Growth and nutritional status of children with homozygous sickle cell disease

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Active renewal policies that required families to submit documentation to verify their continued eligibility were associated with substantial disenrollment. Requiring active eligibility redetermination every 6 months rather than every 12 months resulted in even higher levels of disenrollment over time. Up to one- quarter of children who disenrolled at renewal returned to SCHIP within 3 months (18 percent to 27 percent). A simplified renewal process that automatically reenrolled children in SCHIP unless their families submitted reenrollment forms indicating a change affecting their eligibility substantially reduced disenrollment at SCHIP renewal. In some States with separate SCHIP programs, SCHIP design limited coverage for certain specialty services that are needed by CSHCN. This was done directly by limiting the...

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Nội dung Text: Growth and nutritional status of children with homozygous sickle cell disease

 

  1. Annals of Tropical Paediatrics (2008) 28, 165–189 Growth and nutritional status of children with homozygous sickle cell disease A.-W. M. AL-SAQLADI*{, R. CIPOLOTTI1, K. FIJNVANDRAAT** & B. J. BRABIN**{{ *Faculty of Medicine & Health Sciences, Aden University, Yemen, {Child & Reproductive Health Group, Liverpool School of Tropical Medicine, {Department of Community Child Health, Royal Liverpool Children’s Hospital, Liverpool, UK, 1Department of Medicine, Federal University of Sergipe, Brazil, and **Academic Medical Centre, Emma Kinderziekenhuis, University of Amsterdam, The Netherlands Published by Maney Publishing (c) W S Maney & Son Ltd (Accepted February 2008) Abstract Background: Poor growth and under-nutrition are common in children with sickle cell disease (SCD). This review summarises evidence of nutritional status in children with SCD in relation to anthropometric status, disease severity, body composition, energy metabolism, micronutrient deficiency and endocrine dysfunction. Methods: A literature search was conducted on the Medline/PUBMED, SCOPUS, SciELO and LILACS databases to July 2007 using the keywords sickle cell combined with nutrition, anthropometry, growth, height and weight, body mass index, and specific named micronutrients. Results: Forty-six studies (26 cross-sectional and 20 longitudinal) were included in the final anthropometric analysis. Fourteen of the longitudinal studies were conducted in North America, the Caribbean or Europe, representing 78.8% (2086/2645) of patients. Most studies were observational with wide variations in sample size and selection of reference growth data, which limited comparability. There was a paucity of studies from Africa and the Arabian Peninsula, highlighting a large knowledge gap for low-resource settings. There was a consistent pattern of growth failure among affected children from all geographic areas, with good evidence linking growth failure to endocrine dysfunction, metabolic derangement and specific nutrient deficiencies. Conclusions: The monitoring of growth and nutritional status in children with SCD is an essential requirement for comprehensive care, facilitating early diagnosis of growth failure and nutritional intervention. Randomised controlled trials are necessary to assess the potential benefits of nutritional interventions in relation to growth, nutritional status and the pathophysiology of the disease. Growth retardation in sickle cell disease Introduction (SCD) is complex and multiple factors are likely to contribute, such as the haematolo- It is generally accepted that homozygous gical and cardiovascular state, social factors, sickle cell disease (SS) impairs physical endocrine function and metabolic and growth during childhood and early adoles- nutritional status.1 Growth rate is inversely cence and that affected children are lighter related to the degree of anaemia and is likely and shorter than healthy counterparts. to be associated with deficiency of specific nutrients as well as low nutrient intake, Reprint requests to: Professor B. J. Brabin, Child and decreased absorption and increased losses or Reproductive Health Group, Liverpool School of utilisation.2,3 Tropical Medicine, Pembroke Place, Liverpool L3 For example, the prevalence of under- 5QA. Fax: z44 (0)151 709 3329; email: b.j.brabin@liv. weight in American children with SCD was ac.uk # 2008 The Liverpool School of Tropical Medicine DOI: 10.1179/146532808X335624
  2. 166 A.-W. M. Al-Saqladi et al. 41% for moderate and 25% for severe cross-sectional and three longitudinal). under-nutrition4 with a prevalence of wast- The following data were extracted from ing of 11%.5 Stunting was reported in 44% these studies: age, disease severity, clinical of Ghanaian children and adolescents and presentation and growth parameters, use of almost all those with SS were underweight, blood transfusion, therapeutic interventions, irrespective of height.6 micronutrient status and other nutritional Although growth failure and under- and endocrine assessments, and haemoglo- nutrition are common, the underlying bin genotype. The resulting data were mechanisms have not been well studied tabulated by geographical location, age, and the precise role of intrinsic or extrinsic anthropometric characteristics and types of factors is unclear in relation to inadequate controls. food intake or increased demands associated There are four major genotypes within the with higher energy expenditure and require- definition of SCD: homozygous sickle cell Published by Maney Publishing (c) W S Maney & Son Ltd ments. External and internal factors are (SS) disease, sickle haemoglobin C (SC) disease, sickle cell bz thalassaemia (S bz likely to act together to a different degree thalassaemia) and sickle cell b0 thalassaemia against a variable genetic, environmental (S b0 thalassaemia).7 The internationally and socio-economic background. The aim of this review is to summarise the evidence accepted definition of SCD, two b-globin related to poor growth and under-nutrition gene variants at least one of which is the in children with SCD with regard to sickle cell gene, is used and the gene variant anthropometric status, disease severity, for the four common genotypes are indi- body composition and metabolism, micro- cated when known. In this review, the term nutrient deficiency and endocrine dysfunc- ‘sickle cell anaemia’ is used synonymously tion. An important aspect of these analyses only for homozygous SS disease, and the is determining whether phenotype, nutri- majority of studies reviewed relate to this tional deficits or anaemia individually con- genotype. tribute to growth restriction, or whether it is a combination of these factors which is important. Results Nutritional status and disease severity Inadequate intake can result from anorexia, Methods a prominent symptom in affected children even in the absence of demonstrable infec- A literature search using the Medline/ tion, and it often precedes a painful crisis by PUBMED, SCOPUS, SciELO and days or weeks.8 At the time of hospital LILACS electronic databases for studies admission, energy intake during acute illness published up to July 2007 was conducted. is decreased by as much as 44% of the The search terms sickle cell combined with recommended daily amount (RDA) (SD nutrition, anthropometry, growth retarda- 9%); during follow-up, intake is closer to tion, height and weight, body mass index 90% of RDA.9 Dietary intakes can be (BMI) and specific micronutrients (zinc, reduced markedly prior to admission and iron, vitamins A, B group, C, D, E and remain sub-optimal for weeks.10 In a folate) were used. Additional articles were Jamaican study, no significant relationship identified by checking reference lists of was demonstrated between haemoglobin retrieved articles. From a total of 423 concentration, reticulocyte count or irrever- published studies, 42 with relevant data (25 cross-sectional and 17 longitudinal) sibly sickled cells and anthropometric were selected. In addition, data were made measurements. Correlation with disease available from unpublished studies (one severity, measured by the number of
