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Abnormality of erythrocyte membrane n-3 long chain polyunsaturated fatty acids in sickle cell haemoglobin C (HbSC) disease is not as remarkable as in sickle cell anaemia (HbSS)

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Abstract

Sickle cell disease (SCD) is a group of inherited blood disorders in which clinical illness results from the presence of erythrocytes with sickled haemoglobin (HbS). Blood vessel occlusion is a fundamental pathological process in SCD. Sickle cell haemoglobin C (HbSC) disease and sickle cell anaemia (HbSS) share some pathophysiology and clinical manifestations. However, the former is generally less severe. Erythrocytes of HbSC patients have longer life span, reduced haemolysis, and lower propensity to adhere to vascular endothelium than those of their HbSS counterparts. The structure and function of erythrocytes are strongly modulated by membrane long chain polyunsaturated fatty acids (LCPUFA). We have tested the possibility that HbSC and HbSS patients have different membrane fatty acid composition consistent with the difference in their clinical severity. Steady-state patients, 9 HbSC and 28 HbSS, and 15 HbAA were studied. The HbSC patients had a higher level of linoleic (LA, P<0.05) and docosahexaenoic (DHA, P<0.05) acids, and lower arachidonic acid (AA, P<0.01) and AA/eicosapentaenoic acid (EPA) ratio (P<0.05) in erythrocyte choline phosphoglycerides (CPG) compared with the HbSS group. Similarly, the level of EPA was higher and AA/EPA ratio (P<0.01) lower in serine phosphoglycerides of the HbSC patients. In contrast to the HbSC, the HbSS group had lower levels of EPA (P<0.001), DHA (P<0.05), total n-3 metabolites and total n-3 fatty acids (P<0.001) in erythrocyte CPG compared with the healthy HbAA controls. Moreover, the HbSS patients with disease complications compared with those without complications had reduced DHA and total n-3 fatty acids (P<0.005) in erythrocyte CPG. The abnormalities in erythrocyte in LCPUFA which is manifested by an increase in AA and a decrease in EPA and DHA in HbSS relative to HbSC disease observed in this study are consistent with the contrast in clinical severity between the two entities.

Introduction

Although less common on a global scale than homozygous (HbSS) sickle cell disease (SCD), the compound heterozygous sickle cell-haemoglobin C (HbSC) is one of the most prevalent sickling disorders. It results from the inheritance of one gene for sickled haemoglobin (HbS) from one parent, and the gene for HbC from the other. HbS has valine in the 6th amino acid position of the beta globin chain, instead of glutamic acid as found in normal adult haemoglobin (HbA). HbC has lysine in the same position 6 occupied by valine in HbS [1]. In people with genotype HbSC, approximately 50% of the total haemoglobin in circulation is HbS [2], [3]. The rest is predominantly HbC, with small proportions of fetal haemoglobin (HbF) and HbA2. Whereas homozygous inheritance of either HbS or HbC causes erythrocyte abnormalities and clinical illness, the condition of HbCC individuals is very mild in comparison to HbSS disease. In the compound heterozygous (HbSC) state, the two variant haemoglobins interact to produce abnormalities of red blood cells, and disease generally less severe than HbSS [4], [5].

HbSC and HbSS diseases and their clinical features have considerable similarity. However, HbSC disease is characterised by a lower overall mortality [4], [5] and a prevalence of cholelithiasis, leg ulcers, hepatomegaly, and cardiomegaly [6], [7]. The reasons for these differences are not fully understood. Nevertheless, differences in erythrocytes in half-life, degree of dehydration, adhesiveness, aggregability and percent of serine phosphoglycerides (SPG) in the outer leaflet of lipid membrane have been implicated. These factors are central to the pathogenesis of blood vessel occlusion and destruction of erythrocytes, which are fundamental pathological processes in the sickle cell disorders [3], [8], [9], [10], [11]. Abnormalities of phospholipid molecular species [12], and fatty acid composition of erythrocytes [13] and platelets and mononuclear cells [14] have been reported in HbSS patients. There are no compressive published reports on blood fatty acid status of HbSC. Since n-3 long chain polyunsaturated fatty acids (LCPUFA) have beneficial effects on trans-membrane ion flux, cell hydration, rheology, and deformability [15], [16], [17], [18], we have investigated if HbSS and HbSC patients have contrasting membrane fatty acid composition consistent with the widely recognised difference in clinical severity between the two disease entities.

Section snippets

Subjects

Adult African/Caribbean HbSS (age 19–65 years, n=28) and HbSC (age 26–45 years, n=9) patients, and racially matched healthy controls (age 20–52, n=15) were enrolled from St. Thomas’ Hospital, Medical School, London, UK. All the patients were in steady state—defined as the absence of sickle cell crisis or acute illness from 1 month before, and up to 2 weeks after blood sampling for the study. HbSS or HbSC individuals with HbF up to 10%, any other medical diagnosis in addition to SCD, pregnancy

Haemoglobin levels and leukocyte counts

The HbSC group had higher haemoglobin (11.5 vs. 9.0 g/dl, P<0.001) and lower leukocyte count (7.0×109/l vs. 10.3×109/l, P<0.01) compared with the HbSS patients.

Erythrocyte fatty acids

Fatty acid composition of erythrocyte choline, ethanolamine and serine PS of the HbSC and HbSS patients and healthy HbAA controls is given in Table 1.

Choline phosphoglycerides (CPG). The HbSC patients had higher linoleic (LA, P<0.05) docosahexaenoic (DHA, P<0.05) and lower arachidonic (AA, P<0.01), docosatetraenoic (DTA, 22:4n-6, P<0.05),

Discussion

The results show that both HbSS and HbSC patients have abnormal plasma and erythrocyte membrane fatty acid composition. The abnormality is characterised by an increase in the n-6 long-chain polyunsaturated fatty acids (LCPFA), particularly AA, and a concomitant decrease in the n-3 LCPFA, specifically EPA and docosahexaenoic (DHA). As it is evident from the tables, the study also reveals that the abnormality is less pronounced in the HbSC than in the HbSS patients.

The differences in erythrocyte

Acknowledgments

The Mother and Child Foundation, Sir Halley Stewart Trust, and Thomas H. Smouse Memorial Fellowship Award from the American Oil Chemists’ Society supported this study.

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