![[Banner Image]](images/hprods.gif){kind=small}
![[Home]](images/bhome.gif){kind=small}
![[What's New]](images/bnews.gif){kind=small}
![[Products & Services]](images/bprdsrv.gif){kind=small}
![[Contents]](images/btoc.gif){kind=small}
![[Feedback]](images/bfeed.gif){kind=small}
![[Search]](images/bsrch.gif){kind=small}
Introduction
James R. Eckman, M.D.
Sickle cell syndromes are caused by inheritance of homozygous hemoglobin S or compound heterozygosity for hemoglobin S and hemoglobin C or a beta thalassemia. Clinical manifestations, primarily caused by the altered solubility characteristics of the hemoglobin, include chronic hemolysis, heightened susceptibility to serious infection, and episodic vascular occlusions with ischemic tissue damage, causing pain episodes and ultimately organ failure.
In 1910, the first case of sickle cell anemia was documented in "Peculiar Elongated and Sickled Shaped Corpuscles in a Case of Severe Anemia." Hahn and Gillespie documented that deoxygenation was the primary stimulus for formation of the sickle shape in 1927. In 1949, Linus Pauling demonstrated that the disease was caused by a hemoglobin with abnormal mobility on electrophoresis. It was not until 1956 that V.M. Ingram reported that a substitution of only one amino acid residue out of the 146 in the beta globin chain causes the abnormal functioning of the sickle hemoglobin. This substitution was identified as replacement of the normal glutamic acid by valine in the 6th amino acid position of the beta polypeptide chain. Subsequent studies showed that this substitution allows the hemoglobin molecule to polymerize and form long tactoids which distort the red cell shape, cause changes in blood viscosity, induce changes in the red cell membrane, and ultimately are responsible for all of the manifestations of the disease.
The normal red blood cell contains three types of hemoglobin (Hb) A, Hb F or fetal, and Hb A2. The predominant hemoglobin present after six months of life is Hb A. The substitution of valine for glutamic acid is present in Hb S. Substituting lysine for glutamic acid results in hemoglobin C or Hb C. Other abnormal hemoglobins such as Hb D (Punjab) and Hb E are formed by other amino acid substitutions.
There are two genes on two separate chromosomes coding for beta chain production, one of which is inherited from each parent. If one normal gene and one abnormal gene are passed on by each parent, only half of the hemoglobin chains produced will be abnormal and the individual will be a carrier of the abnormal gene. This heterozygous carrier state (Hb AS) is commonly, and somewhat confusingly, referred to as sickle trait. If an individual inherits an abnormal gene from each parent that is homozygous for Hb S, 80 to100 percent of the hemoglobin in the red cells will be abnormal, causing sickle cell anemia. A clinically similar disease, Hb SC disease, results if an individual is a compound heterozygote for Hb S and Hb C.
Thalassemias may interact genetically with sickle hemoglobin because thalassemia genes cause a reduction in the production of normal globin peptide chains. In the beta thalassemias, production of a normal globin chain is either absent in beta zero thalassemia ( o thal) or markedly reduced in beta plus thalassemia ( + thal). Inheritance of a Hb S gene and a o thalassemia gene results in no production of normal beta globin and a clinical syndrome (Hb S o thal) which is very similar to sickle cell anemia. Inheritance of a Hb S gene and a + thalassemia gene results in production of about 5 to 20 percent hemoglobin A and a clinical syndrome (Hb S + thal or Hb SA) which is usually more mild than sickle cell anemia. All these combinations can be referred to as sickle cell syndromes.