  3. 167 Growth in SCD hospital admissions, showed no significant and BMI, with growth Z-scores approaching normal.16 Those with homozygous SCD association with growth parameters, although a trend towards lower mean weight showed a significant reduction in whole was found in patients who were admitted body protein turnover (from 8.9 g/kg/d to more often.11 In pre-pubertal Jamaican 6 g/kg/d) after splenectomy, thereby con- tributing to positive energy balance17 and children, levels of haemoglobin (Hb) and acceleration in linear growth.18 Therapy fetal haemoglobin (Hb F) decreased with an increasing number of hospitalisations of with hydroxyurea has been reported to both sexes, although levels were positively decrease REE in treated SS children, associated with height and weight only in suggesting that it might curtail a hyper- males.12 metabolic state and offer clinically impor- benefit.19 Vaso-occlusive crises and episodes of tant secondary In the infection could increase energy expendi- Hydroxyurea Safety and Organ Toxicity Published by Maney Publishing (c) W S Maney & Son Ltd ture.13 A strong association between C- (HUSOFT) extension study, improved reactive protein and resting energy expendi- growth rates were demonstrated in SS ture has been described, which might children treated with hydroxyurea. Their indicate a link between inflammation and a increased weight and height resulted in a hyper-metabolic state in SCD.14 Increased growth pattern similar to that of children with Hb S bz thalassaemia or healthy resting energy expenditure (REE) might controls.20 Studies related to growth, spe- relate to erythroid hyperactivity and accel- erated red cell turnover owing to the short cific micronutrients and disease severity are life span of sickled red blood cells. Low Hb considered in later sections of this review. levels and chronic anaemia are associated with hyperdynamic circulation and dete- Growth studies rioration of cardiopulmonary function. This increases workload and, consequently, the Studies reporting growth of patients with demand for energy and nutrients. SCD are summarised in Tables 1–6. Adult There is evidence that nutrient supple- patients are often described as slender with mentation can reduce clinical illness. low weight, relatively tall with long extre- Supplements given by the nasogastric route mities, short trunk, narrow shoulders and to SCD children with growth retardation hips, with a deep chest and increased (weight and height ,5th centile) led to a anterior-posterior diameter. Many of these rapid and sustained increase in growth and a changes were found to be less pronounced reduction of pain crises and episodes of and inconsistent in children, and some infection.15 The authors found no lipid investigators considered this appearance in malabsorption and a normal histological SCD to be an exaggeration of the normal appearance of the intestinal mucosa and characteristics of Africans.21Affected chil- submucosa and concluded that inadequate dren were reported to have poor nutrition energy intake was responsible for the growth and their weight was consistently below the retardation. median reference values. Other therapeutic measures to reduce North American studies (Table 1). An early disease severity or complications (i.e. blood study of the growth of 48 American black transfusion, splenectomy and hydroxyurea) children with sickle cell anaemia (aged 2–13 might lead to improved nutritional status yrs) reported that the majority were thin and growth. Children in the Stroke with low weight and height. There was no Prevention Trial in Sickle Cell Anaemia correlation between growth parameters and (STOP) who received transfusion the clinical course, arterial oxygen satura- regularly over a 2-year period demonstrated tion or family childhood weight patterns.22 significant improvement in height, weight
  4. Published by Maney Publishing (c) W S Maney & Son Ltd TABLE 1. North American studies. 168 Reference* Year Country n Design Age (y) Weight{ Height{ Other assessments Controls Comment Whitten22 1961 USA 48 CS 79 siblings No correlation with C/P 2–13 96% ,5th centile 81% ,5th centile Normal span & U/L segment Stuarts norms or family weight pattern Booker25 1964 USA 18 L 0–2 Around –2 SD – Deceleration began Normal blacks Deficit coincides with start at age 6 m of infection and crises n586 Jimenez23 1966 USA 38 CS 8–17 Significantly Significantly lower Hypogonadism Normal black children, Low U/L segment lower mean mean n589 Span .height McCormack24 1976 USA 46 CS 1–17 Significantly Significantly lower Low MUAC and calf 26 AS, standard of Delayed skeletal matura- lower mean mean circumference local black children, tion in sickle cell trait Bone age retarded (AS) n5900 Kramer26 1980 Canada 14 L 0, 4, 5 Normal at birth, Normal at birth, Muscle mass area and Black term newborn, Growth deficit started at 10 low subsequently low subsequently HC not greatly affected 6 mths of age & increased n571 over time A.-W. M. Al-Saqladi et al. Luban27 1982 USA 55 L 13–18 Significantly Significantly below Delayed sexual NCHS reference Hormonal assays normal below reference reference development in majority Bone age retarded Platt28 1984 USA 2115 CS 2–25 Significantly Significantly below Sexual developmental Howard University Growth deficit in SS .S below reference reference delay study of black children, b thalassaemia .SC, delayed menarche related n52632 to low weight Phebus29 1984 USA 133 L Maximum growth NCHS reference Growth deficit by 2 yrs, 1–18 All ,50th centile All ,50th centile velocity after 14 y (F) M.F & 16 y (M) Henderson5 1994 USA 63 CS 3–18 NCHS reference Impaired growth & puberty 14% ,5th centile 13% ,5th centile 25% ,5th centile 11% wasting (low wt/ht) in 11–18-yr-olds Williams98 1997 USA 61 CS 2–17 NCHS reference 59% families below poverty 22% ,5th centile 19% ,5th centile Inadequate nutritional intake line Cepeda30 2000 USA 30 CS 8–19 Significantly low Significantly low Delayed sexual Age, sex, race & socio– No significant difference in mean difference mean difference maturation by average economic–matched, self–esteem or body image by average 12 kg by average 8 cm 0.75 Tanner stage n530 Wang16 2005 USA 94 L 2–16 NCHS reference Improved growth on long- WAZ 20.71 score HAZ 20.51 score BMI 20.60 Z-score Transfused 53 term transfusion Standard care 41 Zemel31 2007 USA 148 L NCHS reference Puberty affected by 0–18 26% ,5th centile 22% ,5th centile BMI ,5th centile in 24%, puberty delayed impaired growth & by 1–2 y haematological status in F * First author; CS, cross-sectional; L, longitudinal; F, female; M, male; C/P: clinical picture; HC, head circumference; MUAC, mid upper-arm circumference; BMI, body mass index; WAZ, weight-for-age Z-score; HAZ, height-for-age Z-score; { weight or height-for-age unless otherwise stated.
