Regional Variations in Sickle Cell Anemia in Saudi Arabia

Abstract

Original ArticlesRegional Variations in Sickle Cell Anemia in Saudi Arabia George T. Roberts, MB, FRCP(C) Saad B. El-Badawi, MD, CP M. Andrew Padmos, and MD, FRCP(C) Kwesi SackeyMB, ChB George T. Roberts Address reprint requests and correspondence to Dr. Roberts: Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh 11211, Saudi Arabia. From the Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh Search for more papers by this author , Saad B. El-Badawi From the Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh Search for more papers by this author , M. Andrew Padmos From the Department of Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh Search for more papers by this author , and Kwesi Sackey From the Department of Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh Search for more papers by this author Published Online:1 Sep 1988https://doi.org/10.5144/0256-4947.1988.320SectionsPDF ToolsAdd to favoritesDownload citationTrack citations ShareShare onFacebookTwitterLinked InRedditEmail AboutABSTRACTABSTRACTWe examined mean corpuscular volume (MCV), fetal hemoglobin (HbF) levels, and severity of clinical disease in 81 patients with sickle cell anemia from various regions of Saudi Arabia. We found that patients from eastern Saudi Arabia had less severe symptoms, higher mean Hb levels, and lower MCV than patients from other regions. Using a severity index, calculated as the mean value of individual symptoms and physical signs in patients in each region, we found that less severe symptoms were associated with lower MCV. High HbF levels were not confined to Eastern Province patients but were seen in other regions. There was a statistically significant inverse correlation between HbF% and the severity index. We also found that only two of the 24 minimally symptomatic patients had an HbF level less than 18%, whereas among the 57 severely symptomatic patients, 14 (25%) had an HbF level less than 18%, confirming the protective value of a certain minimum level of HbF.IntroductionSome Saudi Arabian patients who are homozygous (SS) for the sickle cell gene show a relatively mild form of clinical sickle cell disease (SCD).1,2 This phenomenon has usually been ascribed to the high level of fetal hemoglobin (HbF) observed in these patients. Black SS patients generally have lower HbF levels and usually have much more severe symptoms of SCD. The modulating effects of HbF are thought to be due to its moderating influence on the gelation of deoxygenated sickle hemoglobin (HbS).3 The mechanism by which increased production of HbF occurs in some cases and populations with SS is unknown. Concurrent α-thalassemia may also ameliorate the clinical severity of SCD, principally, it is thought, by improving sickled cell rheology.4 The unusually high prevalence of α-thalassemia among the Shiite population of eastern Saudi Arabia,5–7 where the mild form of SS occurs, suggests a possible link between α-thalassemia genes and high HbF levels in SCD.While it is true that benign SCD is commonly observed in the well-defined oasis populations in the eastern part, little published information on SCD is available from other parts of Saudi Arabia,8 a country with a land mass of 2.11 million square kilometers. Additional information is clearly required to complete the picture, especially in light of non-Arab genetic input from the East African coastal areas.The purpose of the present study was to examine HbF level and mean corpuscular volume (MCV) in patients with SS from different regions of Saudi Arabia and to relate these findings to clinical and other hematologic features.MATERIALS AND METHODSThe medical records of patients with sickle cell anemia (HbSS) were reviewed and the following information retrieved: age, sex, town of origin, and clinical features including type, frequency, duration, and severity of various crises; transfusion requirement; fever, with or without sepsis; splenomegaly, jaundice, anemia, and bone necrosis. Hematologic parameters examined included total hemoglobin (Hb), percentage of HbS and HbF, and reticulocyte count.Levels of Hb and MCV were determined by standard electronic counters. The HbS level was determined by electrophoresis on cellulose acetate at pH 8.4, using microzone equipment. That the abnormal hemoglobin was HbS was ascertained usually by solubility testing on whole blood using sodium hydrosulfite and/or by microscopy of red cells deoxygenated by sodium metabisulfite on a sealed covered glass slide. Quantitation of HbS and HbF was initially performed by densitometry on cellulose acetate electrophoretic strips. More recently, HbF percentages have been determined by radial immunodiffusion9 using agarose gel plates impregnated with monospecific goat antihuman HbF. In this procedure, 0.2 mL of whole blood was diluted with enough distilled water to give a final Hb