Nutritional Supplement Profile of Adults with Sickle Cell Disease

To the Editor

Sickle cell disease (SCD) is an inherited monogenetic disease with pleomorphic manifestations. Among them, leg ulcers are a debilitating and severe complication, with their frequency depending on genotype, geographic region and socioeconomic status⁽¹⁾. Adequate nutrition is critical during the ulcer healing process⁽²⁾. People with SCD have been found to be deficient in micronutrients such as zinc, magnesium, and vitamins C, A, D and E and may have higher daily dietary nutritional requirements than healthy individuals⁽³⁾. This may be due to increased utilization due to high red cell turnover, compounded by possible decreased absorption in the gastrointestinal tract due to recurrent vasoocclusion in the capillary system of the splanchnic vascular system. The few available studies investigating possible malabsorption in patients with SCD were done in children, meaning they may not capture long term effects of SCD on the gut that may manifest in adults^{(4) (5)}. Inadequate nutritional status may contribute to the formation and the delay in healing of leg ulcers, and thus may be one of the distinguishing factors between patients who develop leg ulcers and those who do not⁽³⁾. Little information exists on the nutritional of status of people with SCD and its impact on the manifestations of the disease. We set to describe the nutritional supplement patterns of a population of people with sickle cell along with their leg ulcer status, and analyze relationships to leg ulcer formation.

We collected anthropometric, laboratory and demographic data in adults with SCD enrolled in the cross-sectional Insights Into Microbiome and Environmental Contributions to Sickle Cell Disease and Leg Ulcers Study (NCT02156102). Participants with and without leg ulcers and of >18 yrs were recruited at steady state, and they were considered “leg ulcer” if they had an active or history of leg ulcer, and “non-ulcer” if they had never had an ulcer. All patients completed a questionnaire about nutritional supplementation (Supplement 1). Descriptive statistics are presented in terms of mean, standard deviation (SD) and percentages. Comparisons were made using Chi-square or Fisher exact tests, and t-test or analysis of variance (ANOVA) followed by post-hoc pairwise comparison with Bonferroni-adjusted p-values. Statistical significance was declared when p-value<0.05. Statistical analysis was performed using SAS version 9.4.

As of December 2017, 151 patients were enrolled in Insights. We report on 147 who had complete nutritional supplement data. The breakdown by genotype is 122 HbSS, 16 HbSC, 5 HbSβ⁰ and 4 HbSβ⁺. Out of the N 147, 62 were male and 85 were female, with a mean age of 39.6 (SD ±10.99) and a mean BMI of 25.2 kg/m² (SD±6.3). BMI differed by genotype: 23.8 in HBSS, 26.1 in HbSβ⁰, 33.9 in HbSC, and 32.9 in HbSβ⁺. The difference in average BMI was significant between HbSS and HbSC (p=<0.0001) and between HbSS and HbSβ⁺ (p=0.01). There was a non-significant trend of patients with leg ulcer to have a lower BMI, as has been shown in prior research (23.9 vs 26.4), but this was in part explained by the fact that most patients with ulcers had HBSS (~93%). Overall, 93.8% of subjects took supplements of any kind. Folic acid was by far the most common, taken by 82.4% of ulcer and 92.4% of non-ulcer patients (p=0.06). Multivitamin and Vitamin D were taken by 35% of ulcer and 32.9% of non-ulcer (p=0.8) The main differences between the two groups were in zinc supplementation, taken by 14.7% of the ulcer participants and 4% of the non-ulcer (p=0.02), and vitamin B complex, taken by 11.8% of ulcer participants and only 1.3% of non-ulcer participants (p=0.008). See Table 1 for the data for all supplements included in the questionnaire. Serum zinc and magnesium levels were in the normal range and were similar in both groups. Serum albumin was within normal range and no different between those with ulcer those without (4.1 vs 4.3 g/dL).

Table 1.

Supplement	Patients with Ulcer: N (%) out of N=68	Patients with No Ulcer: N (%) out of N=79	P-values
MVI	24 (35%)	26 (32.9%)	0.8
Vitamin B complex	8 (11.8%)	1 (1.3%)	0.008
Vitamin C	11 (16.20%)	7 (9%)	0.18
Vitamin E	2 (2.90%)	5 (6.30%)	0.5
Folic acid	56 (82.40%)	73 (92.40%)	0.06
Calcium	11 (16.20%)	13 (16.50%)	0.96
Vitamin D	24 (35%)	31 (39.20%)	0.6
Vitamin B12	5 (7.30%)	11 (13.90%)	0.2
Selenium	1 (1.50%)	1 (1.30%)	0.9
Iron	1 (1.50%)	2 (3%)	0.65
Zinc	10 (14.70%)	3 (4%)	0.02
Fish Oil	5 (7.40%)	11 (13.90%)	0.2
Flaxseed	2 (2.90%)	3 (3.80%)	1
Garlic	1 (1.50%)	2 (3%)	1
Glucosamine	4 (5.90%)	2 (3%)	0.3
Saw Palmetto	0 (0%)	0 (0%)	0
Coenzyme Q10	2 (2.90%)	3 (4%)	1

We report that most patients take folic acid, unsurprising as it has been general practice to recommend folic acid for all patients with SCD. However, the evidence supporting the effectiveness of folic acid’s benefit in SCD is weak ⁽³⁾. Zinc, which has been shown to be helpful in the treatment of SCD leg ulcers⁽¹⁾ is significantly more likely to be taken by patients with leg ulcers than those without, but only 15% of them report taking it. We speculate that this may be due to lack of knowledge on the part of the providers, or difficulty obtaining it under common health insurance coverage. Vitamin B complex is the most significantly different between the two groups, with those in the ulcer group taking it twice as often as those in the non-ulcer group. The compounds present in the B complex supplement are active in wound healing, such as thiamine, pantothenic acid, and folic acid ⁽²⁾. Vitamin D intake was reported by a relatively large portion of the participants (~37%). Our data show that the average BMI of individuals with SCD is approaching that of the general African American population (25.2 vs.~27.9), however, we also report differences in BMI based on the genotype, with HbSS having a significantly lower average BMI than milder genotypes such as HbSC and HbSβ⁺. The effect of an increasing BMI in patients with SCD needs to be evaluated in larger studies, as it is likely to have a negative influence on disease severity and incidence of co-morbidities⁽⁵⁾. While our data cannot use nutritional supplementation to account for differences in incidence of leg ulcers, it shows that overall very few of our participants are taking any nutritional supplementation aside from folic acid. Since proper nutrition is important in wound healing and in overall health, the development of targeted dietary recommendations for patients with ulcers could contribute to improved healing rates in this patient population, as has been demonstrated in other types of wounds.