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    Sickle Cell Anemia (Holistic)

    Sickle Cell Anemia (Holistic)

    About This Condition

    Get support for sickle cell anemia by focusing on your unique nutritional needs. According to research or other evidence, the following self-care steps may be helpful.
    • Fight back with fish oil

      Reduce the frequency of severe pain episodes by taking a daily fish oil supplement providing 33 mg of EPA and 23 mg of DHA for every 2.2 pounds of body weight

    • Think zinc

      Under the supervision of a doctor, take a daily supplement of 100 mg of zinc, plus 2 mg of copper, to help prevent cell damage and speed healing of leg ulcers associated with sickle cell anemia

    • Fill up on fluids

      Drink plenty of water and other fluids to maintain good circulation

    • Take a test

      Have your blood homocysteine levels checked to find out if daily folic acid supplements of 1 to 4 mg are right for you, or to discover if you have a vitamin B12 deficiency that requires treatment

    About

    About This Condition

    Anemia is a deficiency of the oxygen-carrying capacity of red blood cells. Sickle cell anemia is an inherited chronic anemia in which the red blood cells become sickle or crescent-shaped. The symptoms of sickle cell anemia are caused by the clogging of small blood vessels by the sickle cells or by poor delivery of oxygen to the tissues due to the anemia itself.

    A sickle cell crisis is a painful episode that occurs when the body becomes severely deprived of oxygen. The disease and the trait occur in people of African descent, as well as in people from Mediterranean countries, India, and the Middle East, but rarely in people of European descent.

    Symptoms

    Symptoms include fatigue, joint and abdominal pain, irritability, yellow discoloration of the skin and eyes, leg sores, gum disease, frequent respiratory infections, blindness later in life, and periods of prolonged, sometimes painful erections in males. People with sickle cell anemia can have episodes of severe pain in the arms, legs, chest, and abdomen that may be accompanied by fever, nausea, and difficulty breathing. These symptoms occur only in people who inherit copies of the sickle cell gene from both parents. People who inherit a sickle cell gene from only one parent have what is known as sickle cell trait and are without symptoms.

    Eating Right

    The right diet is the key to managing many diseases and to improving general quality of life. For this condition, scientific research has found benefit in the following healthy eating tips.

    Recommendation Why
    Balance nutrition
    Sickle cell patients suffer from nutrient deficiencies, which may be due to increased nutritional needs. Aim to eat a balanced diet high in nutrient-rich, whole foods.

    People with sickle cell anemia suffer from many nutrient deficiencies, but preliminary research on dietary habits shows that food and nutrient intake by sickle cell patients in general meets or exceeds recommendations and is not significantly different from healthy controls.1 , 2 , 3 This suggests the higher rate of nutrient deficiencies may be due to an increased need for many nutrients in sickle cell patients. The effectiveness of dietary interventions in supplying adequate nutrition to meet these higher demands has not been examined.

    Supplements

    What Are Star Ratings?

    Our proprietary ?Star-Rating? system was developed to help you easily understand the amount of scientific support behind each supplement in relation to a specific health condition. While there is no way to predict whether a vitamin, mineral, or herb will successfully treat or prevent associated health conditions, our unique ratings tell you how well these supplements are understood by the medical community, and whether studies have found them to be effective for other people.

    For over a decade, our team has combed through thousands of research articles published in reputable journals. To help you make educated decisions, and to better understand controversial or confusing supplements, our medical experts have digested the science into these three easy-to-follow ratings. We hope this provides you with a helpful resource to make informed decisions towards your health and well-being.

    3 Stars Reliable and relatively consistent scientific data showing a substantial health benefit.

    2 Stars Contradictory, insufficient, or preliminary studies suggesting a health benefit or minimal health benefit.

    1 Star For an herb, supported by traditional use but minimal or no scientific evidence. For a supplement, little scientific support.

    Supplement Why
    2 Stars
    Fish Oil
    250 mg of oil per 2.2 lbs (1 kg) of body weight daily
    Supplementing with fish oil appears to reduce the frequency of severe pain episodes.