  5. Published by Maney Publishing (c) W S Maney & Son Ltd TABLE 2. Jamaican studies. Reference* Year n Design Age (y) Weight{ Height{ Other assessments Controls Comment Ashcroft35 1972 99 CS 12–21 Mostly Variable Bone age retarded Jamaican standard & Younger cases shorter, older cases as tall as controls .–2SD .–2SD local students, n5235 Lowry11 1977 99 CS 2–13 Lower No significant Haematological Jamaican rural standard, No correlation with hospital mean at difference parameters not admission rate n52765 all ages correlated with deficit Ashcroft36 1981 82 L 12–21 All below Below median Menarche delayed by Jamaican rural standard, Height exceeded standard by median 2.3 y ages 16 (F) & 18 y (M) n512,934 Stevens37 1983 64 L 4–6 Significantly Significantly Low MUAC & short Normal AA, sex- & age- Standing/sitting height normal lower mean lower mean limbs matched, n5123 than controls than controls Stevens32 1986 455 L 0–9 Significantly Significantly Sexual & skeletal delay, Age- & sex-matched, Deficit began 2 y earlier in F lower mean lower mean SC not affected than in M n5231 than controls than controls Thomas39 2000 315 L 0–18 Normal at birth, Normal at birth, Growth catch-up at ages NCHS reference Growth reference curves low subsequently low subsequently 15 (M) & 18 y (F) produced from data * First author; CS, cross-sectional; L, longitudinal; F, female; M, male; MUAC, mid upper-arm circumference; AA, normal adult haemoglobin; { weight or height-for-age unless otherwise stated. Growth in SCD 169
  6. Published by Maney Publishing (c) W S Maney & Son Ltd 170 TABLE 3. Latin-American studies. Reference* Year Country n Design Age Weight{ Height{ Other assessments Controls Comment Souza40 1983 Brazil 14 CS Low serum zinc NCHS reference No correlation between 6m–12y All ,10th centile All ,10th centile High serum cupper zinc levels & growth deficit Britto42 1985 Brazil 34 CS 6–20y Significantly lower No significant Menarche & bone age Controls matched by AA n516 A.-W. M. Al-Saqladi et al. mean than controls difference significantly lower than age, race, economic controls status Zago43 1992 Brazil 125 CS 7m–20y 40% ,10th centile 31% ,10th centile Delayed sexual maturation n51041 & Brazilian Post-pubertal weight standard deficit Pellegrini- 1995 Brazil 34 L Growth deficit tends to 0–18y Significantly lower Significantly lower Growth velocity impairment, Siblings AS n59 Braga44 mean than controls mean than controls bone age delay, low serum Non-siblings AA increase with age. zinc & ferritin Hypercupraemia n535 Cipolotti45 2000 Brazil 76 CS NCHS reference Father’s height obtained 9m–20y Median ,50th Median ,50th 41% , expected parental centile centile height from records Silva33 2002 Brazil 100 L 5m–8y WAZ –0.70 score HAZ –0.65 score Low BMI NCHS reference Growth deficit in SS .SC & M .F Gonzales- ´ 1992 Cuba 110 CS 4m–17y No significant No significant No significant difference Cuban standard No significant differences Fernandez46 ´ difference difference in bone age in gestational age or birth weight *First author; CS: cross-sectional; L: longitudinal; F: female; M: male; AA: normal adult haemoglobin; BMI: body mass index; WAZ: weight-for-age Z-score; HAZ: height-for-age Z-score; {weight or height for age unless otherwise stated.
  7. Published by Maney Publishing (c) W S Maney & Son Ltd TABLE 4. African studies. Reference* Year Country n Design Age (y) Weight{ Height{ Other assessments Controls Comment Mpemba- 2001 Congo 72 CS 10–18 Significantly lower Not measured 71% of cases no menarche AA females Only females included. Loufoua51 mean than controls Sexual maturity delayed at 14–18y, 10% in controls n540 in 37% Mabiala- 2005 Congo 91 CS/L 8–14 Significantly lower Significantly lower Lower BMI, lean body Body composition AA n595 Babela50 mean than controls mean than controls mass, body fat % decreased more in cases with severe disease Thuilliez52 1996 Gabon 131 L 0–18 Pubertal delay in 13% African multi- Growth deficit increased 26.7% .–2SD 26.7% .–2SD Menarche mean age 15y ethnic reference with age Ebomoyi47 1989 Nigeria 719 CS 2–13 Local controls SS growth less than All ,50th centile All ,50th centile MUAC ,50th centile n5979 & Harvard controls & standards standard Oyedeji48 1991 Nigeria 102 CS Around 3rd centile Symptom frequency & Nigerian elites Low school performance 9m–17y All ,3rd centile of reference education & high school absence n5421 Modebe34 1993 Nigeria 20 CS 17–35 Significantly lower Significantly lower Low BMI, MUAC & skin Normal siblings Gender-related growth mean in males mean in males folds in males. of similar age difference. Small sample for older Low daily energy intake in n515 males, normal in females group Oredugba49 2002 Nigeria 177 CS 1–18 Around 3rd centile of Around 3rd centile Low MUAC in 21% with Normal children 72% of cases & controls reference of reference maxillary protrusion & of low socio-economic n5122, local malocclusion. anthropometric status. reference No significant growth differences Athale53 1994 Zambia 144 CS 10–38 60% ,5th centile 53% ,5th centile Delayed sexual maturation. NCHS reference Children .10y included. Educational delay & high Frequent psychosocial school drop-out problems *First author; CS, cross-sectional; L: longitudinal; F, female; M, male; AA, normal adult haemoglobin; MUAC, mid upper-arm circumference; BMI, body mass index; { weight or height for age unless otherwise stated. Growth in SCD 171
  8. Published by Maney Publishing (c) W S Maney & Son Ltd 172 TABLE 5. The Middle East and India. Reference* Year Country n Design Age (y) Weight{ Height{ Other assessments Controls Comment Soliman54 1999 Egypt 182 L 1–20 – Slow linear growth 27% ,22 Z-score Low MUAC, U/L segments, Normal n5200. Constitutional velocity increased with 67% ,21 Z-score delayed sexual maturation age, transfusion no effect GR n530, GH A.-W. M. Al-Saqladi et al. defect n525 Mansour55 2003 Iraq 75 CS 18 All patients male, marked 77% ,5th centile 47% ,5th centile BMI ,20 in 77%, delayed Males n575 sexual maturation NCHS reference GR in severe disease Jaiyesimi56 2002 Oman 97 CS – Moderate/severe disease in Age, sex-matched Compared with Jamaican 10m–12y 68% ,5th centile 71% 4% .50th centile n597 & NCHS reference 14% ,3rd & reference 21% .50th centiles Perrine57 1981 Saudi 21 L 0–3 No significant No significant No developmental delay USA & Saudi Mild disease with high difference difference Hb F levels references n521 Al-Saqladi 2007 Yemen 102 CS NCHS reference Author’s unpublished 0.5–15 72% WAZ ,22 55% HAZ ,22 52% BMI ,22 Z-score. Z-score Z-score Low MAUC data Mukherjee58 2004 India 58 CS 2–14 Significantly lower Significantly lower Low BMI, MUAC, sitting Arab–Indian haplotype Normal AA n586 mean than controls mean than controls height, skinfold thickness with severe disease *First author; CS, cross-sectional; L, longitudinal; F, female; M, male; HC, head circumference; MUAC, mid upper-arm circumference; BMI, body mass index; WAZ, weight-for-age Z-score; HAZ, height-for-age Z-score; GR, growth retardation; GH, growth hormone; AA, normal adult haemoglobin; { weight or height for age unless otherwise stated.