concentration of 0.5 g/dL. Of this hemolysate, 4 μL were applied to individual wells in the agarose medium. The plates were incubated at room temperature in a humidified atmosphere for 24 hours. The diameters of precipitin rings were recorded, and the percentage of HbF was read from a graph prepared from known HbF standards. A separate study had shown a close similarity between the results of paired determinations of HbF by radial immunodiffusion and densitometry over the whole range of sensitivity of the methods (r = 0.9261; P < 0.001; n = 62 pairs). The red blood cell (RBC) distribution of HbF was assessed microscopically after acid elution according to the method of Kleihauer et al.10 Hemoglobin A2% (HbA2) was determined by densitometry on cellulose acetate electrophoretic strips, which was convenient to use and compared closely with DEAE microcolumn chromatography, a reference method for HbA2 determination (r = 0.81; P < 0.001; n = 68 pairs).Reticulocyte counts were performed by a standard method after 30 minutes of incubation of equal volumes of whole blood with new methylene blue. The reticulocyte percentage was determined by counting reticulocytes in 1000 RBCs.Specific attempts were made to exclude patients with heterozygosity for HbS and β-thalassemia using parental genotype and/or MCV and HbA2 levels. A separate study had shown that 95% of patients with proved S β-thalassemia had an MCV of 80 fL or less. Thus, any patient who had SCD and an MCV of less than 80 fL was automatically excluded from this study unless examination of both parents showed an AS genotype.Clinical SeverityAssessment of clinical severity in patients with SCD has always been a difficult problem, and various methods of measurement have been used by different authors.1,2,11–14 In the present study, we evaluated clinical severity by determining the presence or absence of a number of symptoms and physical findings. These included bone pain, joint pain, anemia, jaundice, splenomegaly, osteomyelitis, aseptic necrosis of bone, and hand-foot syndrome. No attempt was made to give a qualitative or quantitative evaluation of these findings, except in the case of anemia, in which patients with Hb level of at least 100 g/L were assigned a score of 0, those with Hb of 80 to 99 g/L, a score of 1, 60 to 79 g/L, a score of 2, and less than 60 g/L, a score of 3. Other symptoms or findings were assigned a score of 1 for each symptom and together with the score for anemia were then summed up.The total score of all patients in each regional group was also obtained, and a mean value (the severity index) calculated for the group. Patients who were asymptomatic were assigned a score of 0, those with only one symptom or finding a score of 1, and so on.RESULTSA total of 105 patients were reviewed, and 24 were excluded from further analysis because they had received blood transfusion in the preceding 3 months. Among the 81 evaluable patients (Table 1), there were 54 males and 27 females ranging in age from 1 to 55 years with a mean of 15.1 years (SD ± 11.2). The mean Hb of the whole group was 91 g/L (SD ± 18), the mean HbS was 69.5% (SD ± 12.0) and the mean HbF 27.4% (SD ± 12.7). Distribution of HbF was heterocellular in every instance. The mean reticulocyte count was markedly elevated at 13.8% (SD ± 9.4). The mean MCV was 85.7 fL (SD ± 11.1). The mean HbA2 was 1.6%, and all patients had HbA2 levels of less than 3.8%, that is, lower than the β-thalassemia range in our laboratory.Table 1. Regions of origin, sex, mean age, and mean hematologic values of patients with HbSS.The analysis of patients by region of origin is shown in Table 1. Eight regions are identified: (1) Qatif; (2) Hofuf/Al-Hasa; (3) Riyadh; (4) Dammam, Dhahran, and Al-Khobar; (5) Jeddah, Mecca, and Taif; (6) Medina; (7) Southwest; and (8) other. A total of 36 patients were from the Eastern Province (comparising Qatif, Hofuf/Al-Hasa, Dammam, Dhahran, and Al-Khobar). The distribution of patients by regions is also shown in Figure 1.Figure 1. Map of Saudi Arabia showing the regional distribution of 81 patients with sickle cell anemia.Download FigureThe mean Hb level was significantly higher in Eastern Province patients (101 ± 17 g/L) than in patients from other areas (84 ± 14 g/L; P < 0.001). Mean reticulocyte count was 8.9% in Eastern Province patients compared to 17.7% in others, a significant difference (P < 0.001, Student t test).An attempt was made to examine the relationship between areas of origin and MCV, since it is conceivable that MCV values may be influenced by the prevalence ofα-thalassemia. Figure 2 shows that there is a downward drift of MCV values in patients from west to east. Comparison between MCV of Eastern Province patients (mean, 82.9 fL ± 10.4) and that of all patients from other regions (mean, 87.9 fL ± 11.2) showed that the former was significantly lower (P < 0.05, Student t test).Figure 2. Regional variation