Articles of Interest

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Hundreds of scientific papers have been written on sickle cell and nutrition. In this section, we include both citations and complete articles on sickle cell anemia and related topics that we have found to be of special interest.

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*Anti-sickling effect of dietary thyocyanate in prophylactic control of sickle cell anemia
Agbai, O
J Natl Med Assoc 1986 Nov;78(11):1053-6

*Sickle cell anemia and dietary precursors of cyanate
Houston RG
Am J Clin Nutr 1973 Nov;26(11):1261-4

Oral glutamine supplementation decreases resting energy expenditure in children and adolescents with sickle cell anemia.
Williams R, Olivi S, Li CS, Storm M, Cremer L, Mackert P, Wang W.
J Pediatr Hematol Oncol. 2004 Oct;26(10):619-25.
CONCLUSIONS: After 24 weeks of orally administered glutamine, children and adolescents with sickle cell anemia had a decrease in REE and improvement in nutritional parameters. Those who were underweight had a greater decrease in REE than those of normal body weight. Lowering REE may be an effective way to improve the growth of these children and adolescents...

Arginine therapy: a new treatment for pulmonary hypertension in sickle cell disease?
Morris CR, Morris SM Jr, Hagar W, Van Warmerdam J, Claster S, Kepka-Lenhart D, Machado L, Kuypers FA, Vichinsky EP.
Am J Respir Crit Care Med. 2003 Jul 1;168(1):63-9. Epub 2003 Mar 05.
With limited treatment options and a high mortality rate for patients with sickle cell disease who develop pulmonary hypertension, arginine is a promising new therapy that warrants further investigation.

Oral citrulline as arginine precursor may be beneficial in sickle cell disease: early phase two results.
Waugh WH, Daeschner CW 3rd, Files BA, McConnell ME, Strandjord SE.
J Natl Med Assoc. 2001 Oct;93(10):363-71.

Continued L-citrulline supplementation in compliant subjects continued to lessen symptomatology, to maintain plasma arginine concentrations greater than control levels, and to maintain nearly normal total leukocyte and neutrophil counts. Side effects or toxicity from citrulline were not experienced. Oral L-citrulline may portend very useful for palliative therapy in sickle cell disease. Placebo-controlled, long-term trials are now indicated.


In Vitro Effects of Aged Garlic Extract and Other Nutritional Supplements on Sickle Erythrocytes
Ohnishi ST, Ohnishi T.
J Nutr. 2001 Mar;131(3s):1085S-92S.

On the basis of these in vivo and ex vivo studies, we propose that a cocktail of antioxidants would have beneficial effects in lessening the incidence and severity of crisis and reducing anemia in sickle cell disease

Body composition in children with sickle cell disease.
Barden EM, Kawchak DA, Ohene-Frempong K, Stallings VA, Zemel BS.
Am J Hematol. 2002 Apr;69(4):239-46.

CONCLUSIONS: Children with SCD have impaired growth, delayed puberty, and poor nutritional status. Low z scores for upper arm fat area indicate deficits in fat (energy) stores, and low FFM coupled with low upper arm muscle area indicate muscle wasting and low protein stores. These body-composition abnormalities suggest that the nutritional needs of the African American children with SCD were not being met.

Optimization of folic acid, vitamin B(12), and vitamin B(6) supplements in pediatric patients with sickle cell disease.
van der Dijs FP, Fokkema MR, Dijck-Brouwer DA, Niessink B, van der Wal TI, Schnog JJ, Duits AJ, Muskiet FD, Muskiet FA.
Am J Hematol. 2002 Apr;69(4):239-46.

Using homocysteine as a functional marker, we determined optimal folic acid, vitamin B(12), and vitamin B(6) dosages in 21 pediatric sickle cell disease (SCD) patients (11 HbSS, 10 HbSC; 7-16 years). Optimal dosages are as follows: 700 microg folic acid (3.5-7 U.S. 1989 RDA), 3 U.S. 1989 RDA vitamin B(12) (4.2-6.0 microg), and 3 U.S. 1989 RDA vitamin B(6) (4.2-6.0 mg). A practical daily combination is 1 mg folic acid (4.3-8.5 U.S. 1998 RDA when taken with meals), 6 microg vitamin B(12) (2.5-5 U.S. 1998 RDA), and 6 mg vitamin B(6) (4.6-10 U.S. 1998 RDA). This combination may by simple and relatively inexpensive means reduce these patients' inherently high risk of endothelial damage. Copyright 2002 Wiley-Liss, Inc.