Sickle cell syndromes occur in higher frequency in individuals from geographic areas where malaria was endemic because carriers with abnormal hemoglobin or thalassemia appear to have a modicum of protection against severe malaria infection. These genes have the highest frequencies in Africans, Arabs, Egyptians, Turks, Greeks, Italians, Iranians, and Asiatic Indians. In the United States, the disease is more common in African Americans, however, it is seen in individuals of almost every ethnic background. In African Americans, the incidence of carriers for hemoglobin S is approximately 8 percent, of hemoglobin C about 3 percent, and of beta thalassemia almost 1.5 percent. The estimates of the incidence of sickle cell syndromes are: sickle cell anemia (Hb SS) is 1 in every 625 live Black births; sickle cell hemoglobin C disease (Hb SC) is 1 in every 833 Black births; and sickle cell beta thalassemia (Hb S beta thal) is 1 in every Black 1667 births.
The most widely used diagnostic test for sickle cell syndromes and carrier states is hemoglobin electrophoresis. Definitive diagnosis may require determination of the percentage of each hemoglobin present, red cell indices and count, family studies, or DNA analysis of the genotype. The diagnosis of hemoglobin S-beta thalassemia is most problematic. With hemoglobin S o thal, the MCV is usually less than 80, and the red cell count is elevated and hemoglobin electrophoresis shows Hb S with elevated Hb F and Hb A2 levels of greater than 4.5 percent. In hemoglobin S + thal, hemoglobin electrophoresis shows a preponderance of Hb S with Hb A less than 30 percent (Hb SA) and Hb A2 of greater than 4.0 percent. The MCV is usually low. In sickle cell carriers, Hb A is usually greater than 50 percent Hb S less than 45 percent (Hb AS) with normal Hb A2 level, red cell count, and MCV.
The presence of sickle hemoglobin is sometimes determined by a five minute solubility test (Sickledex). A negative test is only helpful in excluding sickle cell disease in patients older than six months of age, who do not have severe anemia or a very high fetal hemoglobin level. The test is positive if 10 percent Hb S is present, making it impossible to separate sickle cell carriers from individuals with symptomatic sickle cell syndromes. Carriers for hemoglobin C and thalassemias are not detected. Because of these numerous limitations, this test should not be used in the diagnosis of sickle cell syndromes.
The clinical manifestations result from changes of red blood cell deformability and fragility, increases in blood viscosity with blockage of small blood vessels, and red cell membrane changes contributing to hemoglobin polymerization, adherence of erythrocytes to vascular endothelium, and phagocytosis by macrophages. The end result is a hemolytic anemia, increased incidence of serious infection, and ischemic damage throughout the body. In individuals with sickle syndromes there is a life long risk of having complications, however, there are specific ages when many of the manifestations develop. The more common problems in sickle cell syndromes will be presented by the age usual onset.
Infectious complications are prominent early in life and are a leading cause of morbidity and mortality. The great improvement in the prognosis in sickle cell anemia is related to newborn screening for sickle cell disease, vaccination for childhood illnesses, the use of prophylactic antibiotics, and aggressive diagnosis and treatment of febrile events.
In early childhood, the hand-foot syndrome is a common occurrence. This usually occurs once to a few times and responds to conservative treatment with hydration and analgesics.
Acute splenic sequestration is a potential source of morbidity and mortality early in life for children with sickle cell anemia and at any age for those with Hb SC disease and sickle thalassemia. These episodes are characterized by rapid increase in splenic size and decrease in hemoglobin. Treatment includes support and aggressive transfusion with splenectomy for repeated or resistant cases.
Strokes also occur in early childhood. Recent studies suggest that up to 15% of children may have overt or silent strokes during childhood. Chronic transfusion therapy reduces the recurrence rate of overt stroke which may approach 75% without intervention. Transcranial Doppler is being explored as a way of identifying infants at high risk for stroke so that primary prevention may be accomplished.
Gallstones occur in children and adults with increasing frequency with age. Symptomatic gall stones are an indication for cholecystectomy. There is controversy about the management of asymptomatic gall stones.
Acute chest episodes characterized by chest pain, fever, and infiltrates occur at any age. Recent studies suggest that infection, fat embolization, and primary infarction may all lead to this clinical problem. Episodes may be severe, life-threatening events and recurrent episodes may result in chronic lung disease and pulmonary hypertension.
