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Daak, Ahmed A. (2011) Clinical and biochemical effects of omega-3 fatty acid supplementation on patients with homozygous sickle cell disease. Doctoral thesis, London Metropolitan University.
Sickle Cell Disease (SCD) is a group of autosomal recessive genetic blood disorders due to a mutation in the sixth codon of the β goblin gene. The resultant haemoglobin S (HbS) polymerises under low oxygen tension causes rigid, sickled red blood cells. The main clinical manifestations are vaso-occlusisve painful crisis and haemolytic anaemia which lead to degenerative tissue pathology that affect major organs including the brain, eye, lung, spleen, liver, kidney, heart and bone. The pattern of the complications and survival vary considerably between patients. These clinical variations suggest, the outcome of the disease is determined by the interaction of environmental and genetic factors.
According to the classical paradigm, the pathophysiology of vaso-occlusion is primarily due to mechanical blockage of small blood vessels by the deformed sickled red cells. However, the frequency of vaso-occlusive crisis does not correlate with the number of irreversible sickled cells. In contrast, the occurrence of vaso-occlusion events and clinical severity correlate strongly with the degree of leucocyte-erythrocyteendothelial adhesion and inflammatory state. Adhesion, aggregation, elasticity of blood cells and inflammatory response are strongly modulated by cell membrane n-3 and n-6 fatty acids. There is evidence that steady state patients with SCD have abnormal erythrocytes, platelets and mononuclear cell fatty acid composition. The abnormality is characterised by increased levels of arachidonic (AA), adrenic and osbond acids, and reduced levels of docosahexanoic (DHA) and eicosapentnoic (EPA) acids and n-3/n-6 fatty acid ratio. Hence, it is possible that amelioration of the membrane fatty acid abnormality may have beneficial clinical effects on SCD patients.
This research programme investigated whether:
- The beneficial effects of Hydroxyurea (HU), the commonly used treatment for the disease involves modulation of blood cell membrane fatty acid abnomlalities observed in sickle cell disease. HU-treated (n=19) and untreated (n=l7) Homozygous patients and healthy control subjects (n=20) were enrolled from SCD Referral Clinic, Khartoum, Sudan. Blood samples obtained from the three groups were analysed for membrane fatty acids. The data showed that HU-treated patients and healthy controls had comparable levels of docosahexaenoic (DHA) and total n-3 fatty acids in ethanolamine and (EPG) and choline (CPG) phosphoglycerides. In contrast, the untreated group had significantly lower DHA and total n-3 compared with the controls. In addition, HU treatment selectively mobilised arachidonic acid (AA) from the inner cell membrane amino-phosphoglycerides, EPG and serine (SPG) phosphoglycerides. Hence, it appears that the clinical benefits of HU are partially mediated through modulation of blood cell membrane fatty acid composition.
- Supplementation with n-3 FA reduces the frequency of vasa-occlusive crisis through correction of the membrane fatty acid perturbation. One hundred forty patients recruited from Sickle Cell Referral Clinical in Khartoum, Sudan, were randomised to receive high-DHA n-3 fatty acid (n=70) or placebo (n=70) capsules for one year. Treatment with n-3 fatty acids resulted in three fold increase in red cell membrane DHA and EPA, with a concomitant decrease in n6 fatty acids particularly AA. Supplementation with the highly unsaturated and labile DHA and EPA did not induced additional oxidative stress as it was evident by the significant increase in plasma vitamin E concentration and a reduction in activity of red cell Se-glutathione peroxidise.
Treatment with the high DHA n-3 fatty acids for one year reduced the frequency of vaso-occlusive and haemolytic crises, number of blood transfusion, and hospitalisation and absence from school due to SCD associated illnesses. None of the patients in the n-3 fatty acid group but two in the placebo group developed stroke. The patients treated with high-DHA n-3 fatty acids had reduced total white blood cell, integrin and lactate dehydrogenase. These findings suggest that the beneficial action of n-3 fatty acids is mediated through reduction of inflammation and adhesion.
This research programme which was based on an appreciable number of homozygous sickle cell patients clearly demonstrated that HU modulates cell membrane fatty acid abnormality, and supplementation with high-DHA n-3 fatty acids have the potential to be effective and affordable treatment option for patients with SCD. In order to test the generalisability of the effect of n-3 on patients with SCD, a multi-centre study which involve patients from different dietary and genetic backgrounds is warranted.
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