Sickle Cell Disease (SCD)


Sickle cell disease (SCD) comprises a group of inherited blood disorders in which the red blood cells are abnormal in shape and functionality.1 The fact that a variety of clinical manifestations of SCD affect multiple organ systems may make SCD  difficult to diagnose. 

Chronic anemia causes fatigue and exercise intolerance, and in some cases, it may be severe enough that the patient requires transfusions.2 Vaso-occlusive events, in which blood flow to various organs and tissues is blocked by the elongated, sickle-shaped red blood cells, contribute to pain crisis, stroke, acute chest syndrome, avascular necrosis of bone, recurrent infection due to splenic sequestration, cardiac problems, hepatobiliary problems, kidney problems, respiratory issues leading to pulmonary hypertension, and ophthalmological problems causing progressive vision loss.2 

Differential Diagnosis

Acute anemia is differentiated from chronic anemia on the basis of the duration of symptoms and the medical history. Typically, acute anemia occurs abruptly, whereas chronic anemia develops gradually. Usually, the abrupt drop in the level of red cells is temporally related to an event such as acute hemorrhage or hemolysis.3,4 

Aortic arch syndrome is characterized by structural problems in the arteries branching off the aorta. These may be congenital malformations, or they may be caused by trauma or the obstruction of blood flow to the head, neck, or upper extremities by blood clots. It is important to determine whether the blood vessel obstruction in this syndrome is due to blood clots or sickle cells.3,5 

Carotid-cavernous fistula (CCF) is an abnormal connection between the carotid artery or its branches and the cavernous sinus, a large retro-orbital vein. The differential diagnosis of a condition impeding blood flow to the eye should include CCF and SCD.3,6 

Facioscapulohumeral muscular dystrophy is characterized by weakness and atrophy of the muscles around the face, scapula, and proximal upper extremities.7 Weakness and atrophy of these muscles in SCD may be related to chronic anemia, causing fatigue and exercise intolerance, or to the obstruction of blood flow to these muscles, causing pain and decreased strength.2 Cardiac involvement is seen in facioscapulohumeral muscular dystrophy as well as in SCD.2,3,7,8

Familial exudative vitreoretinopathy is characterized by a paucity of blood vessels around the edges of the retina, reducing blood flow to the retina and leading to progressive vision loss.9 The symptoms of this disorder may mimic those that develop when sickle cells obstruct blood flow to the retina, causing retinopathy in SCD.2,3

Gaucher disease is a rare inherited disorder of lipid metabolism in which the bone marrow cavity may expand, resulting in bone marrow infarction.3,10 Patients with SCD may present with bone marrow infarction.2 A difference between Gaucher disease and SCD is that Gaucher disease causes splenomegaly, whereas SCD causes splenic infarction.3

Hemoglobin C disease or trait can be differentiated from SCD with hemoglobin tests, used to identify an individual’s specific type(s) of abnormal hemoglobin. Hemoglobin C is found in the blood of individuals with hemoglobin C disease, and hemoglobin C in combination with normal hemoglobin A is found in individuals with hemoglobin C trait. Persons with SCD have either the homozygous form (HbSS) of the disease or a heterozygous form, in which hemoglobin S is found in combination with another type of hemoglobin, such as hemoglobin C (HbSC). Individuals with sickle cell trait have hemoglobin A and hemoglobin S.11 Those with hemoglobin C disease (HbCC) present with mild hemolysis that causes borderline anemia and splenomegaly.3,12

Hemolytic anemia can be caused by various problems, one of which is SCD. It is important to rule out causes of erythrocyte destruction other than SCD, including autoimmune hemolytic anemia and drug-induced hemolytic anemia. Anemia may also be caused by infections, environmental toxins or chemicals, blood clots in small blood vessels, transfusions of blood from non-matching donors, and other genetic disorders, such as G6PD (glucose-6-phosphate dehydrogenase) deficiency.3,13 

Incontinentia pigmenti affects multiple body systems, particularly the skin. Patients present with blistering rashes, wart-like skin growths, and patches of hyperpigmentation (where the skin develops grey or brown patches) fading to hypopigmentation.14 These may mimic the ulcers and discoloration caused by obstruction of blood flow to the skin in individuals with SCD.2,3 