    In a preliminary trial, 13 patients with sickle cell anemia were given two supplement combinations for seven to eight months each. The first combination included 109 mg zinc , 153 IU vitamin E , 600 mg vitamin C , and 400 ml (about 14 ounces) of soybean oil containing 11 grams of linoleic acid and 1.5 grams of alpha linolenic acid. The second combination included 140 IU vitamin E, 600 mg vitamin C, and 20 grams of fish oil containing 6 grams of omega-3 fatty acids. Reduction in diseased cells was observed only during the administration of the first protocol. The authors concluded that zinc was the important difference between the two combinations and may be a protector of red blood cell membranes.4

    Fish oil alone has also been studied. In a double-blind trial, supplementation with menhaden oil, in the amount of 250 mg per 2.2 pounds of body weight per day for one year, reduced the frequency of severe pain episodes by approximately 45%, compared with placebo.5 This treatment may work by correcting an imbalance between omega-3 and omega-6 fatty acids that occurs in people with sickle cell anemia.6 The beneficial effect of the omega-3 fatty acids present in fish oil was confirmed in another double-blind study.7

    2 Stars
    Folic Acid (High Homocysteine)
    Consult a qualified healthcare practitioner
    In one trial, patients with sickle cell anemia who were given folic acid plus aged garlic extract, vitamin C, and vitamin E saw significant improvement and less painful crises.

    In a preliminary trial, 20 patients with sickle cell anemia were given either 1 mg of folic acid per day or folic acid plus 6 grams of aged garlic extract, 6 grams of vitamin C, and 1,200 mg of vitamin E per day for six months.8 Patients taking the combination had a significant improvement in their hematocrit (an index of anemia) and less painful crises than those taking just folic acid.

    Preliminary research has found that patients with sickle cell anemia are more likely to have elevated blood levels of homocysteine compared to healthy people.9 , 10 Elevated homocysteine is recognized as a risk factor for cardiovascular disease .11 In particular, high levels of homocysteine in sickle cell anemia patients have been associated with a higher incidence of stroke .12 Deficiencies of vitamin B6 , vitamin B12, and folic acid occur more frequently in people with sickle cell anemia than in others13 , 14 , 15 and are a cause of high homocysteine levels.16 A controlled trial found homocysteine levels were reduced 53% in children with sickle cell anemia receiving a 2?4 mg supplement of folic acid per day, depending on age, but vitamin B6 or B12 had no effect on homocysteine levels.17 A double-blind trial of children with sickle cell anemia found that children given 5 mg of folic acid per day had less painful swelling of the hands and feet compared with those receiving placebo, but blood abnormalities and impaired growth rate associated with sickle cell anemia were not improved.18 In the treatment of sickle cell anemia, folic acid is typically supplemented in amounts of 1,000 mcg daily.19 Anyone taking this amount of folic acid should have vitamin B12 status assessed by a healthcare professional.

    2 Stars
    L-Arginine (Pulmonary Hypertension)
    100 mg per 2.2 lbs (1 kg) of body weight, three times per day
    People with pulmonary hypertension (a life-threatening complication of sickle cell anemia) who received L-arginine had significant improvement in one study.

    In a preliminary study, individuals with pulmonary hypertension (a life-threatening complication of sickle cell anemia) received L-arginine in the amount of 100 mg per 2.2 pounds of body weight, three times per day for five days. L-arginine treatment resulted in a significant improvement in pulmonary hypertension, as determined by a 15% decline in the pulmonary artery systolic pressure.20 Longer-term studies are needed to confirm these preliminary results.

    2 Stars
    L-Carnitine
    50 mg per 2.2 lbs (1 kg) of body weight daily
    In a study of children with sickle cell anemia, supplementing with L-carnitine reduced the number of painful crises and improved abnormal heart function and pulmonary hypertension.

    In a preliminary study of children with sickle cell anemia, supplementing with L-carnitine (50 mg per 2.2 pounds of body weight per day for six months) significantly reduced the number of painful crises and significantly improved the abnormal heart function (diastolic dysfunction) that was present in most of the children. L-carnitine supplementation also significantly improved pulmonary hypertension in the children who had this abnormality prior to treatment.21

    2 Stars
    Vitamin B12 (Vitamin B12 Deficiency)
    Consult a qualified healthcare practitioner
    People with sickle cell anemia may be deficient in vitamin B12. Intramuscular vitamin B12 injections improved symptoms for patients in one study.

