GROWTH RETARDATION IN SICKLE-CELL DISEASE TREATED BY NUTRITIONAL SUPPORT

903

the investigation of the effect of nutritional the and absorptive supplementation on growth in growth-retarded children with SCD. These observations

Preliminary Communication GROWTH RETARDATION IN SICKLE-CELL DISEASE TREATED BY NUTRITIONAL SUPPORT

SUBJECTS AND METHODS with haemoglobin SS followed in the Children’s Hospital Medical Center in Oakland, California, had weight or height below the 5th percentile according to National Center for Health Statistics percentile curves.8 In 16 both weight and height were below the 5th percentile. From this group we selected 5 boys in whom a 3-day dietary history demonstrated an adequate intake. Informed parental consent was obtained in all. Absorption studies were performed in the Pediatric Clinical Research Center (PCRC) at the University of California, San Francisco, according to a protocol approved by the UCSF Committee for Human Experimentation. At entry into the study, blood samples were analysed for lymphocyte function, serum albumin, and serum cholesterol. Plasma zinc was determined by atomic absorption spectroscopy.9 29

ELLIOTT VICHINSKY MELVIN B. HEYMAN BARBARA GAFFIELD RICHARD KATZ RICARDO CASTILLO DEBORAH HURST KLARA KLEMAN DANNY CHIU M. MICHAEL THALER ARTHUR J. AMMANN BERTRAM LUBIN

Department of Pediatrics, University of California, San Francisco; Children’s Hospital Medical Center, Oakland; and Bruce Lyon Memorial Research Laboratory, Oakland, California, USA The effect of increased nutritional intake evaluated in 5 growth-retarded children with sickle-cell disease. Growth on recommended daily calorie and protein intakes had been inadequate in all 5. Fat absorption and intestinal mucosal morphology were normal in all 5. 2 children were given nutritional supplementation by nasogastric intubation, 1 received nightly oral formula supplements, and 2 were supplemented with zinc, iron, folate, and vitamin E only. Nutritional supplementation by the nasogastric route produced a rapid sustained increase in growth rate, associated with striking reductions in pain crises and infections which had previously necessitated many hospital admissions. Oral supplementation improved the clinical course but had no effect on growth rate. Mineral and vitamin supplements influenced neither the growth rate nor the clinical course. The observations indicate that nasogastric nutritional supplementation may accelerate growth and reduce the incidence and severity of complications in growthretarded children with sickle-cell disease.

Summary

was

INTRODUCTION

GROWTH retardation is commonly observed in children with sickle-cell disease (SCD).Recent evidence of zinc, iron, folate, vitamins C and E, and lipid deficiencies2-4 suggests that nutritional factors may contribute to inadequate growth in SCD. Abnormal lipid profiles have also been reported in SCD,5 possibly reflecting disturbed fat absorption or metabolism in this disorder. Growth retardation in SCD becomes apparent after 6 months of age,6 as the SS form of haemoglobin S becomes predominant. Entrapment of sickle cells in the intestinal microcirculation may contribute to mucosal injury, with subsequent decreased nutrient absorption or interference with nutrient entry into the circulation.

prompted

function

(31%) of 94 children

Hematology

Assessment

Clinic

at

of Intestinal Function

All subjects were placed on a regular ad libitum diet for 5 days and total intake was measured and recorded. Faeces was collected for 72 h after a 2-day stabilisation period and it was analysed for fatlo. and nitrogen (N). 11 Urine was collected for 24 h for determination of urinary urea nitrogen (UUN). 12 The coefficient of fat absorption (%) was calculated by the formula: Intake (g) - Excretion (g) x (100) Intake (g) <

Nitrogen balance was calculated by formula: Intake (g N) - (UUN + faecal N+3) A vitamin E absorption test was performed on the second hospital day. Plasma andpacked red blood cell vitamin E concentrations were determined3 from samples obtained 0, 2, 4, 6, 8, 12, and 24 h after administration of a standard oral dose (20 IU/kg) of ’Aquasol

E’. A

-

peroral small-intestinal biopsy specimen was obtained at the ligament ofTreitz by means of the paediatric Quinton multipurpose small bowel biopsy tube. Tissue was fixed in 1007o formalin for histological studies and in iced 3% glutaraldehyde for electron microscopic examination.