in MCV from Jeddah, Mecca, and Taif (westernmost) to Qatif (easternmost) (vertical bar spans indicate mean MCV ± SD).Download FigureSince the elevated HbF values could have resulted from stress erythropoiesis, relationship between HbF levels and reticulocyte counts was explored. From Figure 3 it can be seen that higher HbF levels were associated with lower reticulocyte counts (r = -0.45; P < 0.001) (Figure 3), indicating that stress erythropoiesis was not a significant causative factor in inducing high HbF levels. Conversely, higher HbS values were seen in association with higher reticulocyte counts, indicating that sicklemia may be a significant factor in reducing RBC survival.Figure 3. Relationship between HbF% and reticulocyte count (r = -0.45; P < 0.001).Download FigureThe effect of age on HbF levels was also examined by regression analysis in the whole group. No definite statistical relationship was present between HbF levels and age (r = 0.09; P > 0.01). However, when the HbF level was plotted against age, it became apparent that there was a complex relationship between the two parameters (Figure 4): HbF values decreased with age up to approximately 10 years (Figure 5); between the ages of 10 years and 27 years, there was apparently little change in HbF levels (Figure 6). Above 27 years, however, there was a second fall of HbF values (Figure 7). Similarly, the relationship between MCV and age was complex (Figure 8). Between 1 and 26 years, MCV remained relatively constant (Figure 9), but above 26 years there was a fall from a high of 95.3 fL to about 72 fL (Figure 10).Figure 4. Relationship between age (0 to 55 years) and HbF.Download FigureFigure 5. Relationship between age (0 to 10 years) and HbF.Download FigureFigure 6. Relationship between age (10.1 to 27 years) and HbF.Download FigureFigure 7. Relationship between age (27.1 to 55 years) and HbF.Download FigureFigure 8. Relationship between age (0 to 55 years) and MCV.Download FigureFigure 9. Relationship between age (0 to 25 years) and MCV.Download FigureFigure 10. Relationship between age (26 to 55 years) and MCV.Download FigureThe severity of clinical features is shown in Table 2. Patients from the Qatif region had the lowest severity index, and those from Jeddah, Mecca, Taif, and Medina the highest. The severity index was evaluated in relation to reticulocyte count, MCV, and HbF levels by univariate regression analysis. The severity index was directly related to MCV (r = 0.34; P < 0.01), whereas the relation with HbF was inverse (Figures 11 and 12), with the same correlation coefficient.Table 2. Severity index related to region of origin.Figure 11. Relationship between MCV and clinical severity (r = 0.34; P < 0.01).Download FigureFigure 12. Relationship between HbF% and clinical severity (r = -0.34; P < 0.01).Download FigureSeverity of symptomatology was looked at in a different way. The proportion of minimally symptomatic patients was determined for each geographic region (Table 2). There were considerably more minimally symptomatic patients from the regions of Qatif and Hofuf/Al-Hasa than from other areas, and taking the Eastern Province as a whole, 16 of the 36 patients were minimally symptomatic, compared to eight minimally symptomatic patients among the 45 from the rest of the country. This difference in symptomatology between the two groups was significant (P < 0.001; chi-square test). Further examination of the data showed that among 24 minimally symptomatic patients, only two had HbF of less than 18%, whereas among the 57 severely symptomatic patients, 14 had HbF values of less than 18%, a difference that was also significant (P < 0.05; chi-square test). Also, the mean HbF of asymptomatic patients (34.3% ± 12.6) was significantly higher than that of symptomatic patients (24.5% ± 11.7) (Table 3). Furthermore, patients with HbF of less than 18% had a significantly greater mean number of symptoms and signs (3.4 ± 1.6) than the patients with HbF of 18% or higher (2.3 ± 1.6) (Table 4). The latter group had a significantly higher mean MCV (86.2 fL ± 10.7) than the former (83.6 fL ± 12.6) (Table 4). Thus, it would appear that although high HbF levels provide protection against the complications of SS, this occurred independently of low MCV.Table 3. Mean HbF and MCV in asymptomatic and symptomatic patients.Table 4. Mean HbF, MCV, and number of symptoms in patients with low and high HbF.DISCUSSIONSome SS patients in Saudi Arabia have a relatively benign form of sickle cell disease. Because the patient pool from which these observations were made previously was limited to a certain geographic area,1,2 we have conducted a study of the clinical and hematologic features of patients with SS referred to our hospital from various parts of Saudi Arabia. There may have been an element of selection of patients referred, but until recently, this institution has been the principal referral