:  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.
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Media file 18:  Skeletal sickle cell anemia. Osteomyelitis in the same patient as in Image 17. There is a lytic process with periostitis and marked soft tissue swelling that is best seen on the lateral view.
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Media file 19:  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.
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Media file 20:  Skeletal sickle cell anemia. Osteomyelitis in the same patient as in Image 19. On this T2-weighted MRI, the marrow and surrounding tissues are very bright as a result of inflammatory edema.
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Media file 21:  Skeletal sickle cell anemia. Osteomyelitis in the same patient as in Image 20. Axial T2-weighted MRI again shows the marrow edema and surrounding subperiosteal pus collection, with a thin, dark rim representing the periosteal membrane. There is diffuse bright signal intensity in the soft tissues; this represents inflammation and edema.
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Media file 22:  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.
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Media file 23:  Skeletal sickle cell anemia. Bone infarct in the same patient as in Image 22. Bone scan shows an area of increased uptake in the distal femoral metaphysis corresponding to the infarct demonstrated on the previous plain radiograph.
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REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Nuclear Medicine
• Intervention
• Multimedia
• References

• Acurio MT, Friedman RJ. Hip arthroplasty in patients with sickle-cell haemoglobinopathy. J Bone Joint Surg Br. May 1992;74(3):367-71. [Medline].
• 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].
• Dahnert W, ed. Radiology Review Manual. 5th ed. Philadelphia: Lippincott, Williams & Wilkins;. 2003: 158-9.
• Harrison TR, Braunwald E, Fauci A, et al. Principles of Internal Medicine. 15th ed. New York:. McGraw Hill;2001: 2015.
• Leikin SL, Gallagher D, Kinney TR, et al. Mortality in children and adolescents with sickle cell disease. Cooperative Study of Sickle Cell Disease. Pediatrics. Sep 1989;84(3):500-8. [Medline].
• Mukisi-Mukaza M, Elbaz A, Samuel-Leborgne Y, et al. Prevalence, clinical features, and risk factors of osteonecrosis of the femoral head among adults with sickle cell disease. Orthopedics. Apr 2000;23(4):357-63. [Medline].
• Palmer PE, Reeder MM. Tropical Medicine Central Resource. 2000;Available at: http://tmcr.usuhs.mil/tmcr/main.htm. [Full Text].
• Putman CE, Ravin CE, eds. Textbook of Diagnostic Imaging. 2nd ed. 1361-439.
• Sennara H, Gorry F. Orthopedic aspects of sickle cell anemia and allied hemoglobinopathies. Clin Orthop. Jan-Feb 1978;154-57. [Medline].
• Syriopoulou VP, Smith Al. Osteomelitis and septic arthritis. In: Feigin RD, Cherry JD, eds. Textbook of Pediatric Infectious Diseases. 3rd ed. Elsevier Science;1992: 727-46.
• Wintrobe MM, Lee GR, Bithell TC. Clinical Hematology. 9th ed. Baltimore: Lippincott, Williams & Wilkins;1999: 1069-73.

Article Last Updated: Feb 4, 2005