Nutritional Supplementation All 5 boys received outpatient dietary counselling from one of us (B. G.). Patients 1 and 2 received dietary counselling only, plus supplemental iron, zinc, folate, and vitamin E. Patient 3 was placed on a supplemental oral formula (’Ensure’, Ross), providing 400 kcal at bedtime each night. Patients 4 and 5 were given calories by longterm nasogastric feeding. Patient 4 was admitted to hospital at 48 months of age at Children’s Hospital Medical Center and received all nutrients by continuous nasogastric infusion for 6 weeks, the daily intake averaging 143 kcal/kg and 2’77g protein/kg (ensure, ’Controlyte’, Doyle; ’MCT’, Mead-Johnson). During his admission to the PCRC patient 5 was trained to insert an 8-French

TABLE I-ANTHROPOMETRIC MEASUREMENTS AND HAEMATOLOGICAL INDICES IN STUDY

eight; Ht=hetght; TSF=tnceps skin fold;

AlAMC=mid-arm muscle circumference, Hb=haemoglobm.

SUBJECTS

904 TABLE II-DAILY CALORIE AND PROTEIN INTAKE, FAT ABSORPTION, AND NITROGEN BALANCE IN SCD PATIENTS

*Calorie and protein intakes were greater than RDA for age in all 5 subjects. Formulas for computing the coefficient of fat absorption and nitrogen balance are in text. RDA = recommended dietary allowances ND = not done.

(1980).

polyurethane feeding tube (’Entriflex’, Biosearch) nightly, using a metal stylet to assist in placement. After stabilisation in the hospital, he continued to infuse 1000 ml of ’Osmolyte’ (Ross) (1060 kcal, approximately 1/3 of his calories, and 36 -7g protein) by pump nightly during sleep at home. Clinical course and tolerance of the nocturnal feeding regimen were evaluated monthly. RESULTS

At the start of the study the growth of all 5 boys was retarded and there was somatic (skeletal muscle) protein depletion in 3 (table l). Visceral protein status (serum albumin) was within normal limits in all 5. Percentage of T cells was deficient in the 4 boys tested, whereas lymphocyte function, as determined by phytohaemagglutinin and allogeneic cell stimulation, was normal. Cholesterol values were within normal limits in all 5 boys; zinc values were normal in 3 of 4. Table n summarises the data from the balance studies performed in the PCRC. Daily calorie and protein intakes were adequate for age in all patients, as recommended by the Food and Nutrition Board.13 Fat absorption was within normal limits (>93%) in 4 of 5 subjects, and nitrogen balance was positive in 2 of the 3 tested. In the youngest patient (case 4), fat absorption was near the lower limit of normal and nitrogen balance was negative.

I-Vitamin E absorption test after oral administration of aquasol E (20 IIJ/kg). (A) Baseline plasma vitamin E concentration (mgldl) was low in patient 4. 3 patients had a normal increase over 4-8 h, whereas patients 3 and 5 had flat absorption curves. (B) Packed red blood cell vitamin E concentrations (J.tglml) were raised in all 4 subjects tested. In 3, the concentration continued to increase throughout the 24 h period. This increase was not observed in subject 5, and this is consistent with his flat absorption curve.

Fig

TABLE III-CLINICAL COURSE OF SCD PATIENTS

Baseline plasma vitamin E concentrations were within normal limits (0 -8-1’2 mg/dl) in 4 patients and depressed in 1 (fig 1). Plasma vitamin E reached a peak 4-8 h after intake of oral vitamin E in 3 patients; the response in the other 2 was nearly flat. Baseline packed red blood cell vitamin E content was greater in patients than in controls. There was a gradual increase in packed red blood cell vitamin E content in the 24 h after the oral test dose that persisted after plasma levels had returned toward baseline. Histological and electron microscopic examination of the small intestine demonstrated normal mucosa and submucosa in all 5 boys. In patients 1 and 2 there was no change in weight or height

