Sickle-cell anaemia needs more food?
Authors: Hyacinth I Hyacinth
Journal: The Lancet Haematology (2018)

Sickle-cell disease results from a genetic substitution that increases the tendency of haemoglobin to polymerise and deform red blood cells, leading to the characteristic sickle shape. Repeated cycles of sickling and unsickling of the erythrocyte increases their fragility, leading to an increased tendency for haemolysis and, thus, to haemolytic anaemia, resulting in a rapid turnover of red blood cells. The lifespan of red blood cells in patients with sickle-cell anaemia is 8–25 days, as opposed to 100–120 days in individuals without sickle-cell disease. The shortened lifespan of red blood cells increases protein turnover and metabolic rate compared with age-matched, sex-matched, and race-matched controls. Nutritional insufficiency in sickle-cell anaemia is a state of relative undernutrition that occurs from an increase in metabolic demand. Increased inflammation, myocardial energy demand from an increased heart rate, and erythropoiesis are among the reasons for the increased metabolic rate (measured as a high resting energy expenditure) in sickle-cell disease. Although there are no published data on the prevalence of undernutrition among individuals with sickle-cell anaemia, the first direct evidence of this finding was shown in a sample of five patients in a 1985 study by Melvin Heyman and colleagues1Heyman MB Katz R Hurst D et al.Growth retardation in sickle-cell disease treated by nutritional support.Lancet. 1985; 325: 903-906Summary Scopus (68) Google Scholar in the The Lancet. In their Article in The Lancet Haematology, Sharon Cox and colleagues2Cox SE Ellins EA Marealle AI et al.Ready-to-use food supplement, with or without arginine and citrulline, with daily chloroquine in Tanzanian children with sickle-cell disease: a double-blind, random order crossover trial.Lancet Haematol. 2018; (published online March 13.)http://dx.doi.org/10.1016/S2352-3026(18)30020-6Summary Full Text Full Text PDF PubMed Scopus (16) Google Scholar report the results of their invervention with a vascular ready-to-use supplementary food (RUSF) in sickle-cell disease. In this randomised, double-blind crossover study, they assigned children aged 8–12 years with sickle-cell anaemia (who had never received hydroxyurea) to receive either basic RUSF (RUSF-b) or vascular RUSF (RUSF-v; fortified with arginine and citrulline). Additionally, daily chloroquine was given to children in the RUSF-v group and weekly chloroquine to those in the RUSF-b group (which totalled a lower weekly dose than the chloroquine administered to the RUSF-v group). Although the base formulations of RUSF-b and RUSF-v were the same, RUSF-v was fortified by the addition of 5 or 7·5 g of L-arginine ketoglutarate and 2·5 or 3·75 g of L-citrulline, dependent on bodyweight. After 4 months of intervention, children who had received RUSF-v had significantly higher plasma levels of arginine and ornithine compared with children who had received RUSF-b. RUSF-v did not show a differential benefit on vascular function compared with RUSF-b, but RUSF treatment did show a benefit on some measures of endothelial function, namely baseline blood flow and brachial artery diameter at rest, compared with baseline. Overall, RUSF-v did not show any differential benefit on the markers of vascular function, inflammation, or growth compared with RUSF-b but, compared with the baseline and washout timepoints, RUSF resulted in modest but significant improvement in growth and haematological parameters with no significant effect on inflammation. The result of this study is encouraging, although it also raises some questions. How do chloroquine and components of the RUSF interact, and why is there no effect on inflammation? One encouraging and immediately relevant finding from this study is the improvement in growth that was found following RUSF supplementation, notwithstanding the short duration of this study, which is in support of the study by Heyman and colleagues.1Heyman MB Katz R Hurst D et al.Growth retardation in sickle-cell disease treated by nutritional support.Lancet. 