Nutritional Status of Children and Adolescents with Sickle Cell Disease

Sickle cell disease (SCD) is a public health problem that interferes in the nutritional status of children and adolescents. Objective: To describe of the nutritional status and identify the factors associated with the growth deficit or obesity of children and adolescents with sickle cell disease. Methods: Critical analysis of originals articles published in Portuguese, English and Spanish in the electronic bases Medline, SciELO and LILACS with participants of 0 to 19 years old diagnosed with SCD. Results: We identified 37 articles that describe low weight, short stature and overweight or obesity prevalence ranging between 3 and 100%, 8.2% and 24.0%, 1.6% and 22.4%, respectively. The associated factors to the growth deficit were the increase of resting energy expenditure, the presence of low bone density, the high prevalence of low zinc and D-vitamin plasma concentration, the low consume of calcium and D-vitamin, vessel occlusion crises, increased need of transfusions and hormonal amendments presence. Conclusion: Amendments by weight and stature were frequent; however, we note an adjustment once the presence of overweight and obesity already exists in this group. The blood transfusion, the zinc supplementation and the regular use of hydroxyurea has shown benefit in the growth of children and adolescents with sickle cell disease.


Introduction
Sickle cell disease (SCD) is a multisystem disease resulted from a monogenic mutation of the beta globin from hemoglobin that originates hemoglobin S (HbS) [1].The term sickle cell disease encompass an amendments set which hemoglobin S is present, including sickle cell anemia (SCA; HbSS) and the others heterozygosis (HbSC, HbSD, S beta thalassemia, among others) [1].SCD, the heritage disease with bigger prevalence in the world, is originally from Africa and can be found in a variety of countries [1].
Malnutrition between children and adolescents with SCD is described as common historically, making important to evaluate the growth and development in order to identify the growth speed decrease and the delay influential factors early once the low weight and short stature result in psychosocial [2] impacts exacerbating the clinical scenario.
Malnutrition in children and adolescents may be due to innumerable factors, such as the low consumption of food during the pain crisis or increased metabolism due to increased red blood cells turnover due to hyper hemolysis or the severity of the disease.Therefore, our initial hypothesis was that there would be a high prevalence of malnutrition in this group.
The objective of this review is to describe the nutritional status amendments prevalence and to identify Table 1: Articles characteristics included in the review according to author and publication year.

Study objects Anthropometric indicators/ Growth reference standard
Main Results and Conclusion Stevens, et al. 1986 Jamaica [3] 298 HbSS children and 157 HbSC children 3 months to 9 years/ longitudinal and descriptive study.
Evaluating the growth and skeletal maturation of prepubertal children with SCD.

Weight and height
A Jamaican cohort study of sickle cell disease.
Weight and height deficit associated with delayed growth.Singhal, et al. 1994 Jamaica [26] 132 children (44  Somatic peak age postponed by 1.6 years (0.9 to 2.3 years) in the SCA subjects, however the growth of SCA adolescents was normal and presented no difference in the height reached at 17.9 years.The growth rate did not delay in HbSC adolescents.Warrier, et al. 1994 USA [29] 34 SCD children (22 HbSS,4 HbSC, 3 HbSF and 5 had S β thalassemia/6 months to 16.5 years/cross-sectional and descriptive study.
Determining the prevalence of mild and moderate malnutrition in patients with SCD.

Weight (W), Height (H) and Weight/ height Waterlow classification, 1974 and NCHS, 1979
We observed weight loss (< 80%) by Waterlow classification in 41% of boys and 25% of girls with SCD and height deficit (< 90%) in 25% of boys and 25% of girls with SCD.Soliman, et al. 1995 Oman [22] 90 prepubertal children (Tanner 1) (25 with GHD, 15 HbSS and GHD, 30 with normal variants of short stature and 20 with normal stature)/4 to 10 years/cross-sectional and case-control study.Basal concentrations of IGF-1 and IGFBP-3 were significantly lower in the group with SCA and deficient GH secretion.Children with SCA have lower significant IGF-1 production in response to GH, suggesting partial resistance to GH. BMI did not show any difference between the groups, but 9 of the 21 showed slower linear growth speed and lower concentrations of IGF-I and IGFBP-3.de Montalembert, et al. 1997 France [36] 35 children and adolescents with SCD/3 to 20 years (average of 11 years)/longitudinal and descriptive study.
Observing the safety and efficiency of HU in children with severe SCD.