growth rate on treatment. Similarly, growth rate remained unchanged in patient 3, on supplemental formula. However, he has not required admission to hospital since the start of supplementation. In patient 4 there was a remarkable increase in growth rate during the 6-week period of continuous nutritional supplementation via nasogastric tube; his weight increased by 4 -2 kg, his height increased by 3 cm, and triceps skin fold increased from 2-8 mm (<5th percentile) to 10-3mm After his weight decreased discharge, (85-95th percentile). on but linear his usual continued at an diet, growth slightly accelerated rate (10 cm/yr). Although he had often required treatment in hospital for infections and pain crises before nutrition supplementation, he has not been admitted to hospital since supplementation. In patient 5, who received nightly nasogastric nutritional supplementation, there was a dramatic increase in velocity of growth in height, from 2 cm/year to 10 cm/year. He gained 10 kg over 8 months,mid-arm muscle circumference increased from 5 -3cm to 19 -6cm, and triceps skin fold increased from 11 to 14 mm. He had been admitted with increasing frequency to hospital because of infections and painful episodes in the 3 years before evaluation and had had difficulties in social adjustment because of drug dependence. Since nutritional supplementation began he has not required admission to hospital and has not used any medications except paracetamol (acetaminophen) for two minor painful episodes associated with an influenza-like syndrome and an upper-respiratory-tract infection. Complications of nasogastric nutrition supplementation were minor. Patient 4 experienced occasional vomiting (6 episodes) and had diarrhoea for 2 days. Patient 5 had no problems related to therapy. DISCUSSION

The possible relation between digestive or nutritional factors and deficient growth in children with SCD has received little attention. A previous report revealed normal fat balance in 2 children with SCD and normal intestinal

905

Fig 2-Weight and height measurements for 5 SCD patients plotted on charts depicting 5th and 95th National Center for Health Statistics growth

percentiles8.

Patients 1 and 2 received mineral and vitamin supplementation only. Patient 3 received nutrition supplementation as indicated. NG=nasogastric feeding. Oral=oral feeding.

morphology indices

were

in 3 not

others,

but

patient selection and growth

described.14 In the present study, fat

absorption was within the normal range in 4 severely growthretarded children with SCD and was borderline in the remaining patient. Vitamin E absorption was reduced in 2 of 5 children tested, but all had plasma and erythrocyte vitamin E values within normal limits. Thus, lipid malabsorption does not appear to be involved in growth retardation associated with SCD. This conclusion is reinforced by the normal appearance of intestinal mucosa in all 5 patients. Data from several SCD centres indicate that serum cholesterol, lipids, and vitamin E are lower in children with SCD than in age-matched healthy controls. 3-5 Trace elements such as zinc may also be reduced in SCD. Serum zinc concentrations were normal in 3 of 4 growth-retarded patients tested. No additional zinc was provided with the nutritional supplements administered by nasogastric tube to the 2 children in whom there was a striking improvement in growth. Conversely, growth was not improved in 2 other subjects who received mineral supplementation (including zinc) without extra calories. These results raise the possibility that inadequate intake of calories, rather than specific nutritional deficiencies, may be responsible for the retardation of growth in children with SCD. Approximately 1 in 3 children with SCD were growthretarded in our patient population, despite nominally adequate intakes of calories and nitrogen. Enhanced growth velocity was clearly evident in the 2 boys on calorie and protein supplementation by nasogastric tube. Moreover,

supplemental oral calories,

and

patients 4

and 5 received

nasogastric

growth velocity in both of these children greatly exceeded the maximum velocity observed during puberty in a large series of SCD patients.Patient 5 continues to grow in height and weight at an accelerated pace while being maintained on nocturnal nasogastric supplementation. Patient 4, in whom the supplements were discontinued, has reached the 5th percentile in height for age, but rate of weight growth has decelerated. The

positive

responses of these 2

boys

to

additional

calories, combined with lack of effect in the

2 given supplemental minerals and vitamins only and in 1 receiving a single additional meal at bedtime, are consistent with increased metabolic requirements in SCD. Metabolic rates in this disorder may be increased by the stress from pain, infection, or hyperactive bone-marrow, resulting in a relative deficiency of nutrients. All 3 children on calorie supplementation experienced a striking reduction in major complications associated with SCD (table III). Even patient 3, whose growth was not accelerated, did not require admission to hospital for infection or pain while nutritional intake was increased. Similarly, patients 4 and 5 have been essentially symptom-free since nutritional supplementation was initiated. It is possible that reduced energy needs, due to relief from infection or pain crises, contributed to the effectiveness of nutritional therapy in stimulating growth of these

children.