  9. Published by Maney Publishing (c) W S Maney & Son Ltd TABLE 6. European studies. Reference* Year Country n Design Age (y) Weight{ Height{ Other assessments Controls Comment Caruso- 1992 Italy 76 CS 1–17 British referenceModerate growth 16% ,3rd 80% ,50th centile Benin haplotype in majority. Nicoletti59 centile (whites) deficit. No difference 10.5% ,3rd centile Normal level somatomedin C between SS & bS thalassaemia Dickerhoff 2007 Germany 341 L – German & Turkish Unpublished data 2m–43y 12.6% ,3rd 17.3% ,3rd centile centile references Fijnvandraat 2007 Netherlands 91 L 5–15 Weight/height – Dutch reference Author’s unpublished 25% ,22 SD Age 5: 10.6% (whites) data 2.8% ,22 SD Age 5: 3% Age 10: 14.3% Age 10: 2% Age 15: 50% Age 15: 3% Mann60 1981 UK 96 L 3m–19y – Varied clinical manifestations. British reference Ethnic origin: West 11–16% ,22 SD Low mortality (whites) Indies, Africa, Yemen Patey61 2002 UK 56 CS 3–9 Mean weight Mean height Z-score Mean BMI Z-score 0.23 similar Caucasian Significant difference Z-score 0.32 0.28 to (CC) 0.30 but lower than compared with similar n557 Mean (AC) Mean (AC) (AC) 0.82 African/Caribbean ethnic group Z-score 0.93 Z-score 0.59 (AC) n563 Telfer 2007 UK 180 L 2–15 Tanner reference Unpublished data 6.5% ,22 4.2% ,22 Z-score 4.2% ,22 Z-BMI score Z-score Age 2: 2% Age 2: 3.7% Age 5: 1.5% Age 5: 3% Age 10: 6.5% Age 10: 8% Age 15: 6.6% Age 15: 11.5% *First author; CS: cross-sectional; L: longitudinal; F: female; M: male; HC: head circumference; BMI: body mass index; AC: African/Caribbean; CC: Caucasian; {weight or height for age unless otherwise stated. Growth in SCD 173
  10. 174 A.-W. M. Al-Saqladi et al. Jimenez et al.23 compared 20 SS females disease, S bz thalassaemia or S b0 thalas- saemia).28 The mean height and weight of with 774 race-matched controls (11–40 yrs). There was delay in onset of menarche and affected subjects were significantly below age at first pregnancy, decreased fertility and reference values and the difference became an increased incidence of abortion and apparent after 7 years of age. Children with Hb SS and S b0 thalassaemia were consis- premature delivery. In a separate group of 38 cases in the same study, a low weight, tently smaller and less sexually mature than those with SC disease and S bz thalassae- height and upper-to-lower segments ratio was observed compared with 89 control mia. Sexual maturation followed the pattern black children of the same age. McCormack of height and weight, and time of menarche et al.24 reported the growth of 46 American correlated well with weight and age. black children and adolescents with SS Height and weight impairment at all ages disease. In all age groups (1–17 yrs), they and in both sexes compared with published Published by Maney Publishing (c) W S Maney & Son Ltd had lower mean height, weight, mid-upper- growth reference values was reported in a arm circumference (MUAC), thinner body cohort study of 133 SS American children build and delayed skeletal maturation com- followed from early childhood to adoles- cence.29 The deficit in height and weight pared with controls. Height and weight deficit probably occurs had commenced by 2 years, increased with early in life. Booker et al.25 reported weight age and was more pronounced in males of deceleration starting at about 4–6 months of all ages. Growth velocity curves for 13 age, coinciding with the onset of crises and adolescents showed significant delay of infections and continuing during the 1st 2 pubertal growth. The mean difference in years of life. Age-related growth deficit will weight and height in a study of 30 SS be difficult to demonstrate accurately with children (8–19 yrs) paired with matched longitudinal birth cohort studies until neo- controls of the same age, sex, race and natal screening for haemoglobinopathies socio-economic status was a deficit of 12 kg becomes more widely available. In a pro- weight and 8 cm height, with a 0.75-year spective study of 14 Canadian neonates with delay in sexual maturation based on Tanner Hb SS, Kramer et al.26 found no significant staging.30 No difference in body image was differences in birthweight or length com- detected between cases and controls. A pared with controls, indicating an absence recent longitudinal study of 148 SS children of disease effect on fetal growth.26 During showed that the growth deficit for one or follow-up of ten pairs of these children to 3– more indicators occurred in 84% of sub- 6 years of age, a growth deficit was noted jects, and 26%, 22% and 24% were ,5th from about 6 months of age. reference centile for weight, height and In a 3-year longitudinal study which BMI, respectively. Puberty was delayed by included 26 boys and 29 girls with sickle 1–2 years. Disease severity assessed by cell anaemia (13–18 yrs), there was sub- hospitalisation, blood transfusion and hae- normal weight and height and significant matological status was associated with long- retardation in growth velocity. Skeletal itudinal growth in females but not in maturation and sexual development were males.31 The cause for this sex difference significantly retarded but, with adjustment is unclear, but other studies have reported for bone age and Tanner staging, sexual similar findings and related it to differences development was considered appropriate for in the level of Hb, Hb F, energy intake and bone age.27 hormonal changes, especially at the time of A larger, cross-sectional, multi-centre puberty.12,29,32–34 study was undertaken which included 2115 Jamaican studies (Table 2). Ashcroft et al.35 cases with different sickle cell syndromes (1404 SS and the remainder with SC studied growth in 99 adolescents (12–21
  11. 175 Growth in SCD yrs) with sickle cell anaemia who had low (lambda-mu-sigma) method which is used to mean weight and delayed skeletal age (based normalise and smooth growth centile curves.39 Values from the LMS smoothed on hand radiography) compared with nor- mal and sickle cell-trait (AS) controls. curves were used to generate centiles Height differences were variable: younger expressed at selected ages as standard devia- patients were shorter whereas older ones tion scores (Z-scores) using NCHS growth were as tall as controls. reference standards. Mean height and weight Lowry et al.11 studied 99 SS children (2–13 at birth in both sexes were similar to reference yrs) and reported a mean value for weight values but fell away subsequently before below Jamaican reference values for both catching up at around 15 years in girls and 18 years in boys.39 The applicability of this sexes, although little difference was observed in height. In their follow-up study of 82 SS reference curve to countries other than children (2–21 yrs), Ashcroft & Serjeant36 Jamaica needs to be evaluated. Published by Maney Publishing (c) W S Maney & Son Ltd reported that, while the weight deficit per- Latin-American studies (Table 3). In a study sisted, height continued to increase and final of 14 SCD Brazilian children (6 mths–12 height was equal to or better than that of yrs), all had growth retardation and weight normal subjects. This was presumed to be a and height were ,10th centile of the NCHS result of delayed epiphysial fusion with final reference.40 Serum zinc levels were low but height determined by the degree of delay. In a not correlated with growth deficit. Low further study, the anthropometric measure- serum zinc was also reported in 18 SS ments of 64 SS children showed a significant Venezuelan children.41 In 34 Brazilian SCD deficit in mean weight, height and MUAC by patients (6–20 yrs), low weight-for-age but 4–6 years.37 Limbs were shorter than those of not height-for-age was significantly asso- controls, although the sitting–standing height ciated with delayed menarche and bone ratio was normal. age.42 Compared with pubertal matched A longitudinal study of children with SS controls, no difference in levels of serum- and SC disease, followed from birth to 9 follicle stimulating hormone (FSH) or lutei- years of age and compared with normal AA nising hormone (LH) before or after LH– controls, showed no birthweight differences FSH stimulation tests was detected. for either gender; the weight deficit in the SS Another Brazilian study of 86 SS patients children commenced before the end of the 1st year of life.32 The deficit appeared to be under 20 