    Sickle cell anemia may result in vitamin B12 deficiency. A study of children with sickle cell anemia found them to have a higher incidence of vitamin B12 deficiency than children without the disease.22 A study of 85 adults with sickle cell anemia showed more of them had vitamin B12 deficiency than did a group of healthy people.23 A subsequent preliminary trial demonstrated that for patients with low blood levels of vitamin B12, intramuscular injections of 1 mg of vitamin B12 weekly for 12 weeks led to a significant reduction in symptoms.24 Researchers do not know whether people with sickle cell anemia who are found to be deficient in vitamin B12 would benefit equally from taking vitamin B12 supplements orally.

    Preliminary research has found that patients with sickle cell anemia are more likely to have elevated blood levels of homocysteine compared to healthy people.25 , 26 Elevated homocysteine is recognized as a risk factor for cardiovascular disease .27 In particular, high levels of homocysteine in sickle cell anemia patients have been associated with a higher incidence of stroke .28 Deficiencies of vitamin B6 , vitamin B12, and folic acid occur more frequently in people with sickle cell anemia than in others29 , 30 , 31 and are a cause of high homocysteine levels.32 A controlled trial found homocysteine levels were reduced 53% in children with sickle cell anemia receiving a 2?4 mg supplement of folic acid per day, depending on age, but vitamin B6 or B12 had no effect on homocysteine levels.33 A double-blind trial of children with sickle cell anemia found that children given 5 mg of folic acid per day had less painful swelling of the hands and feet compared with those receiving placebo, but blood abnormalities and impaired growth rate associated with sickle cell anemia were not improved.34 In the treatment of sickle cell anemia, folic acid is typically supplemented in amounts of 1,000 mcg daily.35 Anyone taking this amount of folic acid should have vitamin B12 status assessed by a healthcare professional.

    2 Stars
    Zinc
    Take under medical supervision: 100 mg of zinc (plus 2 mg of copper daily to protect against depletion)
    Supplementing with zinc appears to help prevent cell damage and speed healing of leg ulcers associated with sickle cell anemia.

    Antioxidant nutrients protect the body?s cells from oxygen-related damage. Many studies show that sickle cell anemia patients tend to have low blood levels of antioxidants, including carotenoids , vitamin A , vitamin E , and vitamin C , despite adequate intake.36 , 37 , 38 , 39 , 40 , 41 Low blood levels of vitamin E in particular have been associated with higher numbers of diseased cells in children42 and with greater frequency of symptoms in adults.43 A small, preliminary trial reported a 44% decrease in the average number of diseased cells in six sickle cell anemia patients given 450 IU vitamin E per day for up to 35 weeks. This effect was maintained as long as supplementation continued.44

    In another preliminary trial, 13 patients with sickle cell anemia were given two supplement combinations for seven to eight months each. The first combination included 109 mg zinc , 153 IU vitamin E , 600 mg vitamin C , and 400 ml (about 14 ounces) of soybean oil containing 11 grams of linoleic acid and 1.5 grams of alpha linolenic acid. The second combination included 140 IU vitamin E, 600 mg vitamin C, and 20 grams of fish oil containing 6 grams of omega-3 fatty acids. Reduction in diseased cells was observed only during the administration of the first protocol. The authors concluded that zinc was the important difference between the two combinations and may be a protector of red blood cell membranes.45

    Fish oil alone has also been studied. In a double-blind trial, supplementation with menhaden oil, in the amount of 250 mg per 2.2 pounds of body weight per day for one year, reduced the frequency of severe pain episodes by approximately 45%, compared with placebo.46 This treatment may work by correcting an imbalance between omega-3 and omega-6 fatty acids that occurs in people with sickle cell anemia.47

    The zinc deficiency associated with sickle cell anemia appears to play a role in various aspects of the illness. For example, preliminary research has correlated low zinc levels with poor growth in children with sickle cell anemia.48 In a preliminary trial, 12 people with sickle cell anemia received 25 mg of zinc every four hours for 3 to 18 months.49 The number of damaged red blood cells fell from 28% to 18.6%. Addition of 2 mg of copper per day did not inhibit the effect of zinc. (Zinc supplementation in the absence of copper supplementation induces a copper deficiency.) Patients with the highest number of damaged red blood cells had a marked response to zinc, but those with lower levels of damaged cells (less than 20% irreversibly sickled cells) had little or no response.

