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Pediatric and Adult Nutrition in Chronic Diseases, Developmental Disabilities, and Hereditary Metabolic DisordersPrevention, Assessment, and Treatment$

Shirley W. Ekvall and Valli K. Ekvall

Print publication date: 2017

Print ISBN-13: 9780199398911

Published to Oxford Scholarship Online: April 2017

DOI: 10.1093/acprof:oso/9780199398911.001.0001

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Sickle Cell Disease

Sickle Cell Disease

Chapter:
(p.249) 34 Sickle Cell Disease
Source:
Pediatric and Adult Nutrition in Chronic Diseases, Developmental Disabilities, and Hereditary Metabolic Disorders
Author(s):

Omar Niss

Russell E. Ware

Publisher:
Oxford University Press
DOI:10.1093/acprof:oso/9780199398911.003.0034

Abstract and Keywords

This chapter discusses sickle cell disease and related conditions, including biochemical, pathological, and clinical abnormalities and factors to be considered in nutritional evaluation (e.g., growth, nutritional status). Dietary management is specifically discussed, including protein and caloric needs, vitamins and minerals, and effects therapies on growth and development).

Keywords:   sickle cell disease, sickle cell anemia, hemoglobin S, hemolytic anemia, vaso-occlusion, dietary management

Sickle cell disease (SCD) is a group of genetic disorders characterized by the predominance of sickle hemoglobin (Hb S) in red blood cells (RBC). The most common and most severe form of SCD, homozygous Hb SS, occurs when the patient inherits one Hb S gene from each parent. Persons with sickle cell trait (Hb AS) carry the sickle gene but are asymptomatic. Other compound heterozygous conditions occur when a patient inherits an Hb S with an additional β‎-globin gene mutation (e.g., Hb SC, or Hb Sβ‎ thalassemia).

The sickle gene is prevalent among people of African, Italian, Sicilian, Egyptian, Turkish, Arabian, and Asiatic Indian background. In the United States, SCD is found predominantly in African Americans. About 1 of every 12 African Americans has sickle cell trait and is an asymptomatic carriers, and approximately 1 of 400 African-American newborns have the disease.1 Millions are estimated to have SCD worldwide.2

Biochemical, Pathological, and Clinical Abnormalities

Hb S results from a single amino acid substitution of valine for glutamic acid in the sixth position of the β‎-globin chain. In contrast to the usual adult hemoglobin (Hb A), the sickle hemoglobin polymerizes on deoxygenation. This process alters the RBC membrane and changes the cell shape into a sickled form. These sickled RBC have shorter life span, leading to hemolytic anemia. Sickling alters the normal properties and deformability of the RBC, causing vaso-occlusion and vascular dysfunction.

The two primary manifestations of SCD are severe hemolytic anemia and widespread vaso-occlusion and infarction of various organs and tissues. The hemolytic anemia results from the markedly shortened lifespan of the sickled RBC which survive in the circulation for only 10 to 20 days, compared with 120 days for normal RBC. The clinical manifestations that reflect this ongoing hemolytic process include jaundice, pallor, weakness, and fatigue.

The widespread vaso-occlusion results from adherence of the sickled RBC to the lining of blood vessels, which plugs up the small vessels and obstructs blood flow to organs and tissues, leading to infarction and tissue death. Decreased oxygen supply to the bones and bone marrow causes the pain that is characteristic of SCD. The initial pain episode may occur in an infant or toddler, who presents with painful swelling of the hands and feet (dactylitis); in older patients, vaso-occlusion affects the sternum and ribs and the long bones of the arms and legs. Certain factors can trigger a painful episode (i.e., sickle cell crisis), including infection, hypoxia, extremes of temperature, and acidosis. Frequently, there is no obvious precipitating factor.