years of age reported weight and height ,10th centile in 40% and 31% of relatively more marked in girls and a similar cases, respectively, and the weight deficit trend was observed for height. Weight and persisted after puberty.43 In a follow-up of height velocity deficits increased after the 34 SS Brazilian patients (0–18 yrs), age of 7 years and there was a bone age impaired growth velocity increased with difference by 5 years with a retardation of age, and reduced weight and height were 0.4 years in boys and 0.6 years in girls. By associated with low serum zinc and ferritin the age of 8, this had increased to 1 and 1.3 levels.44 Family height channels were eval- years in boys and girls, respectively. uated in 76 SCD children (9 mths–20 yrs) Children with SC disease showed no growth deficit.32 The time of the growth spurt was from Brazil and corrected for parental height. Overall, allowing for mid-parental delayed by 1.4% years in 44 homozygous height, 41% were below the expected centile SCD adolescents and normal height was attained by 17.9 years.38 value and did not attain normal height and weight in adulthood.45 Although the max- Disease-specific growth reference curves imum growth velocity occurred later than for children with homozygous SCD were normal owing to delayed puberty, the produced using data obtained from a cohort of 315 children aged 0–18 years by the LMS magnitude of this spurt did not compensate
  12. 176 A.-W. M. Al-Saqladi et al. the frequency of painful and anaemic crises.50 for the early growth delay and final size remained below normal. This contrasts with Delayed sexual maturation was observed in 72 some Jamaican studies36,38 and the differ- homozygous SCD Congolese girls with delay ence might relate to genetic factors govern- in the age at thelarche and menarche. ing parental stature. In another group of 73 Menarche had not occurred by 14–18 years SS Brazilian children using NCHS reference in 71% of these cases compared with 10% of controls.51 In a study from Gabon, 27% of values, comparison of Z-scores for height 131 children with sickle cell anaemia (,18 or weight-for-age and weight-for-height yrs) had weights and heights ,22 SD showed that almost 10% of cases were under-nourished (Z-score (2).33 After 1 compared with African multi-ethnic reference values.52 In Zambian children with sickle cell year of follow-up, the weight- and height- anaemia, 60% and 53% were ,5th centile for for-age deficits became significant and were greater in boys. Conversely, Gonzales et al.46 ´ weight and height, respectively, compared Published by Maney Publishing (c) W S Maney & Son Ltd with NCHS reference values.53 reported no significant difference in weight, height and bone age in 110 SCD Cuban Middle East and India (Table 5). In a group children less than 17 years of age (74 SS of transfusion-dependent Egyptian children cases) compared with Cuban standards. which included 110 cases of SCD, height African studies (Table 4). Anthropometric was ,22 SD in 27%, and 51% showed a values for weight, height and mid-arm cir- growth velocity ,21 SD. MUAC, triceps cumference of 719 SS Nigerian children were skinfold thickness and BMI were signifi- reported to be ,50th centile of the Harvard cantly lower than in controls, and linear growth was delayed increasingly with age.54 standards, the most marked deficit being weight-for-age.47 Compared with healthy Despite regular blood transfusion, onset of Nigerian children, 85 SS children (9 mths– puberty and sexual maturation were 17 yrs) showed weight and height below and delayed. Mean adult height was not attained around the 3rd centile.48 In a study of 20 in 96% of 75 SCD male Iraqi patients who adults, anthropometric measurements were were all 18 yrs of age, and 45% had delayed lower in males but not in females.34 This was sexual maturation.55 In 97 Omani children (90 SS, 7 S b0 thalassaemia), weights in associated with lower daily energy and macro- nutrient intake by males than by controls. A 68% were below the NCHS 5th centile further study of 177 Nigerian children and compared with 28% of age- and sex- adolescents ( 1–18 yrs) with SCD reported matched non-sicklers. When these data were anthropometric values close to the 3rd centile plotted against Jamaican sickle cell reference values, 14% were ,3rd centile.56 of reference values with no significant differ- ence between cases and controls except at the Nutritional status in 102 SS Yemeni chil- age of 18 years.49 A high prevalence (21%) of dren (6 mths to 15 yrs) was compared with maxillary prognathism and malocclusion was NCHS reference values. Growth deficit reported among cases. However cases and (,22 Z-score) occurred in 72% based on controls were mostly from a lower socio- weight-for-height, in 55% based on height- economic class, which might explain the lack for-age and in 52% based on BMI (A.-W. of significant differences in anthropometric M. Al-Saqladi, unpublished data). In Saudi measurements between the groups. Arabian children, there was no significant Evaluation of body composition in 91 difference in serial height and weight mea- Congolese SS children (8–14 yrs) showed surements during the 1st 2 years of life in significantly lower mean weight, height, BMI, either 14 male or 7 female patients com- lean body mass and percentage of body pared with matched controls from the east- fat than in age-matched AA controls. ern region of the country where the disease is generally mild.57 Alteration in body composition correlated to
  13. 177 Growth in SCD growth than those elsewhere, probably A study of 58 SS Indian children (2–14 indicating better nutrition and quality of yrs) reported significantly lower anthropo- care. metric values for all indicators except the upper/lower segment ratio compared with normal age- and sex-matched controls. Body composition and energy metabolism Males and females were affected equally.58 To understand the nutritional needs and European studies (Table 6). Moderate interventions required in children with growth delay was reported in 76 white SCD, it is important to know the nature Sicilian children (1–17 yrs) with SCD.59 and magnitude of the body compositional Weight and height were ,3rd centile of deficits. A study of body composition in 36 reference values for white British children in Afro-American children with homozygous 16% and 10.5%, respectively. The majority SCD found significantly lower Z-scores for Published by Maney Publishing (c) W S Maney & Son Ltd had Benin haplotypes and showed no weight, height, MUAC or upper arm fat and growth differences compared with b-S muscle in affected children.62 A marked thalassaemia. reduction in fat-free mass (FFM) and body Mann60 reported 61 SS patients (3 mths fat indicated a global deficit of energy and to 19 yrs) in England whose heights were protein stores, suggesting that nutritional .2 SD below the mean Caucasian reference needs were not being met. value. The varied clinical manifestations Whole body protein turnover and resting compared with reports from Jamaica or metabolic rates are higher in SS adults than North America led the author to conclude in AA controls. Protein turnover is an that variation depended on many factors energy-consuming process which could including climate, endemic infection and account for increased energy expenditure. the general standard of nutrition and med- Patients with SCD disease could therefore ical care. Comparison of a further 56 SCD be in a hyper-metabolic state, requiring British children with controls of Caucasian higher energy and protein intake to maintain normal function.63 The resting metabolic (CC) or African/Caribbean (AC) origin showed that they were taller but that their rate was found to be 19% higher in weight and BMI were similar to CC con- homozygous SCD than in AA controls and trols.61 Weight and BMI were significantly the difference was not related to the size of lean body mass.64 When lean body mass or lower than in AC controls but there was no difference in height. Three unpublished FFM are taken into account, REE per kg of FFM was 25–50% higher than normal.65 longitudinal studies were identified, preli- minary data for which are summarised in The composition and tissue-specific meta- bolic rates comprising lean body mass/FFM Table 6. in SS subjects is likely to differ from those of AA controls.64,65 Whole body protein break- Summary. Growth retardation in children with SCD is well established and SS down and synthesis was increased by 32% and 38%, respectively,66 and the energy cost individuals are affected more severely than children with other sickle cell haemoglobi- of increased protein synthesis was estimated nopathies. Growth failure occurs among to be approximately 50% of increased REE.67 This increased energy expenditure affected children in all geographical areas, although the relevance and severity vary and protein turnover could result from with location and are most marked in low- hyperactivity of bone marrow during ery- resource settings. Children with SCD have throblastosis secondary to haemolysis and normal birthweight and length, with growth red cell destruction. The imbalance between restriction commencing between 6 months energy requirements and expenditure and 2 years. European children show better would lead to a marginal nutritional state,