    Chronic leg ulcers occur in about 75% of adults with sickle cell disease. In a controlled trial, sickle cell patients with low blood levels of zinc received 88 mg of zinc three times per day for 12 weeks.50 Ulcer healing rate was more than three times faster in the zinc group than in the placebo group. Zinc supplementation (25 mg 3 times per day for 3 months) also decreased the number of infections in adults with sickle cell anemia.51

    1 Star
    Beta-Carotene
    Refer to label instructions
    Sickle cell anemia patients tend to have low levels of antioxidants, which protect cells from oxygen-related damage. Supplementing with beta-carotene may help correct a deficiency.

    Caution: Synthetic beta-carotene has been linked to increased risk of lung cancer in smokers. Until more is known, smokers should avoid all beta-carotene supplements.

    Antioxidant nutrients protect the body?s cells from oxygen-related damage. Many studies show that sickle cell anemia patients tend to have low blood levels of antioxidants, including carotenoids , vitamin A , vitamin E , and vitamin C , despite adequate intake.52 , 53 , 54 , 55 , 56 , 57 Low blood levels of vitamin E in particular have been associated with higher numbers of diseased cells in children58 and with greater frequency of symptoms in adults.59 A small, preliminary trial reported a 44% decrease in the average number of diseased cells in six sickle cell anemia patients given 450 IU vitamin E per day for up to 35 weeks. This effect was maintained as long as supplementation continued.60

    1 Star
    Garlic
    Refer to label instructions
    In one trial, patients with sickle cell anemia who were given folic acid plus aged garlic extract, vitamin C, and vitamin E saw significant improvement and less painful crises.

    In a preliminary trial, 20 patients with sickle cell anemia were given either 1 mg of folic acid per day or folic acid plus 6 grams of aged garlic extract, 6 grams of vitamin C, and 1,200 mg of vitamin E per day for six months.61 Patients taking the combination had a significant improvement in their hematocrit (an index of anemia) and less painful crises than those taking just folic acid.

    1 Star
    Magnesium
    Refer to label instructions
    In one trial, supplementing with magnesium dramatically reduced the number of painful days for people with sickle cell anemia.

    Low concentrations of red blood cell magnesium have been noted in patients with sickle cell anemia.62 , 63 Low magnesium, in turn, is thought to contribute to red blood cell dehydration and a concomitant increase in symptoms. In a preliminary trial, administration of 540 mg of magnesium per day for six months to sickle cell anemia patients reversed some of the characteristic red blood cell abnormalities and dramatically reduced the number of painful days for these patients.64 The form of magnesium used in this trial, magnesium pidolate, is not supplied by most magnesium supplements; it is unknown whether other forms of magnesium would produce similar results.

    1 Star
    Vitamin A
    Refer to label instructions
    Sickle cell anemia patients tend to have low levels of antioxidants, which protect cells from oxygen-related damage. Supplementing with vitamin A may help correct a deficiency.

    Antioxidant nutrients protect the body?s cells from oxygen-related damage. Many studies show that sickle cell anemia patients tend to have low blood levels of antioxidants, including carotenoids , vitamin A , vitamin E , and vitamin C , despite adequate intake.65 , 66 , 67 , 68 , 69 , 70 Low blood levels of vitamin E in particular have been associated with higher numbers of diseased cells in children71 and with greater frequency of symptoms in adults.72 A small, preliminary trial reported a 44% decrease in the average number of diseased cells in six sickle cell anemia patients given 450 IU vitamin E per day for up to 35 weeks. This effect was maintained as long as supplementation continued.73

    1 Star
    Vitamin B6
    Refer to label instructions
    Vitamin B6 has been shown to have anti-sickling effects on the red blood cells. It can also correct vitamin B6 deficiency, which is common in people with sickle cell anemia.