Other vaso-occlusive complications in SCD include acute chest syndrome and splenic involvement. Acute chest syndrome, which results from pulmonary vaso-occlusion and infarction, can be rapidly progressive or fatal if not treated aggressively.3 Sudden massive trapping of RBC in the spleen leads to acute splenic sequestration in infants and toddlers, which is characterized by a sudden decrease in hemoglobin and can cause hemodynamic instability. Repeated splenic vaso-occlusion leads to autoinfarction of the spleen very early in life, leaving the patient with a markedly increased susceptibility to infections, especially sepsis caused by Streptococcus pneumoniae. The incidence of overwhelming pneumococcal sepsis is 400 times greater in children younger than 5 years of age with SCD than in healthy children.4 A transient aplastic episode can occur when the bone marrow temporarily stops making red blood cells, typically as a result of a viral infection such as parvovirus B19, which causes severe anemia that frequently requires blood transfusion.

Chronic organ damage can affect virtually every organ of the body in SCD. Stroke caused by cerebral vascular occlusion is a devastating complication of SCD.5 Progressive impairment of renal function can be seen in teens and adult patients.6 Chronic leg ulcers resulting from chronic vascular insufficiency are less frequently seen, but they can be debilitating.7 Eye involvement with sickle cell retinopathy can be progressive and may lead to blindness in older patients.8

Growth can also be affected in SCD. Many studies have demonstrated impairment in height and weight in children with SCD compared with healthy age-matched children. The Cooperative Study of Sickle Cell Disease (CSSCD), a national, multicenter, longitudinal study, showed that children with homozygous SCD (Hb SS) had the most severe deficits in growth compared with children with other SCD genotypes.9 Approximately one-third of patients with SCD are below the 5th percentile for height or weight or both, and many have an associated delay in onset of puberty10 and sexual maturation.11,12

Factors To Be Considered in Nutrition Evaluation

Growth and Nutrition Status in SCD

Early studies documented growth retardation and hypogonadism in children with SCD.9 Patients with SCD have decreased weight-for-age, height-for-age, and growth velocity.13 Other measurements such as weight-for-height, sitting height, bony breadths, and limb circumferences are also abnormal.14 SCD patients are born with normal weight and height,15 suggesting that fetal growth is not impaired; however, growth alteration is seen as early as 6 months of age.13 Growth retardation affects boys more than girls and worsens with age.13 SCD patients have significantly lower upper arm fat mass and lower muscle areas, indicating deficient energy stores and protein wasting, respectively.16

Pubertal and Skeletal Maturation in SCD

Delayed pubertal and skeletal maturation are well recognized in SCD9,16,17,18 and are associated with growth retardation.19 The mean age of menarche is delayed in girls with SCD by more than 2 years.11,20 Peak height velocity and skeletal age are also delayed.19,21 Bone mineral density and skeletal maturation are diminished.22,23,24

Despite these abnormalities, the role of endocrine dysfunction in SCD-related growth failure is unclear. Although the hypothalamic-pituitary axis responds appropriately to pharmacological stimuli, decreased testosterone production is not uncommon in adolescents with SCD.25 This indicates that gonadal dysfunction, when present, is more likely to be primary in nature rather than secondary to pituitary dysfunction.12,26 Alterations in the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis have been described in SCD. Patients with SCD have low IGF-1 and IGFBP-3 regardless of their growth pattern.27 Similar to people with other chronic diseases, SCD patients have resistance to intrinsic GH,21 but their response to GH therapy varies. In a small study, five SCD patients who received GH therapy (p.250) demonstrated significant improvement in height.28 Thyroid function is normal in SCD, even when growth is impaired.29,30

Dietary Management

Protein and Caloric Needs

Unmet nutritional needs in SCD can result from decreased dietary intake or increased energy requirements. Although SCD patients may have decreased dietary intake temporarily around the time of acute illnesses,31 their intake at baseline is usually comparable to that in the normal population or only minimally decreased.32,33 Nonetheless, their growth is significantly affected. SCD patients have increased metabolic needs, as evidenced by their increased resting energy expenditure (REE), compared with matched controls.32,34,35,36 The increased REE in SCD reflects a state of hypermetabolism that is caused by multiple factors, including increased myocardial energy demand due to chronic anemia,37 increased cytokine release due to ongoing inflammation,34,38 increased bone turnover and bone remodeling due to recurrent sickling,39 and increased erythropoiesis due to chronic hemolysis.37,40 Together, these factors increase metabolic demands, primarily by increasing protein turnover,41 which contributes to about 50% of the observed increase in REE. Impaired nitrogen economy and increased REE produce a state of undernutrition despite apparently normal dietary intake in SCD.