  14. 178 A.-W. M. Al-Saqladi et al. contributing to growth impairment that bone resorption have been used as indirect might potentially be corrected by energy measures of bone turnover. In adolescents supplements. To adapt to this state, there with sickle cell anaemia compared with AA might be a reduction in physical activity. To controls, these bone marrow resorption and compensate for their high resting metabolic formation markers were increased, suggest- rate, patients with SCD might try to ing increased protein formation and break- economise on energy by decreasing physical down in bone marrow. This could relate to activity. This mechanism cannot compen- elevation in whole body protein turnover and REE in SS patients.76 Bone mineral sate for long-term energy deficiency or the imbalance between metabolic demands and density, assessed by dual-energy X-ray in 25 energy consumption which ultimately lead children and adolescents (9–19 yrs) with to growth impairment.68,69 severe sickle cell anaemia, was found to be Pre-albumin, used to assess nutritional reduced in 64%. This was associated with Published by Maney Publishing (c) W S Maney & Son Ltd status, has been reported to be low in deficient calcium intake and low serum SCD.70 Urinary loss of amino acids might levels of vitamin D.77 also contribute to slow growth. One study Glutamine is the most abundant amino reported no differences in the concentration acid in humans and is the preferred fuel for of serum total proteins between SCD rapidly dividing cells such as reticulocytes. children and controls, but serum levels of Its use in children with sickle cell anaemia pre-albumin, all essential and most non- was reported to be 47% higher than in essential amino acids were significantly controls and to be associated with a 19% lower with higher urinary concentration of increase in REE and a 66% increase in amino acids.71 cardiac output. These changes might be Changes in carbohydrate and lipid meta- attributable to increased haemoglobin bolism in SCD have been evaluated by workload.78 synthesis and cardiac measurement of whole body glucose and Attempts to lower REE using oral gluta- lipid metabolism in adults. Results showed mine led to a reduction of about 6%, which that these were not significantly affected and was greater in children who were under- the plasma concentration of insulin, gluca- weight. Improved BMI and body fat gon, cortisol, nor-epinephrine and epi- components indicated that lowering REE nephrine were similar in patients and by increasing energy intake and glutamine controls.66 Serum levels of total phospholi- administration could be an effective way of pids were within the normal range in promoting growth in children and adoles- children with sickle cell anaemia, while cents with SCD.79 docosahexaenoic acid (DHA), eicosapen- Metabolic studies suggest that children taenoic acid (EPA), total polyunsaturated with SCD have a higher resting metabolic fatty acids (PUFA)72 and cholesterol73,74 rate and REE, which increases their meta- were decreased. With an imbalance between bolic demands and requirements for protein n-3 and n-6 long-chain PUFA in erythro- and energy. Factors which contribute to cytes and plasma, alterations in the lipid higher REE include increases in protein layers of the red-cell wall might be ante- turnover, erythropoieses, cardiac workload cedent to red-cell asymmetry, adhesion and aggregation and precede vaso-occlusion.75 and underlying inflammation. The child’s body composition, nutritional status and Plasma concentration of type I procolla- clinical condition all influence metabolic gen carboxy-terminal propeptide (PICP), rate and nutritional requirements and these the major collagen produced by osteoblasts need to be well defined in order to under- during bone formation, and urinary excre- stand the potential role of nutritional inter- tion of urinary pyridinoline cross-links ventions for improving health. (PYD) formed from type I collagen during
  15. 179 Growth in SCD hypopituitarism.85 Delayed testicular devel- Endocrine dysfunction and growth retardation opment has been demonstrated in male In children with SCD, delayed sexual sicklers, predominantly in boys aged 10–15 maturation is frequently associated with years who had delayed puberty but attained growth retardation.31 Although its contribu- normal sexual maturation.43 tion to growth deficit is unclear, it might not In a longitudinal study of 55 American have a primary endocrine cause.3 Deter- children with SCD and reduced weight, mination of gonadotropin concentrations in height and retarded bone age, there was 40 children with sickle cell anaemia (5–16 delayed sexual maturation which, though yrs) showed a significant increase in LH in prolonged, progressed in an orderly man- children aged 5–10 years and normal levels ner.27 The average age of menarche in in older children. The levels of LH and FSH affected girls was 15.4 vs 12.6 years in were higher in patients than in controls at normal girls. In the majority of these Published by Maney Publishing (c) W S Maney & Son Ltd the same stage of development of secondary children, hormonal assays indicated an sexual characteristics. This suggested a intact pituitary–hypothalamic axis with variation in the rate of maturation of the appropriate adrenal and gonadal responses hypothalamic–pituitary gonadotropin axis and only patients with marked delay in rather than gonadal hypofunction.80 sexual maturation showed lower gonadal Evaluation of gonadal function in adults hormones. Age at menarche in Jamaican with SCD showed that serum testosterone, girls was delayed by 2.4 years in 99 cases dihydrotestosterone (DHT) and androste- with homozygous SS disease, and by 0.5 nedione levels were low.81 High LH and years in 69 SC cases compared with a mean FSH levels were observed before and after age of 13 years in AA controls.86 Weight was stimulation with gonadotropin-releasing found to be the dominant determining hormone, which correlated with testicular factor for age at menarche in cases and size and retarded secondary sexual charac- controls. The authors considered their find- teristics. This suggests that gonadal hypo- ings favoured sub-optimal nutrition as a function is not related to pituitary failure but cause of pubertal delay rather than an is consistent with primary gonadal failure. endocrine component.86 This study also reported reduced erythro- In 80 Saudi patients with sickle cell cyte and hair zinc concentrations which anaemia, hormonal assay showed normal significantly correlated with androgen sta- levels of T3, T4 and growth hormone, low tus. The influence of chronic zinc deficiency levels of cortisol, testosterone and LH, and variable changes in FSH.87 These abnorm- on gonadal growth and function was con- sidered important. Evaluation of the alities occurred more frequently in the hypothalamic–pituitary axis by administra- patients with severe disease. Studies of tion of gonadotropin-releasing hormone– thyroid function have shown that blood thyrotropin-releasing hormones has levels of thyroxine, thyroxine-binding capa- demonstrated higher concentrations of LH, city and the free thyroxine index were not FSH, thyroid stimulatuig hormone and significantly different in 90 SS children (1– 15 yrs) than in AS and AA controls.88 prolactin hormones in male patients than in controls, which suggests a primary gona- Interest in growth hormone dysfunction has dal failure in adults82 and in children with motivated a series of studies by Soliman and extreme retardation of puberty.83 co-workers who demonstrated abnormal- There is also some evidence for partial ities in the growth hormone (GH)/insulin- hypogonadism.84 like growth factor-I (IGF-I) axis.54,89–92 In hypothalamic Signi- ficantly reduced concentrations of testoster- a study of 21 pre-pubertal SS children one, LH and FSH in adults with SS disease with poor growth (height ,10th centile), supports gonadal hypofunction secondary to defective GH secretion and low insulin-like
