Steady-state haemoglobin level in sickle cell anaemia increases with an increase in erythrocyte membrane n-3 fatty acids

https://doi.org/10.1016/j.plefa.2005.03.005Get rights and content

Abstract

The aim of the study was to investigate, whether (a) patients with homozygous sickle cell disease (SCD, HbSS) have abnormal blood fatty acids; (b) the abnormality, if it exists, affects all the plasma and erythrocyte lipids or it is restricted to a particular lipid moiety; (c) there is an association between levels of membrane n-3 or n-6 long-chain polyunsaturated fatty acids (LCPUFA) and the degree of anaemia. Fatty acids of erythrocyte choline (CPG), serine (SPG) and ethanolamine (EPG) phosphoglycerides and sphingomyelin (SPM); and plasma CPG, triglycerides and cholesterol esters of 43 steady-state HbSS patients and 43 ethnically matched, healthy, HbAA controls were analysed. The levels of the n-6 LCPUFA, arachidonic (AA), adrenic and docosapentaenoic acids in erythrocyte CPG (P<0.001) and EPG (P<0.01) were higher in the patients compared with the controls. In contrast, the proportions of eicosapentaenoic acid (EPA) in CPG and EPG (P<0.001) and docosahexaenoic acid (DHA) and total n-3 metabolites in CPG (P<0.001) were lower in the patients. The steady-state haemoglobin level of the patients correlated with erythrocyte DHA (r=0.55, P<0.01), EPA (r=0.38, P<0.05) and total n-3 metabolites (r=0.51, P<0.001) in CPG. Also, it correlated with erythrocyte EPA (r=0.64, P<0.01) and total n-3 metabolites (r=0.42, P<0.01) in EPG. The study revealed an imbalance between n-3 and n-6 LCPUFA in erythrocyte and plasma lipid moieties of the HbSS group. Furthermore, it suggested that correction of the imbalance by supplementation with EPA and DHA could ameliorate anaemia in the patients. This observation is consistent with the results of pilot studies, which demonstrated that treatment with n-3 fatty acids confers clinical benefit to sickle cell patients.

Introduction

Several lines of evidence indicate that clinical disease in patients with sickle cell disease (SCD, HbSS) is not due solely to the point mutation GAG to GTG in the sixth codon of the beta globin gene; rather it is the result of various genetic, cellular, humoral and environmental factors acting in concert [1], [2], [3], [4]. Erythrocyte fluidity, deformability, adhesiveness, blood coagulation [5], [6], [7], [8], [9], and the disruption of normal membrane lipid asymmetry and the consequential shift of reactive pro-aggregatory phosphoglycerides to the outer leaflet of the lipid bilayer are important operative factors in the pathophysiology of SCD.

In normal erythrocytes, membrane phospholipids are distributed asymmetrically between the inner and outer leaflets of the lipid bilayer. The outer leaflet is mainly composed of choline phosphoglycerides (CPG) and sphingomyelin (SPM). The inner leaflet is mostly ethanolamine (EPG) and serine phosphoglycerides (SPG). When red cells sickle, EPG and SPG move from the inner to the outer leaflet, and some CPG shifts to the inner layer [10], [11]. Disruption of normal membrane lipid asymmetry and exposure of the reactive SPG promotes blood coagulation and red cell adherence to other blood cells or vascular endothelium [12], [13], [14], [15]. These processes may facilitate vaso-occlusion and ischaemic organ damage in SCD.

The n-3 and n-6 long-chain polyunsaturated fatty acids (LCPUFA) are vital structural and functional components of cell and sub-cellular membranes. In addition, dihomo-γ- linolenic (DHGLA), arachidonic (AA) and eicosapentaenoic (EPA) acids are the precursors of eicosanoids, potent bio-molecules that regulate cell adhesion, aggregation and inflammation. There is evidence that fluidity, deformability [16], [17], [18] and adhesion [12], [13], [14], [15] of erythrocytes are significantly influenced by alterations of membrane LCPUFA in individuals with and without SCD.

It has been postulated that an imbalance in membrane n-6/n-3 LCPUFA is the antecedent of the loss of membrane asymmetry, blood cell adhesion and aggregation and vaso-occlusion in SCD. In deed, there is evidence that steady-state patients with SCD have abnormal plasma and/or erythrocyte fatty acid composition [19], [20], [21], [22], [23], [24]. However, in most of these studies, either the number of subjects enrolled was small, or only total lipids, total phospholipids or CPG were analysed. Hence, it is not possible to ascertain whether the reported fatty acid abnormalities in patients with SCD affects all the plasma and erythrocyte lipids or it is restricted to a specific plasma or erythrocyte lipid moiety.