Nocturnal nasogastric feeding is an effective, minimally invasive technique for provision of nutritional support for children with other chronic disorders associated with growth

906

retardation, including Crohn’s disease, cystic fibrosis,

and

glycogen storage disease. 15-17 Our observations suggest that nutritional supplementation by nasogastric administration of calories and protein may provide an effective, simple, and relatively non-invasive approach to prophylaxis and management of inadequate growth and other major complications in children with SCD. Assistance with ultrastructural examination of intestinal

biopsies by

Dr

Joseph Goodman is gratefully acknowledged.

Supported in part by the Division of Research Resources Clinical Research Center grant and in part by NIH Grant HL 20985. R. K. was a fellow under the NIH postgraduate training program in pediatric gastroenterology (AM07179). Correspondence should be addressed to M. B. H., Department of Pediatrics, M-650, University of California, San Francisco, California 94143, USA. REFERENCES 1. Phebus CK, Gloninger MF, Maciak BJ. Growth patterns by age and sex in children with sickle cell disease. J Pediatr 1984; 105: 28-33. 2. Prasad AS, Ortega J, Brewer GJ, Oberleas D, Schoomaker EB. Trace elements in sickle cell disease. JAMA 1976; 235: 2396-98. 3. Chiu D, Lubin BH. Abnormal vitamin E and glutathione peroxidase levels in sickle cell anemia. J Lab Clin Med 1979; 94: 542-48. 4. Vichmsky E, Heyman MB, Hurst D. Nutrition in sickle cell anemia (HB SS). Pediatr Res 1984; 18: 251A.

Reviews of Books

Pp 242.$28.50. THIS is an unusual and valuable book, written for medical and non-medical workers who undertake family studies or wish to establish genetic registers. It reflects the experience and skill of two social workers, one American and one British, who have been involved in planning and carrying out large family studies. Mrs Krush has worked with H. T. Lynch and E. A. Murphy in studying families at high risk for cancer, such as those with familial polyposis. coli. Mrs Evans worked with the late C. 0. Carter for many years, on the enormous and well known family studies which have provided useful recurrence risks for multifactorial conditions. Family studies are divided into two main types. In a type I study, an unselected series of patients and their families are investigated in order to provide recurrence risks, to demonstrate which form of inheritance is operating, and to look for genetic heterogeneity. The authors list the criteria which characterise the different forms of inheritance and suggest the numbers of families required to demonstrate each-12 for autosomal dominant inheritance, 60 for autosomal recessive, 20 for X-linked recessive, and approximately 500 for polygenic inheritance. In type II studies, families are investigated for specific reasons, such as the development of carrier tests or the detection of presymptomatic disease. The authors emphasise that the ability to extract useful information from a type I study depends upon whether the data was collected in an unbiased way. Most doctors would realise that inclusion of a proband, solely because he had been referred for special interest, would be incorrect. Perhaps it is not generally realised that important bias can develop during a study, for example if it is easier to trace those probands who are seriously affected, or if it is easier to trace relatives who are affected rather than healthy. The criteria for when to give up trying to trace someone should be as stringent as those for selection of the probands in the first place. After planning a study, skill and experience become necessary in order to trace patients and be able to reassure them, while at the same time encouraging cooperation. The authors’ advice on these points is helpful, and they give examples of letters written to patients inviting their participation, which illustrate that used

to

longer words,

like

genealogical

7.