center of most patients with a wide spectrum of disease from around the Kingdom. Thus, the patients could be considered fairly representative. We have attempted to relate clinical severity to area of origin, HbF level, and MCV. Because of the recognized inaccuracy of mean corpuscular hemoglobin concentration (MCHC) as determined by automated electronic counters,15 we have elected not to evaluate this parameter in the present study.Because of the possible effects of the β-thalassemia gene in lowering MCV values, we have attempted to exclude all patients who could possibly have been S β-thalassemic using classical genetic analysis. These methods are, of course, not absolute and could not with certainty exclude patients with heterozygosity for S δ β-thalassemia, especially since the mean HbA2 level in our patients was so low. However, δ β-thalassemia is very rare in this population. The compounding effects of iron deficiency were also mostly excluded by iron studies in most of the patients. Although serum ferritin levels were not performed in our patients, recent findings from western Saudi Arabia have shown that all SS patients of all ages and both sexes had normal serum ferritin levels.16 Furthermore, we analyzed the Hb, MCV, and MCHC values in our patients according to sex and age. No statistically significant lowering of any of these levels was evident between males and females or between younger (non-menstruating) and older (menstruating and childbearing) females. It seems unlikely, therefore, that putative iron deficiency in menstruating women may have contributed to the lowering of the MCV. Thus, the patients in this report are homozygous sickle cell patients who are iron replete; therefore, any observed low MCV is probably the result of some other mechanism. Our findings indicate that patients from eastern Saudi Arabia tend to have a lower mean MCV (82.9 fL) than those from other parts of the country (87.9 fL), a difference that is highly statistically significant (P < 0.005, Student t test). The most likely cause for the lower MCV of Eastern Province patients is the high prevalence of α-thalassemia in the general region, where 52% to 77% of subjects have been shown, by sensitive analytical methods including DNA hybridization, to carry an α-thalassemia gene.5–7 Information on the prevalence of α-thalassemia genes in the rest of Saudi Arabia is not available. However, it would seem likely that the very high frequencies observed in the Eastern Province would not be maintained in all areas, since variations in other red cell polymorphisms are known to occur in various parts of the country. For example, the early studies of Lehmann et al17 quote figures of 25.05%, 1.52%, and 1.74% for the prevalence of the sickle gene in Eastern Province Shiite, Sunni Nejd, and Sunni Western subjects, respectively. More recently, Bayoumi et al8 have shown marked variation in polymorphisms for glucose-6-phosphate dehydrogenase and Hb type in the tribes from western Saudi Arabia, features which may be contributed to by genetic input from the African continent. Presumably, areas far removed from these influences such as the Nejd and Eastern Province would have different genetic characteristics, including those for the thalassemias, that might be expressed in regional variations of MCV.The effects of low MCV on clinical severity were assessed. Evaluation of severity is usually difficult due to marked patient and observer subjectivity. Our method of assessing severity was to record the presence or absence of a nonquantifiable symptom or sign and assign each of these a score of 1 and to assign scores from 0 to 3, depending on the degree of anemia. This procedure resulted in the accumulation of multiple positive findings, the mean of which gave a severity index for each regional group of patients.Another feature that complicates assessment of severity in patients with SCD are the episodic crises that significantly alter hematologic parameters from their steady state values. Our patients were evaluated during noncrisis conditions, and those who were designated asymptomatic were either previously known SS patients who had no clinical signs, or who were discovered to be SS during the course of investigation for unrelated conditions. Using the severity index, we found by regression analysis that lower MCVs were associated with less severe disease (r = 0.34; P < 0.01) (Figure 11). However, the MCV is, to a considerable extent, dependent on reticulocyte count, and the correlation between the severity index and MCV may be a reflection of the reticulocytosis. We therefore corrected the MCV for reticulocyte count by estimating what the MCV would be when the reticulocyte count was "normalized" to a standard Hb of 140 g/L. By this maneuver, the mean corrected MCV of the group was 80.9 fL compared to the uncorrected value of 86.2 fL. When regression analysis was done between