Assessment of Nutritional Status: Functional Indicators of Pediatric Nutriture

Symposium on Nutrition

Assessment of Nutritional Status: Functional Indicators of Ped iatric N utritu re

Noel W. Solomons, M.D. *

The role of nutrition in pediatric practice is changing. Recent evolution has been brought about in part by newer modalities of delivering nutrients, such as total parenteral nutrition and enteral (tube) feeding, which are discussed elsewhere in this volume. Nutrition has also taken on a new perspective in light of the demonstration of secondary nutrient deficiencies in chronic diseases of childhood such as inflammatory bowel disease 36 and cystic fibrosis. 37 With improvement in biologic knowledge and alimentation techniques has come an increased need to evaluate the nutritional status of children in a precise, reproducible, and meaningful fashion. Are the stateof-the-science (or state-of-the-art) approaches to nutritional status assessment responsive to the new realities and the new demands of pediatric nutrition? Indeed, the traditional nutritional indicators may not provide a quality of nutritional status assessment that complements in sophistication the modern developments in nutritional intervention or newer concepts for biologic inquiry. We must update our conceptual approach and our technical capacities for nutritional status assessment and devise innovative ways to apply them to pediatric practice.

CONVENTIONAL APPROACHES TO NUTRITIONAL STATUS ASSESSMENT Perhaps the oldest form of assessment is the "calorie count," the timehonored estimation of daily dietary intake. This was relied upon based on the erroneous assumption that malnutrition was the result of a reduced consumption of nutrients. This is one causal factor, but, as pointed out by Herbert,18 manifestations of nutrient deficiency can derive not only from altered intake, but also from reduced absorption, excessive wastage, im-

*Affiliated

InvestigatoriVisiting Professor, Institute of Nutrition of Central America and Panama, Guatemala City, Guatemala

Pediatric Clinics of North America-Vol. 32, No.2, April 1985

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Table 1. Generic Summary of Pitfalls and Limitations of Static Indices in the

Assessment of Nutritional Status Samples may be subject to exogenous contamination Circulating nutrient levels may be homeostatically regulated and protected so that stores are depleted before circulating concentrations decline. Circulating nutrient levels may be independently affected by infections. diseases, hormonal status, drugs, other deficiency states, etc. Binding capacity for a nutrient (available binding-sites on transport proteins) may determine circulating levels. The index may reHect only recent intake of nutrient or precursor and not reHect stores. Convenient biopsy material such as hair or blood cells may only represent active (target) tissue, while storage pools may be inaccessible for biopsy. Interpretation can be obscured by "shot-gun" therapy with the nutrient.

paired utilization, or increased requirements for nutrients. Monitoring dietary intake can be important in the nutritional management of a child at risk of malnutrition and for determining whether the prescribed intake goals are being met, but, as pointed out by Kerr et al., 22 it does not measure nutritional status. The models for the commonly employed anthropometric and laboratory indices of nutriture do not derive from clinical medical practice. Rather, they originated in large population surveys such as the international field studies of the Interdepartmental Committee on Nutrition in the National Defense (ICNND) and the domestic surveys of the Health and Nutrition Examination Survey (HANES) and the Ten State Nutrition Survey 1968-1970 (Ten State). Standards for height-for-age, weight-for-age, and weight-for-height were derived from the Boston and Iowa curves, and most recently the NCHS data have been used to define growth adequacy and growth retardation, obesity, and protein-energy malnutrition. With respect to biochemical laboratory indices, determinations used in field surveys, such as urinary excretion of vitamins and metabolites, vitamin-dependent red cell enzymes, and plasma or tissue levels of vitamins and minerals, have been adopted by and adapted to the hospital or clinical laboratory. Such measurements, however, are usually reserved for special clinical inquiries. Most often, a cursory "nutritional screening" assessment is made by the physician or nurse practitioner on the basis of anthropometric data (height, weight) and the "routine" laboratory tests that are part of the autoanalyzer batteries (total serum proteins, serum albumin, serum iron and transferrin saturation, hemoglobin, hematocrit and red cell indices~ BUN, and creatinine). Urinary creatinine can also be included. Such a "profile" is not without merit, as abnormalities often indicate nutritional impairment. It should by no means be considered to be a systematic or comprehensive panel for nutritional assessment, however. The aforementioned classes of anthropometric and laboratory tests measure a level of attainment, or define an equilibrium of plasma or tissue saturation. We have labeled this type of indicator a static index of nutritional status. 35 Under appropriate circumstances, each can provide useful information about human nutrition, but with each there are inherent pitfalls to be avoided and caveats to be recognized (Table 1). As nutritional status