The optimal dietary management in SCD is not known, and studies that address macronutrient and micronutrient replacement in SCD are limited. Because SCD is a multisystem disease, implementing a comprehensive care program early in life can be the most beneficial approach, even in resource-limited settings.42 One small study demonstrated that increasing the caloric intake with nighttime nasogastric feedings produced dramatic increases in height and weight compared with no significant changes in those patients supplemented orally. In addition, there was a decrease in the number of pain episodes and number of hospitalizations among those who recived nasogastric feeding.43 Other therapies that target the severity and complications of SCD may improve growth and development.

Vitamins and Minerals

Several studies have reported micronutrient deficiencies in SCD. Increased vitamin and micronutrient requirements in SCD can be explained by the increased RBC turnover and nutrient losses through increased renal excretion.44 Zinc is the most extensively studied mineral deficiency in SCD.

Zinc

Zinc is an essential trace mineral that is important for physical growth, gonadal development, and immune function. Zinc deficiency is considered a contributing factor to growth failure in SCD. Zinc levels have been associated with decreased liner growth and impaired sexual and skeletal maturation.13,45 Other studies, however, did not find a correlation between plasma zinc levels and linear growth.46

Zinc is primarily found intracellularly and is replete in RBCs, platelets, and neutrophils. The plasma zinc level may not reflect true zinc deficiency in SCD, and patients receiving zinc supplements may have improved linear growth without significant change in their plasma levels.46 Zinc supplementation has a small but significant positive effect on physical growth in otherwise normal children with impaired growth (i.e., non-SCD).47 Similarly, prepubertal children with SCD demonstrated an increase in mean height and arm circumference after zinc supplementation for 12 months, but no difference was seen in weight or body mass index (BMI).48 In one study, SCD patients who did not receive zinc supplements had decreased height and weight for age, whereas patients taking supplements did not.48

In a Cochrane review about the effects of zinc supplementation in SCD, patients who received zinc supplementation showed increases in serum zinc levels and had fewer infections than control groups.49 However, zinc supplements did not appear to influence hemoglobin levels, and there were mixed results regarding the influence of zinc on the frequency of pain crises. More studies are needed to determine the optimal dose, the duration, and the long-term effects of zinc on sexual and skeletal maturation in children with SCD.49

Iron

Iron deficiency is not a common problem in SCD patients, who often have increased body iron due to transfused blood. Similar to other minerals in SCD, iron can become deficient in selected groups of patients, especially nontransfused patients with poor dietary intake. The prevalence of iron deficiency among nontransfused SCD patients ranged from 9% to 20%.50,51,52 The effects of iron deficiency can be severe, especially in growing children.

Early detection and correction of iron deficiency is important, especially in high-risk children who live in poor socioeconomic conditions and have limited access to iron-rich food. The diagnosis of iron deficiency in SCD can be difficult because conventional indices of iron deficiency, such as ferritin and mean corpuscular volume (MCV), can be abnormal in SCD due to inflammation and/or reticulocytosis unrelated to iron deficiency. Children with SCD who have never received a transfusion should be screened for iron deficiency by dietary history and a complete blood count. Nontransfused infants should receive iron-fortified formula or, if breast-fed, vitamin supplementation with iron similar to the recommendations for normal infants. If iron deficiency is documented, a therapeutic trial of iron should be initiated.

