Nutritional supplements that may be helpful: 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.⁴ A study of 85 adults with sickle cell anemia showed more of them had vitamin B12 deficiency than did a group of healthy people.⁵ 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.⁶ 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.

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.⁷ 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.^{8 9} Elevated homocysteine is recognized as a risk factor for cardiovascular disease.¹⁰ In particular, high levels of homocysteine in sickle cell anemia patients have been associated with a higher incidence of stroke.¹¹ Deficiencies of vitamin B6, vitamin B12, and folic acid occur more frequently in people with sickle cell anemia than in others^{12 13 14} and are a cause of high homocysteine levels.¹⁵ 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.¹⁶ 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.¹⁷ In the treatment of sickle cell anemia, folic acid is typically supplemented in amounts of 1,000 mcg daily.¹⁸ Anyone taking this amount of folic acid should have vitamin B12 status assessed by a healthcare professional.

Iron deficiency is relatively common in people with sickle cell anemia, especially in pregnant women and in children.^{19 20} Iron deficiency in people with sickle cell anemia is best diagnosed with a laboratory test called serum ferritin.^{21 22} During sickle cell crises, however, serum ferritin is no longer useful as an indicator of iron deficiency.²³ The value of iron supplementation for people with sickle cell anemia who are diagnosed with iron deficiency is unclear. Iron supplements have, in some reports, reduced the severity of anemia as measured by laboratory tests; however, some reports suggest they may increase the symptoms of sickle cell anemia.^{24 25} Moreover, a state of iron deficiency has been shown to reduce sickling of red blood cells in the blood of people with sickle cell anemia.²⁶ A small trial of iron restriction in patients with sickle cell anemia found improvement in anemia and clinical symptoms as well as decreased red blood cell breakdown during iron restriction.²⁷ A doctor should be consulted before deciding to supplement or restrict iron in sickle cell anemia.

Low concentrations of red blood cell magnesium have been noted in patients with sickle cell anemia.^{28 29} 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.³⁰ 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.

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.^{31 32} Vitamin B6 deficiency has been reported in some research to be more common in people with sickle cell anemia than in healthy people.^{33 34} 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.³⁵ Therefore, evidence in support of vitamin B6 supplementation for people with sickle cell anemia remains weak.

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

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.⁴⁷ In a preliminary trial, 12 people with sickle cell anemia received 25 mg of zinc every four hours for 3 to 18 months.⁴⁸ 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.⁴⁹ Ulcer healing rate was more than three times faster in the zinc group than in the placebo group.