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assessment in pediatrics is often asked to detect marginal states of undernutrition or to monitor serially the changes in nutriture in response to disease or to nutritional interventions, the limitations of static indices become more apparent and more pronounced. PITFALLS AND LIMITATIONS OF STATIC INDICES OF NUTRITURE The overall purpose of nutritional assessment is to determine either total-body content of a given nutrient, or the size of the available body stores of a nutrient. Circulating (serum or plasma) concentrations of a nutrient have potential disadvantages as a nutritional index, since they are often homeostatically regulated. In such situations, they may reflect nutriture, as tissue stores would become depleted before circulating levels begin to change. This is exemplified by calcium, where bone demineralization proceeds with maintenance of normal plasma calcium levels. On the other hand, some vitamins and minerals require specific carriers in the circulation. Depletion of the transport proteins would lower· plasma levels of the nutrient even in the absence of its shortage in the body. Thus, primary changes in the concentration of retinol-binding protein or transferrin will alter the concentrations of vitamin A and iron even when the individual is sufficient with respect to these two nutrients. Similarly, diseases (specifically infections and inflammatory illnesses), drugs, and deficiencies of other nutrients can alter the circulating levels of certain nutrients. Concentrations of zinc, iron, and vitamin A are reduced during infectious/inflammatory stress, while levels of copper are elevated. Finally, plasma and serum samples can be contaminated with exogenous sources of a nutrient, either from release from hemolyzed red cells or, as in the case of trace minerals, from materials used in obtaining, storing, handling, or analyzing the sample. 34 Other body fluids-saliva, sweat, cerumen-have been used as materi~l for nutrient determination. Their use invokes many of the same pitfalls as mentioned for serum and plasma. Urinary excretion of a nutrient or a metabolite is another alternative for static measures of nutritional status. The first limitation is obtaining a clean, non-admixed, quantitative collection of urine, a difficult task in children, especially the very young. The existence of renal conservation mechanisms that respond to nutritional depletion is a prerequisite for the urinary output of a nutrient to be a sensitive and reliable index. For instance, if the urinary excretion reflects only the recent dietary intake of a nutrient, a deficient individual may excrete a normal or increased amount in the urine if he or she has recently consumed the nutrient. Moreover, the changes in the partition of circulating nutrients between free and bound (filterable and nonfilterable) forms will confound evaluation of nutritional status based on urinary outputs. Furthermore, the pathogenesis of nutrient depletion involves the pathologic excess renal wastage of the nutrient. In such cases, one sees an elevated urinary output in the face of a total-body deficiency. Assaying tissue levels is another approach, but only a few tissues of

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the body are readily available for easy, nontraumatic biopsy. Such tissues include the circulating cellular elements (erythrocytes, leukocytes, and platelets), hair, nails, skin, and buccal mucosa. Adipose tissue, muscle, bone, bone marrow, or liver biopsies are usually excessively invasive and inappropriate for most diagnostic situations for nutritional status evaluation in children (or adults). Whether a given biopsy tissue represents an active (target) tissue for the nutrient or a storage site influences its inherent utility as an index for nutritional assessment. When the biopsied site is a target tissue, the forces of homeostatic regulation may come into play. As with any other nutritional index, a tissue level should reflect total-body nutriture or available reserves. This fact has been illustrated poignantly in the context of nutritional hair analyses. 17

