Contents - Previous

Research needs

J.C. WATERLOW (Chairman), J.G.A.J. HAUTVAST, C.J.K. HENRY, B. SCHÜRCH, P.S. SHETTY and R.C. WEISELL

1. Energy expenditure and metabolism
2. Protein metabolism and requirements
3. Body composition
4. Weight gain in children
5. Linear growth
6. Physical activity
7. Infection
8. Functional consequences
9. Variation
List of participants

1. Energy expenditure and metabolism

1.1. Energy expenditure of free-living populations
1.2. More measurements of activity patterns in free-living populations
1.3. Effects of carbohydrates in the diet on fat deposition

1.1. Energy expenditure of free-living populations

There is general agreement that more information is needed on total energy expenditure of free-living individuals, especially hard-working ones, including children, in developing countries.

The doubly-labelled water method can provide this information over extended periods of time. Unfortunately three problems in connection with this method have appeared: (1) some results do not seem biologically plausible; indeed, some astonishing figures were presented at this meeting, (2) there is a world-wide shortage of ¹⁸O, and (3) several mass spectrometers have produced unreliable data. More small-scale validation studies are therefore needed before large-scale studies can be justified.

1.2. More measurements of activity patterns in free-living populations

Just as important as knowing the total energy expenditure of free-living populations is to know their activity patterns. How do they change when dietary intake is supplemented or restricted? In particular, what changes occur in the discretionary activities that are so important for the quality of life?

There is a continuing need for the use of more conventional methods like time-motion studies in combination with indirect calorimetry and individually calibrated heart-rate measurements. Torun has software to analyse heart-rate data which he is willing to make available to other scientists. Manufacturers should be encouraged to produce a simple, relatively inexpensive respirometer that can be used to measure oxygen consumption easily and reliably in the field.

1.3. Effects of carbohydrates in the diet on fat deposition

This issue appears important in connection with the high carbohydrate content of diets in developing countries and dietary changes resulting from rapid urbanization. Urbanization is usually accompanied by a marked increase in dietary fat intake and a corresponding decrease in carbohydrate intake. Will this change in dietary energy substrates influence the capacity for physical performance, in terms of duration and intensity?

2. Protein metabolism and requirements

2.1. Amino acid oxidation
2.2. Amino acid requirements
2.3. Protein requirements during pregnancy and lactation
2.4. Control of urea recycling from the gut
2.5. Limits to the de novo synthesis of 'conditionally essential' amino acids
2.6. Special roles of particular amino acids

2.1. Amino acid oxidation

Control of amino acid oxidation is the key to understanding most aspects of protein metabolism. The overall rate of oxidation is determined by the amount and pattern of amino acids entering the pool and also by the energy supply. Although it has long been known that increasing intake of energy, particularly of carbohydrate, reduces nitrogen excretion and vice versa, virtually nothing is known about the mechanism of this crucial interaction.

2.2. Amino acid requirements

There is consensus that more work is needed both on the total amount and on the pattern of amino acid requirements at different ages. It is probable that the pattern differs for maintenance and for growth. It is not clear why, given an appropriate pattern of intake, the obligatory losses can seldom be met with an efficiency of more than 70%. We have almost no information about the extent to which, under stress, it is possible to economize amino acids by reducing obligatory losses, since almost all previous studies have been done on well-nourished subjects.

2.3. Protein requirements during pregnancy and lactation

Present estimates of protein requirements during pregnancy and lactation assume an efficiency of protein utilization in the range of 0.6 to 0.7. Reliable data, however, are not available to test this assumption. In addition to the unique endocrine responses during these physiologic states, variable rates of weight gain during pregnancy and weight loss during lactation may influence the efficiency of protein utilization significantly.

2.4. Control of urea recycling from the gut

An important area for research is the extent to which urea nitrogen can be salvaged in the large bowel and made available for metabolism, the conditions under which this salvaging occurs, and how far the products can be absorbed and utilized. Although isotopic methods are available for exploring these questions, the experimental evidence is scanty, and a high priority should be given to further research in this area.

2.5. Limits to the de novo synthesis of 'conditionally essential' amino acids

It is increasingly recognized that some amino acids, classically described as 'dispersible' or 'non-essential', may become limiting under conditions of high demand, such as rapid growth or in response to injury. Amino acids in this category are glycine, serine, proline, possibly arginine and cysteine. Collagen in particular, but also the acute phase proteins, contain disproportionately large amounts of these amino acids. It is therefore important to have more information on the rates of de novo synthesis that can be achieved under different conditions, and on factors that may affect those rates.

2.6. Special roles of particular amino acids

Research should be directed towards understanding the regulatory influence of particular amino acids with known or putative actions, such as glutamine, as well as the regulatory influence of overall levels of dietary amino acids on homeostatic, homeorhetic and functional responses. The question whether leucine has a specific effect on protein synthesis is not yet completely resolved.

3. Body composition

3.1. Methods of measurement
3.2. Composition of lean body mass
3.3. Composition of weight gain during pregnancy

3.1. Methods of measurement

Body composition should be measured in virtually all metabolic studies. Underwater weighing is often used as the standard measure of body fat against which other methods are compared. Unusual values for bone mass and density can, however, introduce errors. There are also problems in calculating body fat from skinfold measurements for subjects who are outside the scope of the original Durnin & Womersley equations, since the ratio of subcutaneous to intra-abdominal fat varies with age and gender, and perhaps also with ethnic group and BMI.