    Preliminary research has found that patients with sickle cell anemia are more likely to have elevated blood levels of homocysteine compared to healthy people.74 , 75 Elevated homocysteine is recognized as a risk factor for cardiovascular disease .76 In particular, high levels of homocysteine in sickle cell anemia patients have been associated with a higher incidence of stroke .77 Deficiencies of vitamin B6 , vitamin B12, and folic acid occur more frequently in people with sickle cell anemia than in others78 , 79 , 80 and are a cause of high homocysteine levels.81 A controlled trial found homocysteine levels were reduced 53% in children with sickle cell anemia receiving a 2?4 mg supplement of folic acid per day, depending on age, but vitamin B6 or B12 had no effect on homocysteine levels.82 A double-blind trial of children with sickle cell anemia found that children given 5 mg of folic acid per day had less painful swelling of the hands and feet compared with those receiving placebo, but blood abnormalities and impaired growth rate associated with sickle cell anemia were not improved.83 In the treatment of sickle cell anemia, folic acid is typically supplemented in amounts of 1,000 mcg daily.84 Anyone taking this amount of folic acid should have vitamin B12 status assessed by a healthcare professional.

    In test tube studies, vitamin B6 has been shown to have anti-sickling effects on the red blood cells of people with sickle cell anemia.85 , 86 Vitamin B6 deficiency has been reported in some research to be more common in people with sickle cell anemia than in healthy people.87 , 88 In a controlled trial, five sickle cell anemia patients with evidence of vitamin B6 deficiency were given 50 mg of vitamin B6 twice daily. The deficiency was reversed with this supplement, but improvement in anemia was slight and considered insignificant.89 Therefore, evidence in support of vitamin B6 supplementation for people with sickle cell anemia remains weak.

    1 Star
    Vitamin C
    Refer to label instructions
    Sickle cell anemia patients tend to have low levels of antioxidants, which protect cells from oxygen-related damage. Supplementing with vitamin C may help correct a deficiency.

    Antioxidant nutrients protect the body?s cells from oxygen-related damage. Many studies show that sickle cell anemia patients tend to have low blood levels of antioxidants, including carotenoids , vitamin A , vitamin E , and vitamin C , despite adequate intake.90 , 91 , 92 , 93 , 94 , 95 Low blood levels of vitamin E in particular have been associated with higher numbers of diseased cells in children96 and with greater frequency of symptoms in adults.97 A small, preliminary trial reported a 44% decrease in the average number of diseased cells in six sickle cell anemia patients given 450 IU vitamin E per day for up to 35 weeks. This effect was maintained as long as supplementation continued.98

    In another preliminary trial, 13 patients with sickle cell anemia were given two supplement combinations for seven to eight months each. The first combination included 109 mg zinc , 153 IU vitamin E , 600 mg vitamin C , and 400 ml (about 14 ounces) of soybean oil containing 11 grams of linoleic acid and 1.5 grams of alpha linolenic acid. The second combination included 140 IU vitamin E, 600 mg vitamin C, and 20 grams of fish oil containing 6 grams of omega-3 fatty acids. Reduction in diseased cells was observed only during the administration of the first protocol. The authors concluded that zinc was the important difference between the two combinations and may be a protector of red blood cell membranes.99

    Fish oil alone has also been studied. In a double-blind trial, supplementation with menhaden oil, in the amount of 250 mg per 2.2 pounds of body weight per day for one year, reduced the frequency of severe pain episodes by approximately 45%, compared with placebo.100 This treatment may work by correcting an imbalance between omega-3 and omega-6 fatty acids that occurs in people with sickle cell anemia.101

    1 Star
    Vitamin E
    Refer to label instructions
    Low vitamin E levels have been associated with higher numbers of diseased cells in children and with greater symptom frequency in adults. Supplementing with the vitamin can help restore levels.