HISTORY AND PHYSICAL EXAMINATION FOR NUTRITIONAL SIGNS AND SYMPTOMS The role of the clinical history and the physical examination must be placed in its proper perspective in terms of the new and emerging demands for nutritional assessment in modern pediatrics. In fact, little attention is usually given to the assessment of patients for the classic signs and symptoms of nutrient deficiencies or to the pattern of clinical manifestations in the classic deficiency syndrome of marasmus, kwashiorkor, infantile beri-beri, pellagra, or even to the more recently recognized clinical syndromes of trace mineral (zinc, copper, selenium, chromium, molybdenum), essential fatty acid, or biotin deficiencies. Moreover, our present review does not place emphasis on the detection of physical signs such as glossitis, cheilosis, angular stomatitis, parotid enlargment, skin lesions, subperiosteal hemorrhages, etc. This is not to deny the importance of the recognition of the physical features or symptoms of nutrient deficiency states by the clinician. Physical diagnosis texts and bedside teaching in the medical school should continue to ensure competence in recognizing these signs, symptoms, and syndromes. The relative de-emphasis is motivated more by strategic considerations-namely, that reliance on the history and physical examination as a primary tool in evaluating and monitoring nutritional status is inappropriate given the changing demands in clinical practice and the new realities in nutritional biology. The evolution of nutritonal depletion in an individual involves a sequential course,30 beginning with the de saturation of tissue stores with associated deficits in function. Only later, in the late and final stages of depletion, do physical signs and clinical symptoms become manifest. If a child is under medical management and surveillance, correctable nutritional deficiencies should not generally be allowed to evolve into fullblown clinical syndromes before they are recognized and treated. They should be anticipated on the basis of the clinical circumstances and should be detected earlier by the judicious use of anthropometric and laboratory indices as outlined above and of functional indices discussed below. The clinical examination shares a problem in common with laboratory indices-namely, the nonspecific nature of the indicators, in this case signs

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and symptoms. Alopecia and a scaly dermatitis, for example, may be due to nutritional or to nonnutritional disease. And, if nutritional, they may be related to deficiencies of niacin, riboflavin, protein and energy, zinc, biotin, and/or essential fatty acids. The latter three deficiencies are of special note since their description and recognition are relatively recent, all have been reported in children, and all have been observed in children undergoing total parenteral nutrition. 3, 25, 27 However, in the clinical setting, faced with a child on TPN with alopecia and skin lesions, one would still be forced to resort to specific diagnostic tests to determine which among the potential nutrients was deficient in the given patient. Pediatricians and nurse practitioners are obliged to develop and master the bedside recognition of nutritional-deficiency-related differential diagnoses. Hopefully, in the late twentieth century, however, the major use of these skills will be reserved for situations in which advanced nutritional depletion is the result of factors that occurred prior to presentation of the child (for example, poverty, famine, child abuse, abberant dietary practices) or will be unavoidable (for example, terminal wasting illness). They should not be the routine instruments for the assessment of nutritional status in the context of usual, periodic pediatric care.

CONCEPT OF THE FUNCTIONAL INDEX FOR NUTRITIONAL STATUS ASSESSMENT The demands for nutritional diagnosis in pediatrics have become more complex. The conventional anthropometric and laboratory means have obvious limitations and pitfalls. The history and physical examination is nonspecific, requiring always a laboratory confirmation or a therapeutic trial, and signs and symptoms appear so late in the course of depletion as not to offer a sensitive, precocious detection of the problem. Faced with the need to detect marginal malnutrition, several authors have introduced the concept of the functional assessment of nutritional status. 7-9, 35 Functional assessment, like the static approach, was conceived in the context of international surveys and surveillance,8, 29 but it shows outstanding potential for use in the clinical context as welL Simply stated, a functional index of nutritional status is a test of a physiologic or behavioral function that is dependent upon a given nutrient(s). Perhaps the original functional index of nutritional status was, indeed, growth, the growth pattern of a child being sensitive to alteration by deficiencies of many nutrients. But it was used more in a qualitative than a quantitative sense; formal growth standards were not introduced until the 1940's, and sophisticated analysis of growth velocity dates from the postwar era and is associated with Tanner and his colleagues in London. 40 The first formal, standardized test that could be called a functional index of a nutrient was introduced by Hess in 1913. 19 The Hess test, which involves the enumerations of capillary petechiae under increased venous pressure, was used to detect subclinical scurvy. In the 1930's, the next major breakthrough in functional nutritional assessment was developed in the context of the association of impaired dark adaptation response to early vitamin A deficiency. 10, 43