Weight/height NCHS, 1977
The HU had good tolerance in short and medium term.No difference in growth speed in any of the three groups of children and adolescents.Z-scores were similar at the beginning of the study, after 1 year and after 2 years of treatment, excluding the adverse effect of HU on growth in this cohort.Leonard, et al. 1998 USA [14] 104 HbSS children and adolescents/4 to 18 years/cross-sectional and descriptive study.
Determining the relation of plasma zinc to growth and maturation of children with SCA.

Prevalence of nutritional status changes
The height and weight deficit values vary from 8.2% to 34.9% and from 3.7% to 100% respectively, and overweight vary from 1.6% to 22.4%.The emergence of weight and height compromise seems to be early, as we see in Stevens, et al. [3], which observed weight and height deficit before the age of 2 years on children with SCA.However, we observed overweight/obesity pres-group of the individuals, the nutritional status parameters, the prevalence of nutritional parameter classifications and the described factors that interfered in the nutritional status.

Study characteristics
Predominantly the studies type was descriptive (n = 34) with great variation in the sample number (from 8 to 675 participants) and in age (between 0 to 19 years old) (Table 1).

Study results
The studies applied varied the growth evaluation parameters.In addition, we observed the use of weight in 15 studies; of stature in 18 studies and of anthropometrics indicators in most studies (Height/age (H/A) in 17 History of hand-foot syndrome and more than 3 transfusions per patient were associated with an increased age were associated with an increased risk of malnutrition.
of short stature was related to a history of hand-foot syndrome and to the need for more than three transfusions per patient, in addition, malnutrition with vessel occlusion crises higher to two per year and the need for the first blood transfusion before 12 months old.
In contrast, the predominance of normal and the presence of overweight or obesity observed in the more recent studies [4,6,7,17,19] changes the nutritional profile of this group.These findings are important and possibly results of improved health care for people with sickle cell disease and changes in diet for the world's population.
The existence of extremes, namely of growth deficit or overweight/obesity, reinforces the need to monitor nutritional status, once both may aggravate the pathological conditions of children and adolescents with SCD, favoring a higher contraction of infections [2,34] and respiratory complications [2,34].Some factors affected nutritional status, such as clinical variables (hemoglobin concentration), disease progression (cardiac output and erythropoiesis increase, favoring REE increase), nutritional factors (low food intake and micronutrient depletion) and the type of treatment implemented.In Bennett's study [35] four factors identified contributed to the delayed growth of children with SCA: Endocrine dysfunction, hypermetabolism, inadequate food intake, and micronutrient deficiencies, which reinforces the results found in this review.
The increase in REE [8,36] directly contributes to the increase in energy needs, since it corresponds to 65% to 70% of the total daily energy expenditure [37].Therefore, it can lead to the growth deficit only or when associated with a decrease in food consumption, common in hospitalized children for allergic crisis [8].Individual nutritional monitoring of the child should be implemented in order to minimize hyperoxia, increase daily energy consumption and, consequently, restore nutritional status.Furthermore, lack attention in the monitoring of essential micronutrients for child growth, which are commonly low in consumption, such as calcium [11,12] and vitamin D [12,16] or that were in low serum concentration, such as zinc [14,15] and vitamin D [11,12,16] increases the risk of malnutrition.Therefore, they need to be monitored during the nutritional follow-up.Micronutrient depletion contributes to the onset of low bone mineral density [11,12], of delays in skeletal maturation and growth deficit [15].The importance of this monitor-ence mostly as of 2011's published studies [4][5][6][7].
However, the associated factor with overweight was the biggest Hb concentration, indicating the best disease prognosis, according to Chawla, et al. study [4].Bone mineral density (BMD) was assessed in five studies.Dietary intake of micronutrients in 4 studies (vitamins B12 and A in 1 study, vitamin C in 1 study, vitamin D and calcium (Ca) in 3 studies, zinc (Zn), iron (Fe) and folic acid in 1 study).Zn plasma concentration in 2 studies.Serum levels of Ca in 2 studies and vitamin D in 3 studies.
The presence of low BMD varied between 14% and 56%; Low calcium and vitamin D intake varied between 48% and 75%; Low serum zinc concentration between 15 and 44% moreover vitamin D between 66% and 100%.

Discussion
This review found the following results: a) The magnitude of short stature ranged from 8.2% to 24% and low weight from 3.7% to 100%; b) The presence of overweight or obesity is already detected between 1.6% and 22.4%; c) The factors associated with the growth deficit described in the articles were: Increased resting energy expenditure around 17% and nutritional deficiencies (low calcium and vitamin D intake between 48% and 75%; Low serum zinc concentration between 15 and 44%, vitamin D between 66% and 100%); d) Other factors described (presence of low bone mineral density between 14% and 56%, low Hb concentration, transfusions frequency and onset, complications frequency such as vessel occlusion and hand-foot syndrome, and the presence of hormonal alterations.