Recurrent pain episodes occur at any age but appear to be particularly frequent during late adolescence and early adult life. These unpredictable events are characterized by severe pain in the back, chest, abdomen, extremities and head that are very unpleasant and disruptive to life. Pain episodes are the most common reasons for individuals to seek health care.
Bone disease is common in sickle cell disease. Early risk is primarily from osteomyelitis. Bone infarctions become more common as patients age. Avascular necrosis of the femur and humerus are major causes of chronic pain and disability in older patients.
Leg ulcers are seen in patients older than 10 years of age. They are resistant to therapy and cause significant morbidity.
Ophthalmic complications include proliferative retinopathy, vitreous hemorrhage, and retinal detachment.
Pregnancy causes increased risk for the woman with sickle cell disease and fetal complications occur. Good management maximizes outcome.
Priapism is a distressing complication that occurs at all ages, is difficult to treat, and causes a high incidence of impotence.
End organ damage occurs throughout life. Chronic pulmonary problems causing respiratory failure and pulmonary hypertension and renal failure are leading contributors to death in older patients.
Weight may lag behind that of children without sickle cell disease, however, there is considerable variability. Height is less in older children and adolescents but differences disappear in adulthood. Puberty is delayed significantly in males and females with sickle cell disease. Factors contributing to the delay include anemia, fetal hemoglobin levels, increased protein turnover, and zinc deficiency. Treatment includes good general nutrition, vitamin supplementation for deficiencies, and reassurance that normal maturation will occur.
References
Charache S, Lubin B, and Reid CD. eds. Management and Therapy of Sickle Cell Disease. NIH Publication No. 95-2117, 1995.
Embury SH, Hebbel RP. Mohandas N, Steinberg MH eds. Sickle Cell Disease: Basic Principles and Clinical Practice. New York: Raven Press, 1994.
Sergeant G. Sickle Cell Disease. Second Edition. Oxford: Oxford University Press, 1992.
Bunn HF and Forget BG. Hemoglobin: Molecular, Genetic and Clinical Aspects. W.B. Saunders. Philadelphia, 1986.
Huntsman RG. Sickle-Cell Anemia and Thalassemia: A Primer for Health Professionals. The Canadian Sickle Cell Society, Newfoundland, 1987.
Herrick JB. Peculiar elongated and sickled shaped corpuscles in a case of severe anemia. AMA Arch Intern Med 6:517, 1910.
Hahn EV, Gillespie EB. Sickle cell anemia. Report of a case greatly improved by splenectomy and further observations on mechanism of sickle cell formation. Arch Intern Med 39:233-54,1927.
Pauling L,et al. Sickle cell anemia, a molecular disease. Science 110:543, 1949.
Ingram VM. A specific chemical difference between the globins of human and sickle cell anemia haemoglobin. Nature 178:792, 1956.
Motulsky AG. Frequency of sickling disorders in US blacks. N Engl J Med. 288:31, 1973.
Platt OS, Brambilla DJ, Rosse WF, et al. Mortality in sickle cell disease: life expectancy and risk factors for early death. N Engl J Med 330:1639, 1994.
Barrett-Connor E. Bacterial infection and sickle cell anemia. Medicine 50:97, 1971.
Gaston MH, Verter JI, Woods G, et al. Prophylaxis with oral penicillin in children with sickle cell anemia. N Engl J Med 314:1593, 1986.
Stevens MCG, Padwick M, Serjeant GR. Observations on the natural history of dactylitis in homozygous sickle cell disease. Clin Pediatr 20:311-317, 1981.
Topley JM, Rogers DW, Stevens MCG, Serjeant GR. Acute splenic sequestration and hypersplenism in the first five years in homozygous sickle cell disease. Arch Dis Child 56:765-769, 1981.