Other Trace Minerals

Other trace elements investigated in SCD include copper and magnesium. Copper competes with zinc for similar binding sites in the body, and data confirm a mild increase in plasma copper in SCD patients who are zinc deficient.53,54

Changes in plasma and erythrocyte magnesium levels have also been observed in SCD patients,54 although they were likely a result of a redistribution phenomenon. Plasma selenium levels are significantly lower in SCD patients compared with controls. This finding is consistent with the increased oxidative stress reported in SCD.55,56

Vitamin A

Vitamin A is a fat-soluble vitamin that is essential for growth, development, immune function, and vision. Suboptimal vitamin A status (defined by a retinol level <30 μ‎g/dL) and vitamin A deficiency (retinol <20 μ‎g/dL) are prevalent in children with SCD.57,58 Low vitamin A levels in SCD have been associated with increased hospitalizations, poor growth, and abnormal hematological indices.58 However, in a randomized, placebo-controlled trial, 12 months of vitamin A supplementation at the RDA dose did not improve vitamin A status in children with SCD.57

Zinc is also involved in absorption, transport, and metabolism of vitamin A, primarily by affecting the synthesis of retinol-binding protein. Vitamin A status did not improve even when zinc was supplemented with vitamin A, suggesting that SCD patients may require higher doses of vitamin A.57

In developing countries, vitamin A deficiency is more common and is associated with increased mortality and severe infections even in children without SCD;59 vitamin A deficiency may have worse impact on children with SCD. More studies are needed to determine the optimal treatment of vitamin A deficiency in SCD.

Vitamin D

Vitamin D deficiency is seen in many populations, including breast-fed infants, the elderly people, African Americans, and patients with chronic diseases.60 The serum level of 25-hydroxyvitamin D (25-OHD) is considered a reliable marker of vitamin D status because it represents a summation of cutaneous vitamin D synthesis and dietary intake of vitamin D. Low 25-OHD levels are prevalent among children with SCD compared with healthy African-American children.61,62,63

Decreased oral intake of vitamin D appears to be the most common risk factor for vitamin D deficiency in SCD,61 which contributes to the decreased bone mineral density observed in these children.64 Vitamin D supplementation improves bone mineral density and decreases bone resorption in healthy girls.65 Adult patients who were treated with vitamin D2 and calcium for 12 months had normalization of 25-OHD (p.251) levels and improvement in bone mass density, although the markers of bone resorption remained abnormal.66

There is a correlation between vitamin D deficiency and the prevalence of vaso-occlusive complications in children with SCD.67 Although high doses of vitamin D supplementation may help to improve chronic pain in SCD,68 it is unclear whether vitamin D supplements have a role in the management of acute vaso-occlusive crises.

B Vitamins: Folate, B6, and B12

Previous studies suggested that SCD patients are at risk for folate and B12 deficiency due to accelerated hematopoiesis.69,70 Kennedy and colleagues found that 15% and 3% of SCD patients had low levels of RBC folate and serum B12, respectively, despite folate supplementation.71 The role of these deficiencies in SCD remains undetermined. In a placebo-controlled, randomized trial of folate supplementation in children with SCD, there was no difference in growth, hemoglobin, or SCD-related complications between the two groups.72 In countries such as the United States, where folate fortification of food is common, folate supplementation is not routinely recommended for SCD patients.

Serum folate and B12 levels are determinants of the homocysteine level, and increased homocysteine is associated with increased risk of vascular disease and thrombosis.73 Stroke is a devastating complication of SCD, occurring in 11% of nontransfused Hb SS patients by the age of 20 years.74 Stroke in SCD is primarily caused by cerebrovascular disease, but other factors may contribute to increasing the risk of stroke in some patients. Hyperhomocysteinemia is prevalent among patients with SCD, but its role in the development of stroke is unclear.75 Although there is no correlation between folate and homocysteine levels in SCD,75,76 plasma pyridoxine levels are significantly lower77 and correlate negatively with homocysteine levels,75 suggesting a potential role for pyridoxine deficiency in hyperhomocysteinemia in SCD.

