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AFIP Archives: Gael J. Lonergan, David B. Cline, and Susan L. Abbondanzo Sickle Cell Anemia Radiographics 2001; 21: 971-994 [Abstract] [Full text] [PDF]

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Distinctive geographical diversity determines the destiny of the patients with Sickle cell disease

ANIL K. SAXENA, MD; MRCP (Dublin), RAJAN CHOPRA, MD ( Pathology), KHALIFA AL-MULHIM, DGO; FACHARTZ (Germany)   (20 November 2003)

Distinctive geographical diversity determines the destiny of the patients with Sickle cell disease 20 November 2003
ANIL K. SAXENA, MD; MRCP (Dublin), Consultant Nephrologist, King Fahad Hospital & Tertiary Care Center, Division of Nephrology, Al-Hasa, Eastern province,Saudi Arabia, RAJAN CHOPRA, MD ( Pathology), KHALIFA AL-MULHIM, DGO; FACHARTZ (Germany) Send letter to journal: Re: Distinctive geographical diversity determines the destiny of the patients with Sickle cell disease dranil_31982{at}yahoo.com ANIL K. SAXENA, MD; MRCP (Dublin), et al.	On the basis of the different prototypes of restriction enzyme locations, four different DNA configurations--the beta globin haplotypes associated with the sickle cell gene that designate the independent occurrences of the sickle cell mutation--have been recognized. They are named after the places where they were originally described (1,2). I. Senegal haplotype, on the Atlantic coast of West Africa. II. Bantu or Central African Republic haplotype, in Zaire, the Central African Republic, Angola, and Kenya. III. Benin haplotype, in central West Africa, especially Ghana, Nigeria, Ivory Coast, and southwestern Saudi Arabia. IV. Asian haplotype, in the eastern province of Saudi Arabia (2,3) and central India. The Benin haplotype, with the gene of origin in West Africa, spread along the slave trading routes to North America and the Caribbean region and through migration to the Mediterranean region (Sicily, northern Greece, and southern Turkey) and to southwestern Saudi Arabia. Thus, two diverse forms of sickle cell disease exist in Saudi Arabia: the Benin haplotype in the southwestern region, apparently imported from Africa, and the Asian haplotype in the eastern province, possibly representing an independent local occurrence of the sickle cell mutation. For that reason, Saudi Arabia provides a unique opportunity for studying the clinical effects of the two different haplotypes within similar environments (3). The levels of Hb F vary markedly in patients with sickle cell disease, and some patients maintain high levels of gamma chain synthesis into adult life. Hb F molecules interfere with polymerization of Hb S molecules and hence inhibit sickling; patients with high HbF levels are protected from many of the early life-threatening complications of the disease (4). High levels of Hb F are associated with a milder clinical course, more normal growth, persistence of splenomegaly, less leg ulceration and acute chest syndrome, less end organ damage, and probably greater survival. Compared with patients in southwestern Saudi Arabia, eastern patients have higher hemoglobin and Hb F levels and lower Hb A2 levels, mean corpuscular volume, and reticulocyte and platelet counts. Clinically, eastern patients had less dactylitis, relatively later onset of painful crises, persistent splenomegaly, less acute chest syndrome, and better physical growth with thicker skin folds and possibly longer lifespan (3). While leg ulcerations occur in up to 75% of patients and stuttering priapism in around 40% of postpubertal males in Jamaica (Benin haplotype), they are rare in patients from southwestern Saudi Arabia (regardless of the identical African origin of the beta globin gene haplotype in this region) and the eastern province. However, the influence of haplotype on Hb F levels is not clear, and even greater ambiguity attends the likely effects of haplotype on the clinical course. High Hb F levels generally result in higher total hemoglobin levels (5). Contrary to the common assumption that high hemoglobin levels imply mild disease, a high hemoglobin level may be a risk factor for avascular necrosis of the femoral head, proliferative sickle cell retinopathy, and acute chest syndrome (6,7). The mechanism of high hemoglobin levels determines their clinical significance: High hemoglobin levels associated with high Hb F levels is relatively benign, but alpha thalassemia resulting in high hemoglobin