    Antioxidant nutrients protect the body?s cells from oxygen-related damage. Many studies show that sickle cell anemia patients tend to have low blood levels of antioxidants, including carotenoids , vitamin A , vitamin E , and vitamin C , despite adequate intake.102 , 103 , 104 , 105 , 106 , 107 Low blood levels of vitamin E in particular have been associated with higher numbers of diseased cells in children108 and with greater frequency of symptoms in adults.109 A small, preliminary trial reported a 44% decrease in the average number of diseased cells in six sickle cell anemia patients given 450 IU vitamin E per day for up to 35 weeks. This effect was maintained as long as supplementation continued.110

    In another preliminary trial, 13 patients with sickle cell anemia were given two supplement combinations for seven to eight months each. The first combination included 109 mg zinc , 153 IU vitamin E , 600 mg vitamin C , and 400 ml (about 14 ounces) of soybean oil containing 11 grams of linoleic acid and 1.5 grams of alpha linolenic acid. The second combination included 140 IU vitamin E, 600 mg vitamin C, and 20 grams of fish oil containing 6 grams of omega-3 fatty acids. Reduction in diseased cells was observed only during the administration of the first protocol. The authors concluded that zinc was the important difference between the two combinations and may be a protector of red blood cell membranes.111

    Fish oil alone has also been studied. In a double-blind trial, supplementation with menhaden oil, in the amount of 250 mg per 2.2 pounds of body weight per day for one year, reduced the frequency of severe pain episodes by approximately 45%, compared with placebo.112 This treatment may work by correcting an imbalance between omega-3 and omega-6 fatty acids that occurs in people with sickle cell anemia.113

    References

    1. Tangney CC, Phillips G, Bell RA, et al. Selected indices of micronutrient status in adult patients with sickle cell anemia (SCA). Am J Hematol 1989;32:161?6.

    2. Phillips G, Tangney CC. Relationship of plasma alpha tocopherol to index of clinical severity in individuals with sickle cell anemia. Am J Hematol 1992;41:227?31.

    3. Chiu D, Vichinsky E, Ho SL, et al. Vitamin C deficiency in patients with sickle cell anemia. Am J Pediatr Hematol Oncol 1990;12:262?7.

    4. Muskiet FA, Muskiet FD, Meiborg G, Schermer JG. Supplementation of patients with homozygous sickle cell disease with zinc, alpha-tocopherol, vitamin C, soybean oil, and fish oil. Am J Clin Nutr 1991;54:736?44.

    5. Tomer A, Kasey S, Connor WE, et al. Reduction of pain episodes and prothrombotic activity in sickle cell disease by dietary n-3 fatty acids. Thromb Haemost 2001;85:966?74.

    6. Tomer A, Kasey S, Connor WE, et al. Reduction of pain episodes and prothrombotic activity in sickle cell disease by dietary n-3 fatty acids. Thromb Haemost 2001;85:966?74.

    7. Daak AA, Ghebremeskel K, Hassan Z, et al. Effect of omega-3 (n-3) fatty acid supplementation in patients with sickle cell anemia: randomized, double-blind, placebo-controlled trial. <em>Am J Clin Nutr</em> 2013;97:37?44.

    8. Ohnishi ST, Ohnishi T, Ogunmola GB. Sickle cell anemia: A potential nutritional approach for a molecular disease. Nutrition 2000;16:330?8.

    9. van der Dijs FP, Schnog JJ, Brouwer DA, et al. Elevated homocysteine levels indicate suboptimal folate status in pediatric sickle cell patients. Am J Hematol 1998;59:192?8.

    10. Houston PE, Rana S, Sekhasaria S, et al. Homocysteine in sickle cell disease: relationship to stroke. Am J Med 1997;103:192?6.

    11. Alpert MA. Homocysteine, atherosclerosis, and thrombosis. South Med J 1999;92:858?65 [review].

    12. Houston PE, Rana S, Sekhasaria S, et al. Homocysteine in sickle cell disease: relationship to stroke. Am J Med 1997;103:192?6.