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CLASSIFICATION OF FUNCTIONAL INDICES OF NUTRITURE With the concept of functional assessment established, and its relevance to marginal malnutrition states suggested, Dr. Lindsay Allen and the author35 felt it necessary to catalogue the various approaches that had been taken-often in the context of research-to applying functional tests to the assessment of human nutriture. We identified almost 200 references, and quickly realized that some attempt to articulate and classifY this distinct array of tests was needed, especially if we were to foster the clinical application of this diagnostic approach. We found it convenient to classify functional tests on two levels: (1) in terms of the level of observation, as this would define the kinds of technical skills and laboratory facilities necessary as shown (Table 2) in terms of the anatomic/biologic systems investigated (Table 3). With regard to the level of observation, we found it convenient to divide the test procedures into four categories. First are those that are performed in in vitro systems, to reflect the in vivo capacity of the corresponding function. A straightforward example is the prothrombin time, which hopefully reflects the capacity of the clotting-factor-activated coagulation cascade in the blood stream itself. The in vitro platelet aggregation test has a similar rationale. A wide variety of in vitro functional tests relate to immunity (host-defense functions); a fundamental requirement of these tests is the ability to harvest fluids, cells, or other tissues and maintain them under physiologic conditions. The next categories were measurements made in vivo in the subject him or herself. Tnese can be subdivided into response that can be measured only if elicited or induced by an external stimulation or by the administration of a labeled substrate or a nutrient load. The glucose tolerance test is an example in this area. There were also in vivo responses that were spontaneous expressions of normal physiology. Such tests, as exemplified by dark adaptometry, only require a standardized testing system to quantifY the response, be it sensory, motor, excretory, etc. Finally, we identified a group of functions at the level of the whole organism, functions such as work output and lactation. Of specific importance in pediatrics are growth, sexual maturation, and cognition. This system is shown in Table 2. With regard to the alternative classification scheme related to anatomic and biologic systems, we grouped the index functions into measurements of structural integrity of cells and tissues; host defense capacity; cellular and tissue transport; hemostasis; reproduction; nervous function; work capacity; and hemodynamics. The classification scheme by systems is shown in Table 3.

APPLICATION OF FUNCTIONAL ASSESSMENT IN PEDIATRICS It is important to realize that many of the functional tests in use have been identifed in the context of studies or surveys of children. Those tests that have been reported for pediatric subjects are indicated as such in Table 2. The fact that so many tests emerged in a pediatric context may

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Table 2. Functional Tests of Nutritional Status: Classification by Level of Testing IN VITRO TEST OF IN VIVO FUNCTIONS

INDUCED RESPONSES AND LOAD TESTS IN VIVO

SPONTANEOUS IN VIVO RESPONSES

(J} (J}

RESPONSES OF INDIVIDUALS OR POPULATIONS

t'l (J} (J}

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Leukocyte chemotaxis Leukocyte phagocytic activity Leukocyte bactericidal capacity Leukocyte glycolysis Leukocyte iodination Leukocyte reduction of NBT Serum opsonic activity Lymphocyte (T-cell) blastogenesis White cell interferon production Erythrocyte fragility 75Se uptake by erythrocytes 66Z n uptake by erythrocytes Prothrombin time Platelet aggregation d-U ridine suppression test l4C-formate conversion in lymphocytes Tensile strength of skin

Experimental wound-healing Collagen accumulation in implant sponget Rebuck skin window Delayed cutaneous hypersensitivity Antibody formation Vasopressor responset Radioiron absorption t Radiocobalt absorptiont Thyroid radioiodine uptaket Retinol relative-dose-response Post-glucose plasma chromium response Post-glucose urine chromium response Mixed-function oxidase (l'C0 2) breath testt 14C-histidine (l'C0 2) breath testt I'C-serine (l4C02) breath testt Histidine load for urinary FIGLU Histidine load for urinary hydantoin propionic acid Purine load test for urinary xanthine Sulfur amino acid load test for abnormal sulfur metabolites Sodium bisulfite load test for abnormal sulfur metabolites Glucose load/exercise test for lactate and pyruvate Tryptophan load test for urinary xanthurenic acid Leucine load test for urinary 3-hydroxyisovaleric acid

Dark adaptation Central scotoma size Color discrimination Taste acuity Olfactory acuity Abducens (VI cranial nerve) function Nerve conductiont Skin conductivity Electroencephalography Sleep pattern Muscle function/work capacity Volatile hydrocarbon excretion breath test Capillary fragility (Hess) test Sperm count

*Not generally applicable to a pediatric population. tInappropriate for use in children by virtue of invasive or painful procedures or by virtue of in vivo radiation exposure.