  16. 180 A.-W. M. Al-Saqladi et al. IGF-1 and IGF binding-protein-3 were cases (who were either growth-retarded or demonstrated in 43%, with a reduced normal) than in controls. Despite an ade- response of IGF-1 production to GH injec- quate dietary intake of energy, protein, zinc tion. The disease severity score was signifi- and vitamin A, these children with SCD cantly higher in the group with defective GH were leaner and lighter with lower red secretion than in the group with normal GH blood-cell zinc and serum vitamin A con- secretion. The authors presumed there was centrations, and higher resting energy expenditure than controls.97 These findings partial resistance to GH and that these were major causes of slow growth, especially in were reflected in a survey of 61 American SS individuals with severe SCD.80 Although patients and their families on nutrition reduced elements of the GH/IGF-1 axis in knowledge and practice. Overall, 90% of SS children have been found, growth participants were familiar with the different velocity shows poor correlation with endo- food groups but most failed to consume an Published by Maney Publishing (c) W S Maney & Son Ltd crine assessment of the axis or thyroid appropriate amount of different food function.93 Other investigators have groups, and 59% had incomes below the reported a significant correlation between poverty level. The authors concluded that IGF-1 and height velocity in a sub-group of inadequate intake of nutrients was contri- sicklers with height ,25th centile.94 In an buting to poor child growth in lower socio- economic families.98 A recent study evalu- analysis of different b globulin haplotypes, the CAR/CAR haplotype has shown signifi- ated dietary intake by 24-hour recall over cantly lower mean growth velocity and four annual visits in 97 American children reduced concentration of IGF-1 compared with homozygous SCD and reported a sub- with BEN/BEN haplotype, leading to the optimal intake of many nutrients across all conclusion that delay of growth in SCD was ages, including vitamins D and E, folate, linked to intrinsic factors and disease sever- calcium, magnesium and zinc, with a trend ity.93 In a small study of five SCD children towards poor diet with increasing age, particularly during adolescence.99 with GH deficiency who received GH therapy for >3 years, height Z-scores Folic acid was the first micronutrient improved significantly.95 deficiency to be associated with SCD and has been reported frequently.100–103 Folate The normal pituitary response to stimula- tion tests and the conflicting results of deficiency and megaloblastic erythropoiesis hormonal assessment make it difficult to were observed in about 10% of patients in evaluate the role of endocrinal dysfunction Nigeria, and therapeutic administration of in the pathogenesis of growth impairment. folic acid resulted in improved height and Endocrine function is altered in some weight as well as correction of haematologi- cal changes.104 Other investigators have children with SCD, and hormonal therapy such as GH or IGF-1 might offer therapeu- failed to demonstrate a correlation between tic options. growth retardation and folate deficiency as folate supplementation produced no change in haematological or growth para- Micronutrient deficiency meters.105–108 Routine supplementation in Micronutrient deficiency could be an SCD has been questioned, particularly in important contributor to growth impair- developed countries where folate require- ment in SCD. In an American study of ments could be provided by a fortified food intake.109 Vitamin B6 (pyridoxine) defi- 170 children (aged 2–12 years) with SCD, 22% were ,5th centile in height and/or ciency in adults with SCD has also been weight,96 and the serum levels of zinc, reported.110 In children, assessment of retinol, pre-albumin and retinol binding vitamin B6 status by determination of serum protein were significantly lower in the 40 concentrations of pyridoxal 5-phosphate
  17. 181 Growth in SCD (PLP) (the major co-enzyme of vitamin B6) Iron deficiency might not be associated showed that 77% were below the reference with SCD owing to the availability of iron cut-off, and there were significant positive from red cell destruction and increased associations between PLP levels and BMI intestinal iron absorption in response to Z-scores, weight and MUAC.111 Reduced chronic anaemia.127 Even so, patients levels of other B vitamins including B12112 receiving sporadic transfusions do not and riboflavin113 have been reported. Folic acquire excessive iron burden during the 1st 2 decades of life.128 Iron deficiency in acid and vitamins B6 and B12 are important SCD is common,129 particularly among co-factors in metabolism of the sulphur- containing amino acid homocysteine, and children living in developing countries deficiencies can lead to hyperhomocystein- where iron deficiency anaemia is highly prevalent.130 Depletion of iron storage aemia. In the general population, raised homocysteine concentrations are linked to diagnosed by bone marrow examination Published by Maney Publishing (c) W S Maney & Son Ltd increased risk of cardiovascular disease and was reported in a high proportion of stroke.114 Plasma homocysteine is reported SCD children (36–50%) in India and to be elevated in adults115 and chil- Nigeria.131–133 Iron deficiency was reported dren116,117 with SCD and significantly so in 16% of non-transfused American chil- when complicated by stroke.118 Homo- dren diagnosed by their response to iron therapy.134 This contrasted with a study of cysteine levels can be lowered by supple- mentation with folic acid or vitamins B6 and 104 non-transfused patients who showed no B12. In addition to the maintenance of haematological or biochemical evidence of iron deficiency.135 A study of Jamaican effective erythropoiesis, these micronutri- ents can prevent tissue accumulation of children followed from birth to 5 years homocysteine, thus reducing the risk of reported low serum iron in patients and endothelial damage and thrombosis.119–121 controls by 1 year of age, but levels sub- sequently became normal.136 However, a Serum vitamin A status was reported as marginal in 66% of American children with recent cross-sectional study of 141 Jamaican SCD and deficient in 17%. BMI Z-scores SCD children (1–5 yrs) which used several were low, and there were higher rates of measurements to determine iron status hospital admission of vitamin A-deficient showed that 8.5% of cases were iron- patients than of those with normal levels.122 deficient.137 Although the exact mechanism Zinc deficiency in SCD occurs at levels of iron deficiency in SCD is not clear, the suggesting chronic zinc depletion and most probable cause is excessive urinary loss secondary to chronic haemolysis.138 appears to be associated with chronic haemolysis and hyperzincuria.123 Growth Iron deficiency in SCD might be bene- retardation and hypogonadism were ficial and possibly ameliorate sickling by observed in zinc-depleted men, suggesting decreasing MCHC, which reduces haemo- its contribution to impaired growth and lysis, thus prolonging red-cell life- sexual maturation in SCD.81,124 In 104 span139,140 and reducing painful crises141 American children (0.4–18 yrs), low plasma (which can be precipitated by iron ther- apy).142 Evidence for the clinical benefits of zinc was reported in 44% of SS cases and, compared with SS cases with normal plasma iron deficiency is minimal and is limited zinc, was associated with impairment of because of difficulties in assessing disease severity.143 Iron deficiency is associated with height, weight, FFM, skeletal growth and sexual and skeletal maturation.125 Supple- growth and intellectual impairment144 and, ments of elemental zinc (10 mg/day) given in a growing child with SCD, iron require- for 12 months to 20 children with SCD led ments are increased. Iron-deficient children to improved rates of linear growth but there are at risk of both growth and neurocogni- was no effect on BMI.126 tive impairment imposed by the disease and