Legg-Calvé-Perthes disease is a genetic collagen disorder in which breakdown of the femoral head causes restricted hip movement, pain, and an antalgic gait in young children between the ages of 4 and 8. This disease may mimic avascular necrosis of the femoral head due to restricted blood flow to the bone in SCD.2,3,15

Lupus erythematosus is a chronic autoimmune disease manifesting with widespread symptoms similar to those of SCD, including fatigue, joint pain, inflammation of the blood vessels and soft tissues, kidney disease, cardiac problems, peripheral neuropathy, and painful exacerbation episodes.3,16 

Macroglobulinemia is a rare type of blood cancer in which excessive numbers of white blood cells form in the bone marrow, in turn affecting red blood cell production. This blood cancer manifests with weakness, fatigue, anemia, and neuropathy, mimicking the symptoms of SCD.3,17

Ophthalmological manifestations of leukemia are caused by the direct infiltration of cancer cells into the retina and optic nerve. Retinal hemorrhaging is secondary to anemia and thrombocytopenia.18 In SCD, progressive vision loss may be due to obstruction of blood flow to the retina by sickle cells, as well as to ptosis from para-orbital infarction.2,3 

Osteomyelitis has several different risk factors, including diabetes, hemodialysis, acute injury, bone surgery, immune system compromise, illicit drug injection, and poor circulation, which may be caused by SCD.3,19 

Polycythemia vera is a blood disorder characterized by excessive numbers of  red blood cells, white blood cells, and platelets in the bloodstream; the resulting thickening of the blood causes abnormal clotting. A presentation similar to that of SCD may be due to vaso-occlusion, including deep vein thrombosis, stroke, heart blockage, pulmonary embolism, impaired vision, gout, and splenomegaly.2,3,20  

Pulmonary embolism develops when a blood clot suddenly lodges in an artery within the lungs, affecting breathing. SCD similarly affects respiration, and acute chest syndrome may develop if pulmonary blood vessels are blocked by sickle cells.2,3,21

Rheumatoid arthritis is an autoimmune disorder characterized by inflammation, pain, and swelling in multiple joints.22 Symptoms may mimic those of SCD, such as dactylitis and vaso-occlusive events blocking circulation to the joints.2,3 

Septic arthritis is inflammation of a joint due to an infection of the blood.23 Sepsis is a widespread, life-threatening, extremely painful response of the body to infection that may result in multiorgan failure.24 These conditions may be more common in individuals with chronic diseases like SCD, who are predisposed to infection because of their compromised immune systems.2,3,23 Septic arthritis may also develop following joint replacement, recent joint surgery, intravenous drug use, acute joint injury, immunosuppressive drug use, or bacterial infections in the blood or elsewhere in the body.23

Talc and cornstarch emboli in the small blood vessels of the retinae, lungs, and brain of drug users cause reduced vision, respiratory issues like pulmonary hypertension, and neurological conditions like central nervous syndrome infarction. 25-27 The symptoms of talc and cornstarch emboli may mimic those of pulmonary hypertension, acute chest syndrome, central nervous system problems, and retinopathy, all of which occur in individuals with SCD; therefore, a thorough and accurate history of drug use must be obtained during screening.2,3

Upper respiratory tract infection may be more frequent in SCD because the immune system is weakened when sickle cells cause splenic sequestration. It is important to determine whether an upper respiratory tract infection is primary (caused by viruses or bacteria) or secondary (caused by viruses or bacteria in persons with immune function problems related to a disorder such as  SCD).2,3,28 

Uveitis with pars planitis is swelling and inflammation of the uvea, which supplies the retina with blood. It is associated with autoimmune disorders, infection, exposure to environmental toxins, or external injury to the eye. The pars plana is located between the iris and the choroid and becomes inflamed in a specific form of uveitis.29 This condition can mimic retinopathy caused by obstructed blood flow to the retina in SCD.2,3

In valvular heart disease, abnormal function of the 4 heart valves is caused by regurgitation, prolapse, or stenosis. Because the ejection fraction is reduced, cardiac output must increase to maintain sufficient oxygenation throughout the body.30 In SCD, increased cardiac output compensates for reduced oxygen saturation in the arteries due to sickle cells.31 The increased cardiac output often results in left ventricular diastolic failure and pulmonary hypertension, which are frequent comorbidities in individuals with SCD.32