Clin North Am 1980; 27: 429-47. 8. National Center for Health Statistics: NCHS growth curves for children 0-18 years, United States. Vital and health statistics, series 11, no 165. Health Resources Administration, Washington, DC, 1977, United States Government Printing Office. 9. Smith JC Jr, Butrimovitz GP, Purdy WC. Direct measurement of zinc in plasma by atomic absorption spectroscopy. Clin Chem 1979; 25: 1487-91. 10. van de Kamer JH, ten Bokkel Huinink H, Weyers HA. Rapid method for determination of fat in feces. J Biol Chem 1949; 177: 347-55. 11. Fleck A, Munro H. The determination of organic nitrogen in biological materials: A review. Clin Chim Acta 1965; 11: 2-12. 12. Paulson G, Ray R, Sternberg J. A rate-sensing approach to urea measurement. Clin Chem 1971; 17: 644. 13. Food and Nutrition Board, National Research Council. Recommended daily dietary allowances, 9th ed. National Academy of Sciences, Washington, DC, 1980. 14. Rahbar F, Scott RB, Jilly P. Studies in sickle cell anemia: preliminary observation on gastrointestinal digestion and absorption. J Nat Med Ass 1977; 69: 103-04. 15. Greene HL, Slonim AE, Burr IM, Moran JR. Type I glycogen storage disease: five years of management with nocturnal intragastric feeding. J Pediatr 1980; 96: 590-95. 16. Greene HL, Helinek GL, Folk CC. Nasogastric tube feeding at home: a method for adjunctive nutritional support of malnourished patients. Am J Clin Nutr 1981; 34: 1131-38. 17. Greene HL. Nutritional supplementation in malnourished patients with cystic fibrosis Cystic Fibrosis Club Abstracts 1984; 25: 19.

simple short letter which was used for contacting probands with pyloric stenosis who had been operated on at the Hospital for Sick Children, London over thirty years earlier. Tracing was successful for 75% of patients, and it was interesting that for some of them the study provided their first opportunity to learn about the cause of

Anne J. Krush, Johns Hopkins University School of Medicine, Baltimore, MD, and Kathleen A. Evans, Medical Research Council Clinical Genetics Unit, London. Springfield, Illinois: Charles C. Thomas. 1984.

are

6.

B, Krauss R, Kleman K, Simmons E, Chiu D. Reduced total serum cholesterol (TC), high density (HDL) and low density (LDL) lipoproteins in patients with sickle cell anaemia (SCA). Blood 1979, 54 (suppl I): 30A. Kramer MS, Rooks Y, Washington LA, Pearson HA. Pre- and postnatal growth and development in sickle cell anemia. J Pediatr 1980; 96: 857-60. Vichinsky EP, Lubin BH. Sickle cell anemia and related hemoglobinopathies. Pediatr

surveillance, than their British counterparts. In contrast, there is a

Family Studies in Genetic Disorders

Americans

5. Lubin

and

their upper abdominal scar! The book also describes how best to record data so that it is in a readily available form for genetic analysis. There is no doubt that this book is unique and will become a classic. It should be mandatory reading for everyone involved with a family study. Clinical Genetics, Department of Paediatrics and Child Health,

SARAH BUNDEY

University of Birmingham

Acute

Coronary Care

PrincIples and Practice. Edited by Robert M. Califf and Galen S. Wagner, Duke University Medical Center, Durham, North Carolina. Boston and Dordrecht: Martinus Nijhoff. 1985. Pp 556. Dfl365;$99.50; 75.95. CONCEPTS of acute myocardial ischaemia and infarction have

undergoing continuous evolution over the last 25 years. Recently, attention has been directed mainly at mechanisms of the acute event (particularly in regard to thrombosis) and the potential role of drugs both in limiting infarct size (especially thrombolytic agents) and in preventing reinfarction and death after recovery from

been

exciting area of research and a large knowledge acquired in the last decade. Nevertheless, the therapeutic implications are far from established; the

acute event.

amount

of

This is

an

has been

modes of treatment are being introduced with immense enthusiasm but it is uncertain whether such therapies should be given routinely to patients with acute ischaemic events. This volume attempts to summarise present knowledge in the field in 58 chapters, each of which is quite short but well referenced. Standards of writing, presentation, and illustration are high. The book is outstandingly successful in painting the pathophysiological background of ischaemic heart disease. Thus, contributions on regulation of myocardial blood-flow distribution, relation between coronary blood flow and injury (reversible and irreversible), spasm, thrombosis, and autonomic imbalance are most instructive. This book is not a working manual for doctors and paramedical staff in the coronary care unit. While it is true that the proven value of such units is largely confined to prevention and treatment of arrhythmias and conduction disturbances, no more than 40 pages are devoted to this topic; there is virtually no discussion of the new