  18. 182 A.-W. M. Al-Saqladi et al. compounded by iron deficiency. These (540 mg/kg/d) has been used to elevate consequences should be considered before erythrocyte magnesium and prevent potas- iron supplementation is withheld. sium loss by inhibition of the K-Cl co- Vitamin E deficiency occurs in SCD,145 transport system, resulting in improved with a high prevalence in children in sickle red-cell hydration and a decrease in developing countries.146,147 Vitamin E has the median number of painful days during a 6-month period of magnesium therapy.159 anti-oxidant properties that could protect red cells against oxidative stress and its Several micronutrient deficiencies have administration leads to a decrease in the been reported in patients with SCD. Folic percentage of irreversibly sickled cells, acid is widely administered, usually daily, to symptoms.148 which might alleviate children with SCD, although the optimal 149 and D150 and Deficiency of vitamins C dose is unclear, which relates to uncertainty of minerals such as magnesium151 and concerning the daily requirement. Other Published by Maney Publishing (c) W S Maney & Son Ltd selenium152 has been reported, although nutrients such as zinc, glutamine, l-arginine the exact pathophysiological consequences and anti-oxidants might have therapeutic and contribution to growth delay in SCD benefits, and their clinical efficacy needs to are unclear. The potential benefits of be determined. individual nutrient or multi-micronutrient supplementation remain to be established. Food substances with anti-oxidant activ- Future Perspectives ity, which might protect red cell membranes from oxidative injury, have been used to Under-nutrition relates to increased mor- treat SCD.153,154 In a small pilot study, oral bidity and mortality in all children, and administration of dietary omega-3 fatty acid, contributes to poor clinical outcome and provided as menhaden fish oil containing severity of disease in children with SCD. docosahexanoic acid and eicosapentanoic Despite major advances in understanding acid, produced significant reduction in the the molecular and genetic basis for SCD, mean number of painful crises, blood there has been little progress towards coagulability and platelet adhesion molecule lessening the obvious nutritional problems expression.155 Omega-3 fatty acids are faced by these children.160 There has been important components of red cell mem- limited evaluation of a variety of nutritional branes and their blood levels have been interventions that could influence the nat- ural history of SCD.161 Improving the correlated with indices of disease severity and haemoglobin concentration in steady- nutritional status and growth of these state SCD. This suggests that there are children could have a favourable impact on clinical benefits through protection against their clinical course and prognosis. Evalua- haemolysis and reduction in vaso-occlusive tion of a comprehensive clinical care pro- episodes or ischaemic organ damage.156 L- gramme in a sub-Saharan Africa setting arginine is the natural amino acid substrate produced encouraging results and showed for the synthesis of nitric oxide, a potent that improved growth and reduced disease severity can be attained.162 There are good vasodilator that is deficient during sickle cell crises. When administered orally at a dose of opportunities for such programmes with the 0.1 g/kg three times a day, it led to a introduction of neonatal screening, the significant reduction in pulmonary artery identification of children with SCD at birth systolic pressure in SCD patients with and early interventions using essential pulmonary hypertension.157 This is consis- health packages. tent with vaso-constriction being a signifi- Growth monitoring with appropriate cant contributor to vaso-occlusion.158 Oral nutritional support as part of the compre- supplementation of magnesium pidolate hensive care of children with SCD should be
  19. 183 Growth in SCD promoted. If the types of nutritional defi- are required. There are few studies from ciency are known, then clear nutritional Africa and the Arabian Peninsula and advice and care can be given by health increased efforts are required to address workers to children and their families. This this disparity, particularly in low-resource allows the identification of children who do settings. not adhere to nutritional interventions and of high-risk cases. It might facilitate the use of alternative interventions including drugs, Acknowledgment hormones or other treatments in specific cases. We thank Drs R. Dickerhoff (Asklepios Small stature and delayed sexual maturity Kinderklinik, Germany) and P. Telfer can carry long-term psychological conse- (Royal London Hospital, UK) and their quences that affect the ability of the colleagues for providing the unpublished Published by Maney Publishing (c) W S Maney & Son Ltd adolescent with SCD to form normal anthropometric data listed in Table 6. relationships with the opposite sex, leading to low self-esteem and depression.163 Growth retardation has been associated with References impaired mental development and a low 1 Serjeant GR. Sickle Cell Disease, 2nd edn. Oxford: intelligence quotient,164 and nutritional Oxford University Press, 1992. interventions with their potential for 2 Enwonwu CO. Nutritional support in sickle cell improving long-term growth and develop- anaemia: theoretical considerations. J Natl Med ment could improve prognosis, particularly Assoc 1988; 80:139–44. 3 Wethers DL. Delayed growth and sexual matura- if commenced in early childhood before tion in sickle cell disease. Ann N Y Acad Sci 1989; growth retardation becomes established. 565:137–42. These interventions might lead to reduction 4 Warrier RP, Kuvibidila S, Gordon L, Humbert J. in the severity of crises and vascular com- Transport proteins and acute phase reactant plications, or episodes of vasoconstriction. proteins in children with sickle cell anaemia. J Natl Med Assoc 1994; 86:33–9. There is little information on the influ- 5 Henderson RA, Saavedra JM, Dover GJ. ence of several important genetic poly- Prevalence of impaired growth in children with morphisms on nutritional status in SCD. homozygous sickle cell anaemia. Am J Med Sci For example, methylene-tetrahydrofolate 1994; 307:405–7. reductase deficiency, which is not infre- 6 Konotey-Ahulu F. The sickle cell disease patient: quent in subjects with SCD,165–168 would natural history from a clinico-epidemiological study of the first 1550 patients of Korle Bu influence host folate status and homocys- Hospital Sickle Cell Clinic. Watford, UK: teine metabolism with possible effects on Tetteh-A’Domeno, 1996. sickle cell vasculopathy. Similarly, glucose- 7 Serjeant GR. The clinical features of sickle cell 6-phosphate dehydrogenase deficiency disease. Baillieres Clin Haematol 1993; 6:93–115. ` could affect severity of haemolysis in sickle 8 Scott RB, Ferguson AD, Jenkins ME, Clark HM. Studies in sickle-cell anaemia. VIII. Further cell anaemia, although some studies of observations on the clinical manifestations of this genotype have shown little additive sickle-cell anaemia in children. Am J Dis Child effect.169 Pooled data from studies of 1955; 90:682–91. different haplotype profiles need to be 9 Malinauskas BM, Gropper SS, Kawchak DA, interpreted carefully, taking these various Zemel BS, Ohene-Frempong K, Stallings VA. factors into consideration. Impact of acute illness on nutritional status of infants and young children with sickle cell disease. In order to assess the benefits for child J Am Diet Assoc 2000; 100:330–4. growth and the reduction of disease severity, 10 Fung EB, Malinauskas BM, Kawchak DA, et al. randomised trials of nutritional interven- Energy expenditure and intake in children with tions in infancy and early childhood com- sickle cell disease during acute illness. Clin Nutr bined with appropriate health care packages 2001; 20:131–8.
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