levels with low Hb F levels is potentially deleterious (5). A cold moist climate is a major precipitating factor for painful crisis in West Africa, the Caribbean, and North America (which all largely have the Benin haplotype); a hot arid climate may predispose to dehydration as a risk factor for painful crisis in Saudi Arabia (8,9). Worldwide, chronic renal failure is a key predictor of poor outcome in patients with sickle cell disease. While hemodialysis and renal transplantation generally remain the standard treatments, little is known about the long-term outcome of hemodialysis in patients with end-stage sickle cell nephropathy with respect to the presence of different beta globin gene haplotypes in different populations in which the disease is prevalent. In a retrospective cohort study performed at the hemodialysis facility of our tertiary care center in eastern Saudi Arabia between January 1992 and January 1999, an overall prevalence of end-stage sickle cell disease of 5.4% was recorded. Although the mortality rate of 11.59% per year (81.8% of patients died over 7 years) for hemodialysis patients observed in the study is considerably lower than the 16.34% per year rate (83% died over 5 years) reported by Powars et al in African American patients, the early onset of end-stage renal disease, higher prevalence of hepatitis B and hepatitis C viral infections, and substantially elevated frequency of vascular access-related septicemia seem to be the potential determinants of suboptimal survival of end-stage sickle cell nephropathy patients receiving long-term hemodialysis (10). Poor survival rates are largely related to the bacterial and viral infections in this asplenic population; these rates may also be attributable to hepatic failure related to iron overload and chronic hepatitis, as hemodialysis creates a high-risk environment for the transmission of hepatitis C virus in association with the obligatory need for vascular access sites and extracorporeal blood circulation (11). Oxidative stress caused by hemodialysis filters and sickle cell disease itself affects cell-mediated immunity adversely in the already immunocompromised hemodialysis population (12,13). However, the significantly lower mortality rate of end-stage sickle cell nephropathy patients in eastern Saudi Arabia (Asian haplotype) compared with that of African American patients (largely Benin haplotype) may conceivably be an additional difference in the survival of sickle cell disease patients receiving hemodialysis. References 1. Pagnier J, Mears JG, Dunda-Belkhodia O, et al. Evidence for the multicentric origin of the sickle cell hemoglobin gene in Africa. Proc Natl Acad Sci USA 1984; 81:1771-1773. 2. El-Hazmi MAF. Beta globin gene haplotypes in Saudi sickle cell anemia patients. Human Heredity 1990; 40:177-186. 3. Padmos MA, Roberts GT, Sackey K, et al. Two different forms of homozygous sickle cell disease in Saudi Arabia. Br J Haematol 1991; 79: 93-98. 4. Stevens MCG, Hayes RJ, Vaidya S, Sergeant GR. Fetal hemoglobin and clinical severity of homozygous sickle cell disease in early childhood. J Pediatr 1981; 98: 37-41. 5. Maude GH, Hayes RJ, Sergeant GR. The hematology of steady state homozygous sickle cell disease: interrelationships between haematological indices. Br J Haematol 1987; 66:549-558. 6. Hawker H, Neilson H, Hayes RJ, Sergeant GR. Haematological factors associated with avascular necrosis of the femoral head in homozygous sickle cell disease. Br J Haematol 1982; 50:29-34. 7. Fox PD, Dunn DT, Morris JS, Sergeant GR. Risk factors for proliferative sickle nephropathy. Br J Ophthalmol 1990; 74:172-176. 8. Redwood AM, Williams EM, Desai P, Sergeant GR. Climate and painful crisis of sickle cell disease in Jamaica. Br Med J 1976; 1:66-68. 9. Addae SK. Mechanism for the high incidence of sickle cell crisis in the tropical cool season. Lancet 1971; 2:595-597. 10. 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 1991; 115:614. 11. Saxena AK, Panhotra BR, Sundaram DS. The role the type of vascular access plays in the transmission of hepatitis C virus in a high prevalence hemodialysis unit. J Vasc Access 2002; 3:158-163. 12. Latscha BD, Jungers P, Witko-Sarsat V. Immune system dysregulation in uremia: role of oxidative stress. Blood Purif 2002; 20:481-484. 13. Nath KA, Grande JP, Haggard AJ, et al. Oxidative stress and induction of heme oxygenase-1 in the kidney in sickle cell disease. Am J Pathol; 2001:158: 893-903.