    13. al-Momen AK. Diminished vitamin B12 levels in patients with severe sickle cell disease. J Intern Med 1995;237:551?5.

    14. Lin YK. Folic acid deficiency in sickle cell anemia. Scand J Haematol 1975;14:71?9.

    15. Natta CL, Reynolds RD. Apparent vitamin B6 deficiency in sickle cell anemia. Am J Clin Nutr 1984;40:235?9.

    16. Alpert MA. Homocysteine, atherosclerosis, and thrombosis. South Med J 1999;92:858?65 [review].

    17. van der Dijs FP, Schnog JJ, Brouwer DA, et al. Elevated homocysteine levels indicate suboptimal folate status in pediatric sickle cell patients. Am J Hematol 1998;59:192?8.

    18. Rabb LM, Grandison Y, Mason K, et al. A trial of folate supplementation in children with homozygous sickle cell disease. Br J Haematol 1983;54:589?94.

    19. Waterbury L. Anemia. In Barker LR, Burton JR, Zieve PD. Principles of ambulatory medicine, 4th ed. Baltimore: Williams & Wilkins, 1995, 605.

    20. Morris CR, Morris SM Jr, Hagar W, et al. Arginine therapy: a new treatment for pulmonary hypertension in sickle cell disease? Am J Respir Crit Care Med 2003;168:63?9.

    21. El-Beshlawy A, Abd El Raouf E, Mostafa F, et al. Diastolic dysfunction and pulmonary hypertension in sickle cell anemia: is there a role for L-carnitine treatment? Acta Haematol 2006;115:91?6.

    22. Osifo BO, Adeyokunnu A, Parmentier Y, et al. Abnormalities of serum transcobalamins in sickle cell disease (HbSS) in Black Africa. Scand J Haematol 1983;30:135?40.

    23. al-Momen AK. Diminished vitamin B12 levels in patients with severe sickle cell disease. J Intern Med 1995;237:551?5.

    24. al-Momen AK. Diminished vitamin B12 levels in patients with severe sickle cell disease. J Intern Med 1995;237:551?5.

    25. van der Dijs FP, Schnog JJ, Brouwer DA, et al. Elevated homocysteine levels indicate suboptimal folate status in pediatric sickle cell patients. Am J Hematol 1998;59:192?8.

    26. Houston PE, Rana S, Sekhasaria S, et al. Homocysteine in sickle cell disease: relationship to stroke. Am J Med 1997;103:192?6.

    27. Alpert MA. Homocysteine, atherosclerosis, and thrombosis. South Med J 1999;92:858?65 [review].

    28. Houston PE, Rana S, Sekhasaria S, et al. Homocysteine in sickle cell disease: relationship to stroke. Am J Med 1997;103:192?6.

    29. al-Momen AK. Diminished vitamin B12 levels in patients with severe sickle cell disease. J Intern Med 1995;237:551?5.

    30. Lin YK. Folic acid deficiency in sickle cell anemia. Scand J Haematol 1975;14:71?9.

    31. Natta CL, Reynolds RD. Apparent vitamin B6 deficiency in sickle cell anemia. Am J Clin Nutr 1984;40:235?9.

    32. Alpert MA. Homocysteine, atherosclerosis, and thrombosis. South Med J 1999;92:858?65 [review].

    33. van der Dijs FP, Schnog JJ, Brouwer DA, et al. Elevated homocysteine levels indicate suboptimal folate status in pediatric sickle cell patients. Am J Hematol 1998;59:192?8.

    34. Rabb LM, Grandison Y, Mason K, et al. A trial of folate supplementation in children with homozygous sickle cell disease. Br J Haematol 1983;54:589?94.

    35. Waterbury L. Anemia. In Barker LR, Burton JR, Zieve PD. Principles of ambulatory medicine, 4th ed. Baltimore: Williams & Wilkins, 1995, 605.

    36. Tangney CC, Phillips G, Bell RA, et al. Selected indices of micronutrient status in adult patients with sickle cell anemia (SCA). Am J Hematol 1989;32:161?6.