Effect of zinc supplementation on growth and body composition in children with sickle cell disease.
Zemel BS, Kawchak DA, Fung EB, Ohene-Frempong K, Stallings VA.
Biochem Med Metab Biol. 1988 Feb;39(1):64-8.

CONCLUSIONS: Prepubertal children with SCD-SS may have zinc deficiency and may benefit from zinc supplementation to improve linear growth and weight gain.

Carbamylation of hemoglobin in vivo with chronic sublethal dietary cyanide: implications for hemoglobin S.
Jackson LC, Oseguera M, Medrano S, Kim YL.
Biochem Med Metab Biol. 1988 Feb;39(1):64-8.

Carbamylation of the hemoglobin in sickle cell anemia has been demonstrated to improve the status of this hemoglobinopathy. Using an animal model of West African human patterns of chronic sublethal dietary cyanide ingestion, 12 miniature swine consuming either 0, 0.4, 0.7, or 1.2 mg of cyanide/kg body weight/day were studied for 24 weeks to determine if this dietary regime could produce irreversible carbamylated hemoglobin. Throughout the study, the hematological status of all animals remained similar; however, the levels of carbamylated hemoglobin as measured by nanomoles of valine hydantoin varied proportionally to dietary sublethal cyanide intakes, indicating that these natural dietary levels could effect an important and presumably permanent modification of the hemoglobin's beta chain. Serum thiocyanate levels were also positively correlated with cyanide ingestion loads (r = 0.83, P less than 0.01). The implications of these findings in swine are important for the millions of humans with hemoglobin S who regularly consume similar levels of dietary cyanide and for our assessments of the biochemical and medical status of hemoglobin S under natural conditions.

Interaction of Antioxidants and Their Implication in Genetic Anemia
Chan AC, Chow CK, Chiu D.
Proc Soc Exp Biol Med. 1999 Dec;222(3):274-82.

The generation of reactive oxygen species (ROS) is a steady-state cellular event in respiring cells. Their production can be grossly amplified in response to a variety of pathophysiological conditions such as inflammation, immunologic disorders, hypoxia, hyperoxia, metabolism of drug or alcohol, exposure to UV or therapeutic radiation, and deficiency in antioxidant vitamins. Uncontrolled production of ROS often leads to damage of cellular macromolecules (DNA, protein, and lipids) and other small antioxidant molecules. A number of major cellular defense mechanisms exist to neutralize and combat the damaging effects of these reactive substances. The enzymic system functions by direct or sequential removal of ROS (superoxide dismutase, catalase, and glutathione peroxidase), thereby terminating their activities. Metal binding proteins, targeted to bind iron and copper ions, ensure that these Fenton metals are cryptic. Nonenzymic defense consists of scavenging molecules that are endogenously produced (GSH, ubiquinols, uric acid) or those derived from the diet (vitamins C and E, lipoic acid, selenium, riboflavin, zinc, and the carotenoids). These antioxidant nutrients occupy distinct cellular compartments and among them, there are active recycling. For example, oxidized vitamin E (tocopheroxy radical) has been shown to be regenerated by ascorbate, GSH, lipoic acid, or ubiquinols. GSH disulfides (GSSG) can be regenerated by GSSG reductase (a riboflavin-dependent protein), and enzymic pathways have been identified for the recycling of ascorbate radical and dehydroascorbate. The electrons that are used to fuel these recycling reactions (NADH and NADPH) are ultimately derived from the oxidation of foods. Sickle cell anemia, thalassemia, and glucose-6-phosphate-dehydrogenase deficiency are all hereditary disorders with higher potential for oxidative damage due to chronic redox imbalance in red cells that often results in clinical manifestation of mild to serve hemolysis in patients with these disorders. The release of hemoglobin during hemolysis and the subsequent therapeutic transfusion in some cases lead to systemic iron overloading that further potentiates the generation of ROS. Antioxidant status in anemia will be examined, and the potential application of antioxidant treatment as an adjunct therapy under these conditions will be discussed.