References

  1. What is sickle cell disease? CDC.Centers for Disease Control and Prevention. Reviewed December 14, 2020. Accessed November 30, 2021.
  2. Maakaron JE. Sickle cell disease clinical presentation. Medscape. Updated November 2, 2021. Accessed November 30, 2021.
  3. Maakaron JE. Sickle cell disease differential diagnoses. Medscape. Updated November 2, 2021. Accessed November 30, 2021.
  4. Alder L, Tambe A. Acute anemia. In: StatPearls [Internet]. StatPearls Publishing; 2021. Accessed November 30, 2021.
  5. Aortic arch syndrome. MedlinePlus. Updated November 23, 2021. Accessed November 30, 2021. 
  6. Carotid-cavernous fistula (CCF). Michigan Medicine. Accessed November 30, 2021.
  7. Sickle cell disease. Cleveland Clinic. Reviewed February 25, 2020. Accessed November 30, 2021. 
  8. Palladino A, D’Ambrosio P, Papa AA, et al. Management of cardiac involvement in muscular dystrophies: paediatric versus adult forms. Acta Myol. 2016;35(3):128-134. 
  9. Familial exudative vitreoretinopathy. MedlinePlus. Accessed November 30, 2021.
  10. Gaucher disease. MedlinePlus. Accessed November 30, 2021.
  11. Hemoglobin-C trait. The Family Connection. Accessed November 30, 2021.
  12. Milton BA. Hemoglobin C disease. Overview. Medscape. Updated March 15, 2021. Accessed November 29, 2021.
  13. Hemolytic anemia. MedlinePlus. Accessed November 30, 2021.
  14. Incontinentia pigmenti. MedlinePlus. Accessed November 30, 2021.
  15. Legg-Calvé-Perthes disease. MedlinePlus. Accessed November 30, 2021.
  16. Systemic lupus erythematosus. MedlinePlus. Accessed November 30, 2021.
  17. Waldenström macroglobulinemia. MedlinePlus. Accessed November 30, 2021.
  18. Wu L. Ophthalmologic manifestations of leukemias clinical presentation. Medscape. Updated July 27, 2020. Accessed November 29, 2021.
  19. Osteomyelitis. MedlinePlus. Accessed November 30, 2021. 
  20. Polycythemia vera. MedlinePlus. Accessed November 30, 2021.
  21. Pulmonary embolism. MedlinePlus. Accessed November 30, 2021.
  22. Rheumatoid arthritis. MedlinePlus. Accessed November 30, 2021.
  23. Septic arthritis. MedlinePlus. Accessed November 30, 2021.
  24. What is sepsis? CDC. Centers for Disease Control and Prevention. Reviewed August 17, 2021. Accessed November 29, 2021. 
  25. AtLee WE Jr. Talc and cornstarch emboli in eyes of drug abusers. JAMA. 1972;219(1):49-51. doi:10.1001/jama.1972.03190270027007
  26. Lamb D, Roberts G. Starch and talc emboli in drug addicts’ lungs. J Clin Pathol. 1972;25(10):876-881.
  27. Enevoldson TP. Recreational drugs and their neurological consequences. J Neurol Neurosurg Psychiatry. 2004;75(suppl 3):iii9-iii15. doi:10.1136/jnnp.2004.045732
  28. Alkindi S, Al-Yahyai T, Raniga S, Boulassel MR, Pathare A. Respiratory viral infections in sickle cell anemia: special emphasis on h1n1 co-infection. Oman Med J. 2020;35(6):e197. doi:10.5001/omj.2020.89
  29. Uveitis. MedlinePlus. Accessed November 30, 2021.
  30. Heart valve diseases. MedlinePlus. Accessed November 30, 2021.
  31. Lindsay J Jr, Meshel JC, Patterson RH. The cardiovascular manifestations of sickle cell disease. Arch Intern Med. 1974;133(4):643-651. doi:10.1001/archinte.1974.00320160137012
  32. Wood KC, Gladwin MT, Straub AC. Sickle cell disease: at the crossroads of pulmonary hypertension and diastolic heart failure. Heart. 2020;106(8):562-568. doi:10.1136/heartjnl-2019-314810

Reviewed by Debjyoti Talukdar, MD, on 12/2/2021.

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