Abstract of evidences
The weight and length at birth of the child with SCD are usually normal and change until the end of the first year of life, culminating with low weight and short stature in childhood [2].However, the child can reach normal height in adolescence, because the growth spurt occurs late due to delay in the closure of the epiphyses, which allows the recovery of stature in the adult phase [2,26].As for short stature, it usually was associated with low bone mineral density [10][11][12] and the deficiency of some micronutrients such as zinc [15,16], calcium [12] and vitamin D [11,12].The Kazadi study [25] noted that the increased risk The different treatments evaluated presented benefits or minimized the growth deficit; However, more studies are necessary to evaluate the late effects of each type of treatment.Early diagnosis and appropriate treatment can reduce or avoid complications of the disease, so it is extremely important to follow up with professionals from different specialties, as well as the family and the community to know about the disease and its basic care [44].
The present study evidenced a high prevalence of weight and height deficits in this group, existing, although, the presence of overweight/obesity in those with better clinical conditions.The main factors associated with the growth deficit were described, which may lead to a more adequate clinical practice, since it makes it possible to prevent the occurrence of both growth and obesity deficits.Therefore, evidence-based interventions designated to prevent and minimize these changes in nutritional status.

Limitations
The studies analyzed have several methodological limitations.First, most studies have a wide breadth of age, mixing infants, preschoolers, schoolchildren, adolescents, and young adults.Secondly, they did not investigate the action of different physio pathological and therapeutic aspects in the same group of children and adolescents.Third, there was a variability of several growth reference standards, which did not allow the comparison of the data.Finally, there was a predominance of descriptive cross-sectional studies, which did not allow to conjecture a possible time line between the associated factors and the compromising of nutritional status.
ing was evident in the randomized clinical study which, when supplementing children with SCA with 10 mg of elemental Zn for 12 months, showed significant stature gain [15].
Adequate clinical follow-up of the person with SCD usually results improvement in hemoglobin concentration.Adequate levels of hemoglobin in these patients, as evidence shows, avoid important complications such as aplastic crisis, splenic sequestration crisis, stroke, among others [27].In addition, it was also observed that children with lower P/I were those with lower Hb concentration [19]; And those with higher Hb concentrations [5] were associated with overweight and obesity, as well as with the use of hydroxyurea (HU) [8,38] and continuous blood transfusion [21].Endocrine compromise is also one of the factors that interferes with these children's growth.Those with SCD and low stature had low basal IGF-1 [21][22][23][24] concentrations and/or IGF-binding protein-3 (IGFBP-3) [21,23,24] and/or growth hormone (GH) deficient [21][22][23].The deficiency of these hormones relates to slow growth and short stature in children with SCA, however, the Ca, the micronutrient involved in growth, was normal in evaluated children [21].Soliman, et al. [22] identified the presence of empty turmeric saddle in all children who had GH deficiency, which is suggestive of ischemic lesion in the pituitary gland.Therefore, in the persistence of nutritional deficits it is necessary to investigate these hormones.
In relation to the studied treatments [8,19,[38][39][40], these seem to positively impact on growth and development by improving the clinical picture of the disease.However, should be noted that the studies with HU [8,38,39,41] had a small sample number, ranging from 8 to 84 patients and short follow-up periods, from 4 months to 2 years.The results with the HU use in the nutritional state ranged from no difference in growth velocity [36] to weight gain, height [8,39] and fat free mass [41].
Another treatment, hematopoietic cell transplantation (HCT) seems to not impair growth [40,42], but it is not advisable to perform it in the next period or during the growth spurt of adolescence [40,43].The association between growth deficiency and HCT may be related partly to gonadal toxicity due to the busulfan (BU) doses administered.The likelihood of growth speed reduction is higher if the inhibitory effect of BU on gonadal function is exercised before the completion of the pubertal growth peak or the institution of hormone replacement therapy [40].Despite this study [40] did not describe growth improvement with transplantation, it brings important contributions in guiding the most appropriate moment for its realization, in order to avoid losses in growth.Walters, et al. [42] observed improvement in linear growth after transplantation, however, they described the adverse effect of BU on the ovarian function of five of seven girls evaluated with age above 13 years old.

Fung
for age in the last year of follow-up.Weight-for-age Z-score Males: -1.2 ± 1.1 (-3.2 to 1.1) Puberty postponed in 1-2 years and mean age of menarche was 13.2 years.Bone age delayed by 1.3 ± 1.5 years in the age group of 10 to 15 years old.