    37. Chiu D, Vichinsky E, Ho SL, et al. Vitamin C deficiency in patients with sickle cell anemia. Am J Pediatr Hematol Oncol 1990;12:262?7.

    38. Jain SK, Ross JD, Duett J, Herbst JJ. Low plasma prealbumin and carotenoid levels in sickle cell disease patients. Am J Med Sci 1990;229:13?5.

    39. Jain SK, Williams DM. Reduced levels of plasma ascorbic acid (vitamin C) in sickle cell disease patients: its possible role in the oxidant damage to sickle cells in vitro. Clin Chim Acta 1985;149:257?61.

    40. Natta C, Stacewicz-Sapuntzakis M, Bhagavan H, Bowen P. Low serum levels of carotenoids in sickle cell anemia. Eur J Haematol 1988;41:131?5.

    41. Essein, EU. Plasma levels of retinol, ascorbic acid and alpha-tocopherol in sickle cell anemia. Centr Afr J Med 1995;41:48?50.

    42. Ndombi IO, Kinoti SN. Serum vitamin E and the sickling status in children with sickle cell anemia. East Afr Med J 1990;67:720?5.

    43. Phillips G, Tangney CC. Relationship of plasma alpha tocopherol to index of clinical severity in individuals with sickle cell anemia. Am J Hematol 1992;41:227?31.

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

    45. Muskiet FA, Muskiet FD, Meiborg G, Schermer JG. Supplementation of patients with homozygous sickle cell disease with zinc, alpha-tocopherol, vitamin C, soybean oil, and fish oil. Am J Clin Nutr 1991;54:736?44.

    46. Tomer A, Kasey S, Connor WE, et al. Reduction of pain episodes and prothrombotic activity in sickle cell disease by dietary n-3 fatty acids. Thromb Haemost 2001;85:966?74.

    47. Tomer A, Kasey S, Connor WE, et al. Reduction of pain episodes and prothrombotic activity in sickle cell disease by dietary n-3 fatty acids. Thromb Haemost 2001;85:966?74.

    48. Pellegrini Braga JA, Kerbauy J, Fisberg M. Zinc, copper and iron and their interrelations in the growth of sickle cell patients. Arch Latinoam Nutr 1995;45:198?203.

    49. Brewer GJ, Brewer LF, Prasad AS. Suppression of irreversibly sickled erythrocytes by zinc therapy in sickle cell anemia. J Lab Clin Med 1977;90:549?54.

    50. Serjeant GR, Galloway RE, Gueri MC. Oral zinc sulphate in sickle-cell ulcers. Lancet 1970;2:891?3.

    51. Bao B, Prasad AS, Beck FWJ, et al. Zinc supplementation decreases oxidative stress, incidence of infection, and generation of inflammatory cytokines in sickle cell disease patients. Transl Res 2008;152:67?80.

    52. Tangney CC, Phillips G, Bell RA, et al. Selected indices of micronutrient status in adult patients with sickle cell anemia (SCA). Am J Hematol 1989;32:161?6.

    53. Chiu D, Vichinsky E, Ho SL, et al. Vitamin C deficiency in patients with sickle cell anemia. Am J Pediatr Hematol Oncol 1990;12:262?7.

    54. Jain SK, Ross JD, Duett J, Herbst JJ. Low plasma prealbumin and carotenoid levels in sickle cell disease patients. Am J Med Sci 1990;229:13?5.

    55. Jain SK, Williams DM. Reduced levels of plasma ascorbic acid (vitamin C) in sickle cell disease patients: its possible role in the oxidant damage to sickle cells in vitro. Clin Chim Acta 1985;149:257?61.

    56. Natta C, Stacewicz-Sapuntzakis M, Bhagavan H, Bowen P. Low serum levels of carotenoids in sickle cell anemia. Eur J Haematol 1988;41:131?5.

    57. Essein, EU. Plasma levels of retinol, ascorbic acid and alpha-tocopherol in sickle cell anemia. Centr Afr J Med 1995;41:48?50.

    58. Ndombi IO, Kinoti SN. Serum vitamin E and the sickling status in children with sickle cell anemia. East Afr Med J 1990;67:720?5.

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