Work productivity Play activity Spontaneous activity and inquiry Growth velocity Birthweight Sexual maturation Cognitive performance Lactation performance* Fertility* Fecundity* Disease resistance Social competence

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Table 3. A Systems Classification of Functional Indices of Nutritional Status

SYSTEM/FUNCTIONAL TEST-

Structural Integrity Erythrocyte fragility Capillary fragility Tensile strength of skin Experimental wound healing Collagen accumulation in implant sponge Lipoprotein peroxidation (breath ethane/pentane) Host Immune Defense Leukocyte chemotaxis Leukocyte phagocytosis Leukocyte bactericidal capacity Leukocyte metabolism (glycolysis, iodination) Serum opsonic activity White cell interferon production Lymphocyte blastogenesis Delayed cutaneous hypersensitivity (skin test) Rebuck skin window Transport Intestinal absorption Radioiron absorption Radiocobalt absorption Plasma/tissue transport 65Zn uptake by erythrocytes 75Se uptake by erythrocytes Retinol relative-dose-response Post-glucose plasma or urine response Thyroid radioiodine upatke Hemostasis Prothrombin time Platelet aggregation Reproduction Sperm count Nervous System Function Dark adaptation Color discrimination Central scotoma Olfactory acuity

NUTRIENTS RELATED TO FUNCTION

Vitamin E. selenium Vitamin C Copper Zinc Zinc

REPORTED USE IN CHILDREN

POTENTIALLY INAPPROPRIATE FOR CHiLDRENt

+ + + +

Vitamin E, selenium

Protein-energy, Protein-energy, Protein-energy, selenium Protein-energy,

zinc, iron iron iron,

+ + +

iron, zinc

+

Protein-energy Protein-energy Protein-energy, zinc, copper Protein-energy, zinc

+ + +

Protein-energy

+

+

Iron Iron

+

+ +

Zinc Selenium Vitamin A Chromium

+ +

+

+

Iodine Vitamin K Vitamin E, zinc Energy, zinc

+ +

Vitamin A, zinc, vitamin E + Vitamin A Vitamin A, vitamin E Vitamin A, vitamin B12 , + zinc Taste acuity Vitamin A, zinc + Nerve conduction Protein-energy, vitamin + + B12 , thiamin Skin conductivity Protein-energy + + Abducens (VI cranial nerve) function Thiamin + Electroencephalography Protein-energy + Sleep pattern Protein-energy + Table continued on opposite page

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Table 3. A Systems Classification of Functional Indices of Nutritional Status (Continued) POTENTIALLY REPORTED SYSTEM/FUNCTIONAL TEST*

Work C apacity/ Hemodynamics . Task performance/endurance VO z max VO z submax Heart rate (cumulative) Vasopressor (tilt table) response Unclassified d-uridine suppression test

NUTRIEJ'(TS RELATED TO

USE IN

INAPPRO· PRIATE FOR

FUNCTION

CHILDREN

CHILDREJ'(t

Protein-energy, Bj, B" B6 , iron Protein-energy, Protein-energy, Protein-energy, Vitamin C

vitamins

+

iron iron iron

+ +

Vitamin BIz, folacin

+ + +

*Tests of pathways in intermediary metabolism and those of the whole individual or populations have not been included in this classification scheme. tlnappropriate for use in children by virtue of invasive or painful procedures or by virtue of in vivo radiation exposure.