High-dose vitamin C: a risk for persons with high iron stores?
Gerster H.
Int J Vitam Nutr Res. 1999 Mar;69(2):67-82.
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The contribution of vitamin C (ascorbic acid) to the prevention of iron deficiency anemia by promoting the absorption of dietary non-heme iron-especially in persons with low iron stores--is well established. But the question has been raised whether high-dose intakes of vitamin C might unduly enhance the absorption of dietary iron in persons with high iron stores or in patients with iron overload, possibly increasing the potential risk of iron toxicity. Extensive studies have shown that overall the uptake and storage of iron in humans is efficiently controlled by a network of regulatory mechanisms. Even high vitamin C intakes do not cause iron imbalance in healthy persons and probably in persons who are heterozygous for hemochromatosis. The uptake, renal tubular reabsorption and storage of vitamin C itself are also strictly limited after high-dose intake so that no excessive plasma and tissue concentrations of vitamin C are produced. The effect of high-dose vitamin C on iron absorption in patients with iron overload due to homozygous hemochromatosis has not been studied. Of special importance is the early identification of hemochromatosis patients, which is assisted by the newly developed PCR test for hereditary hemochromatosis. Specific treatment consists of regular phlebotomy and possibly iron-chelating therapy. These patients should moreover avoid any possibility of facilitated absorption of iron and need to limit their intake of iron. Patients with beta-thalassemia major and sickle cell anemia who suffer from iron overload due to regular blood transfusions or excessive destruction of red blood cells need specialized medical treatment with iron chelators and should also control their intake of iron. The serum of patients with pathological iron overload can contain non-transferrin-bound iron inducing lipid peroxidation with subsequent consumption of antioxidants such as vitamin E and vitamin C. The role of iron in coronary heart disease and cancer is controversial. Early suggestions that moderately elevated iron stores are associated with an increased risk of CHD have not been confirmed by later studies. In vitro, ascorbic acid can act as a prooxidant in the presence of transition metals such as iron or copper, but in the living organism its major functions are as an antioxidant. High intakes of vitamin C have thus not been found to increase oxidative damage in humans. Accordingly, the risk of CHD or cancer is not elevated. On the contrary, most studies have shown that diets rich in vitamin C are inversely related to the incidence of these diseases.

A decrease in irreversibly sickled erythrocytes in sickle cell anemia patients given vitamin E.
Natta CL, Machlin LJ, Brin M.
Am J Clin Nutr. 1980 May;33(5):968-71.

Patients with sickle cell anemia were given 450 IU of vitamin E (as alpha-tocopherol) per day for 6 to 35 weeks. Plasma tocopherol levels increased from 0.7 +/- 0.2 mg/g lipid pretreatment, to 2.3 +/- 0.3 mg/g lipid. The percentage of circulating irreversibly sickled red cells decreased from 25 +/- 3% pretreatment to 11 +/- 1% after vitamin E administration (P less than 0.001). The percentage of irreversibly sickled red cells remained below pretreatment levels as long as the vitamin was administered (up to 35 weeks). The biochemical and clinical implications of these observations are discussed.

Zinc deficiency in patients with sickle cell disease
Prasad AS.
Am J Clin Nutr. 2002 Feb;75(2):181-2.

Zinc deficiency is relatively common in adult patients with SCD, affecting 60–70% of the adult SCD patients in our center (2, 6). Our diagnosis of zinc deficiency is based on zinc concentrations in lymphocytes and granulocytes in SCD patients. Hyperzincuria and a high protein turnover due to increased hemolysis significantly increase the daily zinc requirement in SCD patients, which is not met by the usual dietary intake. The role of intestinal absorption and endogenous zinc loss is not known.