The aim of the current study was to investigate, if (a) patients with homozygous SCD disease (HbSS) have abnormal blood fatty acids; (b) the fatty acid abnormalities in erythrocyte and plasma have a similar pattern; (c) there is an association between levels of membrane n-3 and/or n-6 LCPUFA, and the degree of anaemia.

Section snippets

Subjects, materials and methods

Forty-three, 26 male and 17 female, HbSS patients aged 11–43 years (mean±SD; 21±22) were enrolled from the Haematology Clinics, University of Nigeria Teaching Hospital, Enugu, Nigeria. Forty-three, racially matched, healthy HbAA controls, 30 male and 13 female, aged 20–52 years (26±26) were also recruited from individuals visiting the hospital. 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

Erythrocyte fatty acids

The percent fatty acid composition of erythrocyte phospholipids—CPG, EPG and SPG, and SPM is presented in Table 1, Table 2.

Erythrocyte CPG

Erythrocytes from HbSS patients contained higher proportions of arachidonic (AA, P<0.001), adrenic (22:4n-6, P<0.001), docosapentaenoic (22:5n-6, DPAn-6, P<0.01), α-linolenic (ALA, P<0.001) acids and total n-6 metabolites (P<0.001) compared with healthy controls. In contrast, the patients had lower proportions of linoleic (LA, P<0.001), eicosapentaenoic (EPA, P<0.001),

Discussion

This comprehensive investigation shows that steady-state HbSS patients have abnormal blood fatty acid composition. Although the abnormality was more pronounced in plasma and erythrocyte CPG, it was manifested in all the lipid fractions analysed. This blood lipid perturbation was characterised by higher levels of n-6 fatty acids particularly, adrenic, DPAn-6 and AA, and lower n-3 fatty acids, EPA and total n-3 metabolites, in erythrocyte CPG and EPG. The n-3 fatty acids, EPA, DPA and DHA were

Acknowledgements

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

References (37)

Cited by (22)

  • Pilot assessment of omega-3 fatty acids and potassium thiocyanate in sickle cell anemia patients with conditional peak systolic cerebral artery blood velocity

    2021, Blood Cells, Molecules, and Diseases
    Citation Excerpt :

    First, DHA and EPA increase the resistance of erythrocytes to hemolysis [8], and so would reduce anemia which predisposes to increased velocity of blood flow. Consistent with this concept, previous studies show direct correlation between erythrocyte content of omega-3 fatty acids and steady state haemoglobin level in SCD [21]. Potassium thiocyanate has a mild anti-sickling effect [7] which could reduce premature destruction of red blood cells, reduce anemia, and add to or synergize with the anti-hemolytic effect of DHA and EPA.

  • Biochemical and therapeutic effects of Omega-3 fatty acids in sickle cell disease

    2020, Complementary Therapies in Medicine
    Citation Excerpt :

    In our opinion, bioactive lipids might be effective in alleviating inflammation and treatment of acute VOC, but they are unlikely to constitute an effective substitution of DHA and EPA in prevention of VOC. Clinical observational studies have shown positive correlation between omega-3 fatty acid level in RBC membrane and Hb levels in patients with SCD.97 In addition, as early as 2001, results of a small clinical study showed that omega-3 fatty acids, administered as menhaden fish oil containing 12 % EPA and 18 % DHA, could reduce pain episodes in patients with SCD.98

  • SC411 treatment can enhance survival in a mouse model of sickle cell disease

    2020, Prostaglandins Leukotrienes and Essential Fatty Acids
    Citation Excerpt :

    These measurements were used to confirm that SC411 at 36 and 180 mg/kg/day had the propensity to raise overall DHA and EPA levels (Fig. 1A,B). We also measured arachidonic acid, a known inflammatory mediator, as it is reportedly higher in sickle cell patients [25]. The results suggest a reduction in AA levels (Fig. 1C, D) which is expected because it is well-established that EPA and DHA can lower AA [26,27].

  • Relationship of Omega-3 fatty acids DHA and EPA with the inflammatory biomarker hs-CRP in children with sickle cell anemia

    2019, Prostaglandins Leukotrienes and Essential Fatty Acids
    Citation Excerpt :

    The balance between omega-3 and omega-6 fatty acids and the relative levels of lipid mediators generated from these fatty acids at the site of inflammation, therefore, may play a role in the pathogenesis of inflammation and its resolution. Studies have shown that O3FA levels in SCD are decreased in multiple lipid fractions from several blood components with marked changes noted in the red cell PC and PE fractions [42–48]. Choline and ethanolamine containing phospholipids are the major inner and outer plasma membrane phospholipids [20,21], respectively.

View all citing articles on Scopus
View full text