represent a commentary on the limitation of the other diagnostic approaches and the perceived need to improve the approaches to nutritional assessment of children. The scope of this review does not permit an exhaustive recounting of the experience with functional assessment in children. Examples of some of the more important and instructive applications will suffice to illustrate the state-of-the-art of applications of functional indices in pediatrics. Growth and Body Composition The most important functional index of nutriture in children is growth. Both ponderal and linear growth can be used in functional assessment, the objective is not the same as that of conventional anthropometry-that is, to determine the adequacy of height and weight attainment-but the functional index relates to the velocity of growth; as such, it requires serial measurement. Based on the precision with which height and weight of young children can be measured, theoretical estimates of the minimal detectable real increments have been made;45 changes in height can be measured with more sensitivity and assurance than changes in body mass, but the procedures to obtain accurate measurements of stature are more complex and rigorous. An example of the application of growth as a functional index can be seen in the work of Kirschner et al., 23 who studied children presenting with juvenile Crohn's disease. Shown in Figure 1 is the change in growth attainment and growth velocity of a typical patient whose rate of height gain slowed prior to the onset of clinical symptoms. Aggressive nutritional therapy reversed the growth arrest and stimulated compensatory growth. Growth has also proven to be a useful index of nutritional status and dietary adequacy of breast-fed infants at different stages of lactation. Information that is even more articulate and dynamic as a reflection of nutritional status can be gained by assessing changes in body composition.

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Age, years I 2 3 4 5 6 7 8 9 10 II 12 13 14 15 16 17 18 19

eM 180 97 65 50 15 3

170 160 150 140 130 120 110 100 90 80 70 60 50

t

Ox a Rx Figure 1. The pattern of linear growth (main curve) and the interval changes in growth velocity (insert) in a child who presented with Crohn's disease and growth arrest. Initiation of nutritional and medical therapy (arrow) reversed the growth arrest, stimulating recovery of stature. From Kirschner, B., Voinchet, 0., and Rosenberg, I. H.: Growth retardation in inflammatory bowel disease. Gastroenterology, 75:504-511, 1978. Reproduced with permission.

Golden and Golden l l showed that zinc deficiency predisposed to a greater gain of new tissue as fat during nutritional repletion of children with marasmus and kwashiorkor. In zinc adequacy, a greater fraction of weightgain was as lean tissue. Stable isotope technology using heavy water-2 H 2180--can now be applied to the precise assessment of body composition change in children. 31 Also under development are methods to assess body composition using electrical impedance. 24 Red Cell Fragility The antioxidant nutrients-vitamin E and selenium-protect cells against the oxidative destruction of the unsaturated lipids in membranes. Gordon et al. 14 developed a quantitative in vitro test of red cell fragility in the presence of an oxidative stress, hydrogen peroxide, to assess tocopherol deficiency in children. The Gordon test was used recently by Sokol et al. 33

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as a functional index of vitamin E nutriture in children with cholestatic liver disease; in cholestasis, the static index of vitamin E status is confounded by a disease-related elevation of circulating lipoproteins, elevating serum vitamin E levels out of proportion to body stores. Glucose Tolerance The analytic determination of chromium and chromium compounds is so tedious and treacherous,l1 that changes in physiologic responses in relationship to a supplemental trial of chromium is the most practical diagnostic approach. Since chromium deficiency influences the action of insulin on peripheral tissue, impaired glucose tolerance is a consequence. The glucose tolerance test has been used to assess chromium status of children with protein-energy malnutrition. 15, 20 Immune Function Many components of the host immune defense system are susceptible to damage by nutrient deficiencies. 5 Clinical tests of all limbs of the immune system have become fairly routine in hospital laboratories. The most common use delayed cutaneous hypersensitivity via skin test antigen reactivity. White cell chemotatic migration and in vitro mitogen-stimulated blastogenesis of B- and T-cell precursor lymphocytes are also widely available. Using pediatric zinc depletion as an example of a nutrient deficiency state, each of the aforementioned immunity tests has been used to assess zinc status and the response to zinc therapy. 6, 12, 26, 44 Changes in thymus size is yet another interesting immune index. 13 Its determination is conventionally performed by thoracic x-rays, exposing the subject to radiation. Nuclear magnetic resonance (NMR) scanning will potentially provide a nonradioactive, nonhazardous means to quantify nutrient-responsive changes in the size of the thymus and other lymphoid tissues. Important pitfalls in the use of immune indices include the fact that disease per se impairs immunity, that many nutrients can influence the same function, 5 and that pharmacologic amounts of some nutrients can stimulate immune function even where a preexisting deficiency of this nutrient was not the initial cause of immunodepression.

