Correspondence

Elderly Survivors with Homozygous Sickle Cell Disease

N Engl J Med 2007; 356:642-643February 8, 2007

Article

To the Editor:

Prolonged survival in homozygous sickle cell disease is more common than previously thought. A Jamaican study1 in 1968 described 60 patients who were 30 years of age or older, and the Cooperative Study of Sickle Cell Disease in the United States2 estimated a median survival of 42 to 48 years.

The Sickle Cell Clinic at the University of the West Indies has treated 102 patients (64.7% women) who survived beyond their 60th birthday; of these patients, 58 are now dead, 4 have emigrated, and 40 are still alive. The diagnosis of homozygous sickle cell disease was based on criteria that excluded sickle cell–β⁰-thalassemia or sickle cell–hereditary persistence of fetal hemoglobin. None of the patients received hydroxyurea, and only two patients with renal impairment received regular transfusions. The ages of the patients ranged from 60.2 to 85.6 years, with a marginal excess of women (67.5%, P=0.01). Sickle cell–α⁺-thalassemia was homozygous in 12% of patients and heterozygous in 39%, with a normal alpha-gene number in 46%; the trend failed to reach statistical significance (χ²=2.4, P=0.12). The Benin beta-globin haplotype was homozygous in 76% of the patients, and none had the Bantu, Senegal, or Asian haplotype.

Fetal hemoglobin levels were on average 4.9% higher among these patients than values extrapolated from the Jamaican Cohort Study of Sickle Cell Disease (P<0.001) and exceeded 10% in 16 women (24%) and in 5 men (14%), which suggests that higher fetal hemoglobin levels probably conferred protection in childhood. Family studies showed that 13 of 30 siblings of patients with homozygous sickle cell disease (43%) were over the age of 60 years, but their median survival (56.9 years) did not significantly exceed the median survival of 44.6 years in the Sickle Cell Clinic, as calculated by a standard statistical adjustment (P=0.07), or 56.3 years, as calculated by an adjustment for death rate (P=0.34).3

Hemoglobin values declined in both men and women, but more steeply in men (mean decrease, 2.6 g per deciliter) than in women (2.3 g per deciliter), and fell by 0.02 g per deciliter for every 10-unit increase in the creatinine level (P=0.001), or by 0.6 g per deciliter for every 1-unit increase in the natural-log–transformed creatinine level (Figure 1Figure 1Most Recent Hemoglobin Level and Serum Creatinine Level (Natural-Log–Transformed) in 97 Elderly Patients.). Renal impairment increased with age4 and affected 34 of 40 patients (85%), on the basis of a sensitive definition.5 An incidental presentation occurred in 16 patients (40%). Seven patients reported having had no bone-pain crises (18%); bone pain decreased with age in 30 of the remaining 33 patients; 58% of the patients had a history of leg ulcers. Pregnancy had a benign outcome, with 78 of 96 pregnancies (81%) resulting in live births. In these elderly survivors, high fetal hemoglobin levels and possible familial clustering were consistent with genetic factors. Some features, such as an incidental presentation and successful pregnancy outcomes, suggested an intrinsically mild course, whereas other features, such as severe bone pain, were ameliorated with age. In this group of patients, α-thalassemia did not promote survival, and the group was too homogeneous to show any effect of the beta-globin haplotype. The major clinical problems emerging with age were renal impairment and decreased levels of hemoglobin.

Graham R. Serjeant, M.D., F.R.C.P.
Sickle Cell Trust (Jamaica), Kingston 6, Jamaica

Douglas R. Higgs, M.D., F.R.C.P.
Weatherall Institute of Molecular Medicine, Oxford OX3 9DS, England

Ian R. Hambleton, Ph.D.
University of the West Indies, Barbados, West Indies

5 References

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Citing Articles (12)

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   Giulia Paroni, Davide Seripa, Francesco Panza, Filomena Addante, Massimiliano Copetti, Grazia D’Onofrio, Fabio Pellegrini, Luigi Fontana, Alberto Pilotto. (2011) Klotho locus, metabolic traits, and serum hemoglobin in hospitalized older patients: a genetic association analysis. AGE
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   M.A. Bender, Katie R. Nielsen. 2011. Hemoglobinopathies. , 1191-1206.
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   Micheline Maier-Redelsperger, Pierre Lévy, François Lionnet, Katia Stankovic, Jean-Philippe Haymann, Guillaume Lefèvre, Virginie Avellino, Jean-Pierre Perol, Robert Girot, Jacques Elion. (2010) Strong association between a new marker of hemolysis and glomerulopathy in sickle cell anemia. Blood Cells, Molecules, and Diseases 45:4, 289-292
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   Vijay G. Sankaran, Guillaume Lettre, Stuart H. Orkin, Joel N. Hirschhorn. (2010) Modifier genes in Mendelian disorders: the example of hemoglobin disorders. Annals of the New York Academy of Sciences 1214:1, 47-56
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   Xandra W. van den Tweel, Johanna H. van der Lee, Harriët Heijboer, Marjolein Peters, Karin Fijnvandraat. (2010) Development and validation of a pediatric severity index for sickle cell patients. American Journal of Hematology 85:10, 746-751
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   Rosalba Di Marzo, Roberta Calzolari, Deborah Rund, Aurelio Maggio. 2010. Modifier Genes in the Haemoglobinopathies. .
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   Greice De Lemos Cardoso, João Farias Guerreiro. (2010) Molecular characterization of sickle cell anemia in the Northern Brazilian state of Pará. American Journal of Human Biology 22:5, 573-577
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    Danitza Nebor, Cédric Broquere, Karine Brudey, Danielle Mougenel, Vanessa Tarer, Philippe Connes, Jacques Elion, Marc Romana. (2010) Alpha-thalassemia is associated with a decreased occurrence and a delayed age-at-onset of albuminuria in sickle cell anemia patients. Blood Cells, Molecules, and Diseases 45:2, 154-158
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11. 11

    G. R. SERJEANT, B. E. SERJEANT, K. P. MASON, I. R. HAMBLETON, C. FISHER, D. R. HIGGS. (2009) The changing face of homozygous sickle cell disease: 102 patients over 60 years. International Journal of Laboratory Hematology 31:6, 585-596
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12. 12

    D. R. Higgs, W. G. Wood. (2008) Genetic complexity in sickle cell disease. Proceedings of the National Academy of Sciences 105:33, 11595-11596
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