1985; 325: 903-906Summary Scopus (68) Google Scholar In a study of mice with sickle-cell disease, Capers and colleagues3Capers PL Hyacinth HI Cue S et al.Body composition and grip strength are improved in transgenic sickle mice fed a high-protein diet.J Nutr Sci. 2015; 4: e6Crossref PubMed Google Scholar showed improved lean body mass and grip strength when supplementing mouse food with additional L-arginine. In more recent animal studies,4Archer DR Stiles JK Newman GW et al.C-reactive protein and interleukin-6 are decreased in transgenic sickle cell mice fed a high protein diet.J Nutr. 2008; 138: 1148-1152Crossref PubMed Scopus (25) Google Scholar, 5Hyacinth HI Capers PL Archer DR Hibbert JM TNF-α, IFN-γ, IL-10, and IL-4 levels were elevated in a murine model of human sickle cell anemia maintained on a high protein/calorie diet.Exp Biol Med. 2014; 239: 65-70Crossref PubMed Scopus (8) Google Scholar mouse food that provided 35% of calories from protein caused a significant decrease in the blood concentrations of inflammatory cytokines. Another question raised by Cox and colleagues' study is that, despite the short follow-up period, it is not clear why the frequency of pain crises was not considered as a key outcome. The study did find that frequency of pain crises did not differ between the intervention and washout periods. In their study, Morris and colleagues6Morris CR Kuypers FA Lavrisha L et al.A randomized, placebo-controlled trial of arginine therapy for the treatment of children with sickle cell disease hospitalized with vaso-occlusive pain episodes.Haematologica. 2013; 98: 1375-1382Crossref PubMed Scopus (95) Google Scholar showed that parenteral arginine administration resulted in a significant reduction of opioid use by patients with sickle-cell disease who had been admitted to hospital for pain crises. Heyman and colleagues also showed a significant reduction in pain frequency associated with supplemental feeding with a formula that provided additional calories. Given the prominence of pain to the pathophysiology of sickle-cell disease, it should be considered as an outcome in future studies. Undernutrition as a component of sickle-cell disease cannot be overemphasised, especially in developing countries. A current and important challenge is in development of a nutritional formulation that addresses the several nutrient deficiencies in these patients. Several studies7Zemel BS Kawchak DA Fung EB Ohene-Frempong K Stallings VA Effect of zinc supplementation on growth and body composition in children with sickle cell disease.Am J Clin Nutr. 2002; 75: 300-307Crossref PubMed Scopus (99) Google Scholar, 8De Franceschi L Bachir D Galacteros F et al.Oral magnesium pidolate: effects of long-term administration in patients with sickle cell disease.Br J Haematol. 2000; 108: 284-289Crossref PubMed Scopus (93) Google Scholar, 9Osunkwo I Ziegler TR Alvarez J et al.High dose vitamin D therapy for chronic pain in children and adolescents with sickle cell disease: results of a randomized double blind pilot study.Br J Haematol. 2012; 159: 211-215Crossref PubMed Scopus (53) Google Scholar, 10Prasad AS Beck FW Kaplan J et al.Effect of zinc supplementation on incidence of infections and hospital admissions in sickle cell disease (SCD).Am J Hematol. 1999; 61: 194-202Crossref PubMed Scopus (109) Google Scholar have shown benefits of single-nutrient supplementation, including improved growth, reduction in the frequency of pain, and reduction in the incidence of infection. However, the optimum combination of nutrients in a nutritional formulation is yet to be determined, and the study by Cox and colleagues makes important progress towards this goal. In African and low to middle income countries, a holistic approach that combines these nutritional supplements and their benefits is much needed since more complex approaches (such as bone marrow transplant, chronic blood transfusion, and gene therapy) for managing sickle-cell disease are often not affordable or feasible. I am a co-inventor of a nutritional supplement (Nutrical-1) for treating sickle-cell disease (US patent no. 9375451). Ready-to-use food supplement, with or without arginine and citrulline, with daily chloroquine in Tanzanian children with sickle-cell disease: a double-blind, random order crossover trialRUSF providing 500 kcal/day results in small weight gains in children with sickle-cell disease. However, even without arginine and citrulline fortification, RUSF seems to ameliorate arginine dysregulation and might improve endothelial function. Long-term studies are required to assess whether these physiological effects translate to improved clinical outcomes and better growth and development in patients with sickle-cell disease. Full-Text PDF Open AccessSickle-cell anaemia—keeping alive Wethers' legacyThe beginning of 2019 witnessed mixed news for the sickle-cell anaemia community. On Jan 10, the results on the first trial of hydroxyurea—the recognised standard of care for patients with sickle-cell disease based on evidence from high-income countries—done in Sub-Saharan Africa were published. Realising Effectiveness Across Continents with Hydroxyurea (REACH), a phase 1–2, open-label, international trial, showed the safety, activity, and feasibility of treating young children with sickle-cell disease with hydroxyurea in this endemic region where the condition is worsened by coexisting malaria and malnutrition. Full-Text PDF