NOTES ON DIAGNOSTIC DECISION-MAKING Increasing sophistication in diagnostic deCision-making in clinical medicine has developed in recent years. 16, 21 It has been recognized that converging indicators from a number of indices are more reliable than any single abnormal values. This derives from the realization that an "abnormal" value represents a probability statement, not an absolute classification. Designation as abnormal is based on a finding outside of the "limits of normal," or beyond a cprtain cut-off level. This cut-off criterion usually represents the upper or lower tail of the distribution of values in a "healthy" reference population. If one assumes normal (Gaussian) distribution and a two standard deviation displacement from the mean as the accepted cut-off level, then 2.5 per cent of the healthy individuals in the population will

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have "abnormal" values. A similar probability issue will obtain with functional assessment if the performance is indexed to the distribution of values in a normal population. In children, such standards would likely be agedependent, and care would have to be taken to use the appropriate cut-off for a given patient. However, with respect to functional indices, this conventional approach is not ideally suited to diagnostic decision-making. A fundamental limitation is the lack of large bodies of normative data on the various indices in healthy populations of children. Moreover, functional tests are often more difficult to standardize among laboratories than are simple biochemical measures. A unique difference between functional and static indices, namely the tendency of performance to reach a certain optimal plateau, opens up a new approach to the definition of nutritional adequacy and inadequacy. With plasma levels of nutrients we have the possibility of an increasing circulating concentration operating as a linear response to nutrient intake even after the point of full nutritional repletion has been reached. Physiologic functions generally reach a stable peak level within a given person after the nutritional limitations have been corrected. In other words, if an individual has deficient immune function due to a nutrient deficit, the restoration of body reserves will improve the function only to a given level, at which point the performance will plateau at a given level for that individual. This allows us to rephrase the diagnostic question when applying a functional index. Instead of asking if an individual's performance is within the confidence limits for a well-nourished peer group, we can ask if that individual has enough of a nutrient supply to maximize his or her performance on a nutrient-dependent function. Logistically, this often requires serial measurement of the function before, (? during), and after a therapeutic trial of supplementation with the nutrient in question. This gives a clearer end-point to the definition of nutritional adequacy than is offered by the static indices of nutriture. FUNCTIONAL INDICES INAPPROPRIATE FOR CHILDREN Certain functional indices are inappropriate for children. These include functions that apply only to sexually mature adults, tests that involve radioactive exposure, and tests that are excessively invasive or painful. For instance, sperm production and testosterone responses have been used to assess zinc status in men,1. 28 but puberty is an obvious prerequisite for these elevations. Likewise, fertility and lactation performance are being used in population studies of adult women2 , but would be inappropriate indices in a population of schoolgirls. On the other hand, delayed menarche may be useful in adolescent girls if used in association with other biologic markers of development such as bone age and Tanner staging. A relative contraindication for the use of a functional index in pediatrics is the requirement for the use in vivo of radiOisotopes. The intestinal uptake of 59 Fe is a sensitive index of bone marrow iron stores. Although this fact has been demonstrated widely (including in a cohort of German children),4 its generalized use to assess pediatric iron status would, of course, be

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condemned. A surrogate for the long-half-lived iron radioisotopes are the rapidly excreted radiocobalt isotopes 58CO and 60Co; the fractional excretion in 6 hours has been used to assess "iron absorption" capacity,39, 41, 42 but even this radiation exposure (equivalent to that of a Schilling test of vitamin Bl2 absorption) is best avoided in children if possible. The radioiron or radiocobalt absorption tests might be considered in a pediatric patient, however, when the alternative for assessing iron status would be a bone marrow aspiration. There are indeed instances in which the conventional static indices of iron status are altered by disease. In chronic inflammatory bowel disease, for example, both transferrin and ferritin metabolism are altered, obscuring the meaning of the low circulating proteins as indicators of iron nutriture. If a patient would need baseline assessment of iron status and regular surveillance, and assuming that the duodenal mucosa is intact, an alternative to serial bone marrow sampling to guide iron replacement therapy in such a patient would be isotopic absorption tests (cobalt or iron). Despite the radiation exposure, they might be the preferred alternative and the less invasive diagnostic procedure in comparison to bone marrow aspiration. The final classes of diagnostic procedures for functional assessment of nutriture that might be contraindicated in children are those in vivo tests that involve electrostimulation (nerve or neuromuscular conduction studies) or those of hemodynamic responsiveness or maximal work (play) capacity. However, the technical development of appropriate, painless, nonstressful, and standardized surrogates for the conventional physiologic procedures used in adults is one of the challenges for the future of functional evaluation of nutritional status in children.