the corrected MCV and the severity index, the correlation coefficient was 0.22, which was just significant at the P < 0.05 level. Thus, a lower severity index is definitely related to lower MCV. Why this is so is not clear, but it may be expected, a priori, that smaller RBCs traverse the capillaries of the microcirculation more easily than larger ones. Why some of our patients had low MCV values is not known, but since we have reasonably excluded β-thalassemia and iron deficiency, it seems likely that interacting α-thalassemia is contributory, especially in Eastern Province patients.Several recent studies have provided conflicting evidence about the ameliorating role of α-thalassemia and microcytosis in SCD. For example, Steinberg et al18 found that no clear advantage was associated with microcytosis, β-thalassemia, or α-thalassemia. In another study involving patients with HbSC disease, Steinberg and associates19 found no reduction in vaso-occlusive complications associated with α-thalassemia genotypes. On the other hand, the data provided by Serjeant et al,4 Higgs et al,13 Embury et al,20 and Mears et al21 support the view that microcytosis and thalassemia lessen the severity of SCD. Our findings are in agreement with this latter view.Our study has also confirmed that HbF levels in SS patients in Saudi Arabia are markedly elevated, but that this phenomenon is not restricted to patients from the Eastern Province.1,2 No significant difference was observed between HbF levels in Eastern Province patients (31.2% ± 10.0) and others (24.3% ± 13.8). The study also confirmed that the severity of SCD was influenced by high HbF levels (Figure 12). Patients with higher HbF levels had lower severity indexes (r = 0.34; P <0.01). It was also apparent on further examination of the data that only two of the 24 patients with minimal symptoms (less than two) had HbF levels of less than 18%, whereas in patients with two or more symptoms, 14 of 57 (25%) had HbF levels of less than 18% (P < 0.01). This finding is similar to that of Powars et al22 who demonstrated that for major organ failure such as stroke and aseptic necrosis of bone, a threshold level of 10% HbF was protective, whereas for recurrent clinical crises, a threshold level of 20% was protective.The mechanism by which HbF reduces the severity of SCD is not completely understood, but may be related to the increased gelation time of HbS in the presence of HbF.3 Of more fundamental importance is the mechanism by which increased synthesis of HbF is induced or continues postnatally in SCD and other hematologic disease states. The available evidence indicates that it is under genetic control23 and may be related to a gene that codes for synthesis of a high ratio of G-gamma globin chain, at least in some populations of African origin.24 The age of the subject also plays a role, but this role is reduced as age advances. Pembrey et al have shown that the level of HbF decreased significantly with age in patients with SS during the first 20 years.25 We have observed a similar trend in our series of only 81 patients, certainly up to the age of 10 years. However, between the ages of 10 and 26 years, HbF levels apparently remained constant, although a further subsequent fall was observed after the age of 26 years. Stress erythropoiesis does not appear to have a role in increased HbF production in our series of patients; examination of the relationship between HbF levels and reticulocyte counts showed instead a significant inverse correlation (r = -0.45; P < 0.001) (Figure 3). This probably indicates that higher HbF levels are associated with less severe hemolysis and therefore less severe bone marrow stress. The MCV and HbF would seem to act as independent variables in influencing clinical severity of SCD because examination of the relationship between the two variables by regression analysis showed no significant correlation (r = -0.12: P > 0.10) and because among the severely symptomatic patients with HbF of less than 18%, MCV tended to be lower than in the less severely affected patients with HbF of 18% or greater (Table 4). Recent findings demonstrating multicentric origins for the sickle gene in Africa, the Arabian peninsula, and the Indian subcontinent,26,27 together with the associated genetic variability in the levels of HbF, could explain some of the variability in clinical symptoms. However, our findings also suggest that a more formal examination of the relationship between α-thalassemia genotypes and their effects on MCV and HbF levels in SS patients should be undertaken.ARTICLE REFERENCES:1. Perrine RP, Brown MJ, Clegg JB, et al.. "Benign sickle-cell anemia" . 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Volume 8, Issue 5September 1988 Metrics History Accepted3 January 1988Published online1 September 1988 KeywordsAnemiasickle cellInformationCopyright © 1988, Annals of Saudi MedicinePDF download