Certain genetic polymorphisms influence folate metabolism and homocysteine status in SCD, adding to the complexity of hyperhomocysteinemia and its possible contribution to thrombosis.78 Further studies are needed to clarify the impact of these metabolic pathways on growth and on development of SCD complications such as stroke and whether there is a role for nutritional supplementation designed to mitigate complications.

Effects of SCD Therapies on Growth and Development

Newborn screening programs allow for early detection of SCD and early interventions with potential beneficial effects on growth and development. Medical interventions that target the symptoms and complications of SCD can ameliorate the cause of nutritional deficiencies and improve growth.

Despite significant progress in understanding the molecular pathophysiology of SCD, therapeutic options remain limited. Stem cell transplantation provides a cure for the disease, but its use is limited by the availability of suitable donors and the significant toxicity associated with the transplantation process. The only clinically available disease-modifying treatment modalities are the oral agent hydroxyurea and blood transfusions.

Hydroxyurea

Hydroxyurea is the only agent approved by the US Food and Drug Administration (FDA) for treatment of adults with SCD. It is an oral medication with proven benefits in decreasing many acute and chronic complications of SCD, including pain episodes, acute chest syndrome, hospitalizations, and the need for blood transfusions.79 Hydroxyurea may also have effect in preserving organ function80 and decreasing mortality.81

Current guidelines recommend starting SCD patients on hydroxyurea as early as 9 months of age.82 Hydroxyurea use in children did not have harmful effects on growth parameters.83,84 On the contrary, infants with SCD who took hydroxyurea in the Hydroxyurea Safety and Organ Toxicity (HUSOFT) study demonstrated significant improvement in growth, especially the boys.85 Other studies have shown that hydroxyurea use in children is associated with improvement in weight, height, body fat, fat-free mass, and a subjective increase in appetite.86 Growth improvement in SCD patients taking hydroxyurea is at least partially mediated by a decrease in REE.86 The effect of hydroxyurea on SCD patients in developing countries, where growth and nutritional deficiencies are more prevalent and advanced, has not been studied.

Blood Transfusion

Although transfusion of donor RBCs can ameliorate many SCD complications, blood transfusions are associated with many complications, including iron overload and alloimmunization. Blood transfusion is limited to certain indications such as secondary stroke prophylaxis and cannot be routinely used in all patients. SCD patients who received regular blood transfusions in the Stroke Prevention (STOP) Trial for Sickle Cell Anemia had significant improvements in weight, height, and BMI.87 This positive effect possibly resulted from amelioration of anemia, which is a major contributor to the increased energy expenditure in SCD. REE increased in five SCD patients who received a single blood transfusion,88 although the exact mechanisms by which blood transfusions improve growth in SCD remain unclear.

Follow-up and Summary

The clinical manifestations of SCD involve chronic hemolytic anemia and recurrent, unpredictable bouts of pain related primarily to vaso-occlusion and bone infarction. Patients also experience increased numbers of infections and frequent hospitalizations. All of these factors contribute to hypermetabolism, increased protein and bone turnover, and enhanced REE. Despite their increased caloric needs, many children with SCD have poor dietary intake, especially when ill. These factors contribute to the progressive growth delay in SCD that starts as early as 6 months of age.

The significance of the various micronutrients that are low in SCD patients and their relationship to growth and complications such as stroke are not completely understood. More studies are needed to define these relationships more precisely and to determine the benefit of micronutrient supplementation. Treatments that minimize the anemia and vaso-occlusive episodes, such as hydroxyurea or blood transfusions, allow for growth improvement, especially if initiated early in life. As more infants are started on hydroxyurea early in life, the growth patterns in SCD may change. Additional nutrition interventions in SCD therapy are under investigation. The effect of these interventions in the developing countries, where SCD is common and nutritional deficiencies are prevalent, is unknown and needs to be studied.

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