CHALLENGE FOR THE FUTURE: ADAPTATION OF FUNCTIONAL INDICES TO CHILDREN

As discussed above, not all procedures used for functional testing have a risk benefit ratio that makes them appealing for pediatric application. For other tests cited by Solomons and Allen,35 however, adaptation of the procedure might be necessary to improve their usefulness in children. In vitro tests present only the theoretical limitation that enough cells (red cells, granulocytes, lymphocytes, macrophages, or platelets) can be harvested from a quantity of blood that is acceptable; that is, hemoglobin status or hemodynamics are not jeopardized in obtaining the sample. For example, if 50 ml of blood are routinely used in standard adult procedures, a "miniaturized" or "micromethod" might have to be developed to make do with a considerably lesser volume from an agent. Voluntary collaboration and attention-span limitations might compromise the performance of young children on interactive cognitive tests or sensory function tests such as color discrimination or dark adaptation. We were successful in applying the rapid dark adaptation test to children as young as 4 years,38 but for infants and toddlers some ingenous further modification of the visual test procedures would be needed. This is also true for taste and olfactory acuity tests and visual-field assessment in the

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very young subject. Another novel approach for in vivo loading tests involving the excretion of urinary metabolites would be to impregnate diapers with color-reacting indicator reagents. This might obviate the need for catheterization, suprapubic punctures, or tedious quantitative balance collection procedures to quantify urinary excretion. CONCLUSION

The assessment of nutritional status is becoming increasingly important in pediatrics in several contexts: (1) diseases that predispose to specific nutrient depletion; (2) drug, radiation, or surgical therapies with potential antinutritional effects; (3) inborn errors of metabolism involving nutrient utilization; and (4) intervention with oral/enteral or parenteral nutritional support regimens. Nutritional status can be assessed by physical examination and history, but recognizable clinical signs and symptoms appear only in the advanced stages of a nutritional problem. Serial monitoring and detection of marginal (subclinical) degrees of malnutrition require the judicious use of the other modalities of diagnostic assessment of nutriture, namely anthropometric; hematologic and biochemical (static); and physiologic/behavioral (functional). The static indices of nutritional status are important, but they have limitations and pitfalls that are not always recognized. Total reliance on blood and tissue levels of nutrients, for example, will lead to serious over- or under-diagnosis of many deficiency states. They may also fail to indicate reliably the response to nutrient supplementation for repletion. Tests of the physiologic functions subtended by and dependent on certain nutrients-functional indices of nutritional status-have an important and emerging role to play in the assessment of nutriture in pediatric as well as adult patients. They can be used to confirm or refute the indications given by conventional static indices, and they can be used longitudinally to monitor changes in nutritional status. They also have pitfalls and limitations, and some procedures may be unsuitable for children, or may need special pediatric adaptation. On the other hand, they are often interactive and are frequently less invasive and less stressful than blood tests or urine collections. Diagnostic decision-making with functional indices differs at times from that for static indices, with an individual's optimal response being the decisive criterion. Most importantly, functional indices are based on the biologic significance to the organism of a given nutrient and serve to guide the practitioner to consider the potential functional consequences of each nutritional problem. Today, nutritional well-being should mean more than a computer print-out sheet of laboratory values all referenced to the "limits of normal." Functional assessment of nutritional status permits a more holistic determination that the biologic purposes served by the nutrients in human metabolism are being adequately-if not optimally-fulfilled. Greater attention to functional assessment in children should be given. It will pave the way for improvements and refinements in the technical and conceptual bases for this diagnostic approach in pediatric medicine.

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