Emond AM, Collis R, Darvill D, Higgs DR, Maude GH, Serjeant GR. Acute splenic sequestration in homozygous sickle cell disease: natural history and management. J Pediatr 107:201-206, 1985.
Solanki DL, Kletter GG, Castro O. Acute splenic sequestration episode in adults with sickle cell disease. Am J Med 80:985, 1986.
Ohene-Frempong K, Weiner SJ, Sleeper LA, et al. Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood 91:288-294, 1998.
Moser FG, Miller ST, Bello JA, et al. The spectrum of central nervous system abnormalities in sickle cell disease as defined by magnetic resonance imaging: a report from the Cooperative Study of Sickle Cell Disease. Am J Neuroradiol 17:965, 1996.
Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. New Engl J Med 339:5-11, 1998.
Ponz M, Kane E, Gill FM. Acute chest syndrome in sickle cell disease: etiology and clinical correlates. J Pediatr 107:861, 1985.
Castro O, Brambilla DJ, Thorington BD, et al. The acute chest syndrome is sickle cell disease: incidence and risk factors. Blood 84:643-649, 1994.
Vichinsky EP, Williams R, Das M, et al. Pulmonary fat embolism: a distinct cause of severe acute chest syndrome in sickle cell anemia. Blood:3107-3112, 1994.
Platt OS, Thorington BD, Brambilla DJ, et al. Pain in sickle cell disease New Engl J Med 325:11-16, 1991.
Milner PF, Kraus AP, Sebes JL, et al. Sickle cell disease as a cause of osteonecrosis of the femoral head. N Engl J Med 325:1476-1481, 1991.
Milner PF, Kraus AP, Sebes JL, et al. Osteonecrosis of the humeral head in sickle cell disease. Clin Orthop 289:136-143, 1993.
Koshy M, Entsuah R, Koranda A, et al. Leg ulcers in patients with sickle cell disease. Blood 74:1403-1408, 1989.
Serjeant GR. Leg ulceration in sickle cell anemia. Arch Intern Med 133:690-694, 1974.
Fox PD, Dunn DT, Morris S, Sergeant GR. Risk factors for proliferative sickle retinopathy. Br J Ophthalmol 74:172-176, 1990.
Web DKM, Darby JS, Dunn DT, et al. Gallstones in Jamaican children with homozygous sickle cell disease. Arch Dis. Child. 64:693-696, 1989.
Milner PR, Jones BR, Dobler J. Outcome of pregnancy in sickle cell anemia and sickle hemoglobin C disease. Am J Obstet Gynecol 138:239-245, 1980.
Powars DR, Sandhu M, Niland-Weiss J, et al. Pregnancy in sickle cell disease. Obstet Gynecol 67:217-218, 1986.
Koshy M. Sickle cell disease and pregnancy. Blood Reviews 9:157-164, 1995.
Emond AM, Homan R, Hayes RJ, Sergeant GR. Priapism and impotence in homozygous sickle cell disease Arch Intern Med 140:143-147, 1980.
Sharpsteen JR, Powars D, Johnson C, et al. Multisystem damage associated with tricoporal priapism in sickle cell disease. Am J Med 94:289-295, 1993.
Allon M. Renal abnormalities in sickle cell disease. Arch Intern Med 150:501-504, 1990.
Falk RJ, Jennette JC. Sickle cell nephropathy. Adv Nephrol 23:133-147, 1994.
Powars DR, Elliott-Mills DD, Chan L, et al. Chronic renal failure in sickle cell disease: risk factors, clinical course, and mortality. Ann Intern Med 115:614-620, 1991.
Johnson CS, Verdegem TD. Pulmonary complications of sickle cell disease. Semin Resp Med 9:287-296, 1988.
Powars DR, Weidman JA, Odom-Maryon T, et al. Sickle cell chronic lung disease: prior morbidity and risk of pulmonary failure. Medicine 67:66-76, 1988.