Most of the many high-technology methods that exist nowadays are not suitable for use in the field, particularly in the Third World. The greatest danger, at the moment, seems to be the uncritical use of bioimpedance measurements. Many cheap and easy-to-use bioimpedance measuring devices are on the market and used rather uncritically, i.e., without taking into account the many assumptions underlying the method. In many instances the formulae used to infer body composition from bioimpedance are not even known.

3.2. Composition of lean body mass

Estimates of muscle mass based on creatinine output suggest that underweight subjects have a larger ratio of visceral to muscle mass. As a consequence, functions such as BMR and protein turnover, when related to LBM, have higher values than might be expected. Therefore, for the interpretation of such measurements, it is important to partition the LBM, and we need better methods of doing this.

3.3. Composition of weight gain during pregnancy

Prepregnancy BMI appears to influence gestational weight gains associated with desirable pregnancy outcomes. Improved estimates of body composition during pregnancy are needed. Estimates of protein and energy requirements (and therefore P/E ratios) depend heavily on estimates of body composition. There are very few measurements, however, of maternal body composition during pregnancy in groups of women with diverse prepregnancy BMI and a wide range of gestational weight gains, as they occur in most populations.

4. Weight gain in children

4.1. Variability of weight gain and its effect on protein requirements
4.2. Factors limiting protein deposition
4.3. Effects of frequent versus intermittent feeding on growth
4.4. Quantitative and qualitative requirements for catch-up growth

4.1. Variability of weight gain and its effect on protein requirements

Traditional requirement estimates have been based on the assumption that growth occurs regularly from day to day. In reality this is not so, and the dietary intake must suffice to meet the demands of catch-up on 'good' days to compensate for growth failure on 'bad' days. The FAO/WHO/UNU Expert Consultation of 1981 attempted, for lack of factual evidence, to solve this problem in a purely empirical way, by adding 50% to the daily growth requirement, calculated as increment per month divided by 30. This situation is extremely unsatisfactory. We need more information on the day-to-day variability in weight gain. There is good evidence that the variability is greater under conditions of environmental stress; therefore information should be collected under different environmental conditions. Longitudinal studies assessing weight daily are needed, particularly in infants and young children. Although they would have to be collected over a long time period, similar data would also be useful in adolescents.

4.2. Factors limiting protein deposition

Why do children not grow faster, even when they receive plenty of protein, energy and other nutrients? Even the fetus in utero utilizes for growth only a modest proportion of the nutrients supplied to it. At the opposite end of the scale, in trauma and severe illness, it may be impossible to achieve a positive nitrogen balance whatever the nutrient supply. As has long been realized, the regulation of growth depends not only on nutrients but also on endocrine factors. More recently cytokines have been brought into the picture. We do not know how far infections and trauma may produce factors that inhibit growth. More fundamental research is needed in this area.

4.3. Effects of frequent versus intermittent feeding on growth

There is some evidence from animals, less from children, that the frequency of feeding is positively related to weight gain.

4.4. Quantitative and qualitative requirements for catch-up growth

The composition and amount of tissue deposited during catch-up growth varies. There is the need to define the extent to which the availability of specific nutrients limits or determines the pattern and amount of lean tissue deposition. As far as amino acids are concerned, the scoring pattern for the preschool child is almost that of tissue protein. Current recommendations based on theoretical calculations need to be tested under realistic conditions. More information may exist from premature babies, surgical patients and other groups than may be assumed when one only looks at the nutrition literature.

5. Linear growth

5.1. Potential causes of stunting
5.2. Reversibility of stunting

5.1. Potential causes of stunting

Large numbers of children in the Third World are retarded in their linear growth (stunted). This cannot be explained on genetic grounds. Research is needed at the cellular level on the mechanisms of linear growth retardation and delayed skeletal maturation. Infection may play an important role, perhaps primarily via anorexia. Dietary factors that could be involved include protein, specific amino acids, zinc, iron, calcium, and phosphate. Cytokines and IGF1 appear to affect bone growth, and bone growth inhibition seems to be part of the inflammatory response. Seasonal variations in linear growth have been observed in Nepal.

5.2. Reversibility of stunting

Evidence that stunting is reversible exists from studies of children changing homes, undergoing deworming, etc. Intervention studies need to be designed in such a way that effects of different nutrients, activity, etc., can be examined separately. The problem should be studied up to and including adolescence and puberty.

6. Physical activity

6.1. Effects of physical activity on metabolism and body composition
6.2. Energy intake and physical activity
6.3. Changes in life-style

6.1. Effects of physical activity on metabolism and body composition

Research is needed on the effect of physical activity on the efficiency of energy and nitrogen utilization and on nitrogen-sparing. Is there also an interaction between physical activity and nutrition affecting the maintenance of lean body mass? Bedrest leads to a catabolic state almost immediately. There are studies suggesting that physically active children grow faster than less active peers and that moderately active children spare protein. These findings are rather surprising and need to be confirmed by replication.

6.2. Energy intake and physical activity

The studies on seasonality presented at the IDECG meeting in Guatemala suggested that, in adults, when intakes are restricted, the need to maintain occupational activity takes precedence over maintenance of body weight. Data on children, however, seem to show that they react differently, decreasing activity but maintaining growth. In view of the evidence for widespread inadequacy of energy intakes in Third World children, more studies are urgently needed of the effects of marginal energy restriction on physical activity and of the long-term consequences for mental and behavioural development. Such studies should include observations on the effects of providing supplements of protein and energy. Another important subject, already mentioned, is the extent to which energy restriction reduces discretionary activities, particularly in women. This requires observational studies, probably by social scientists.

6.3. Changes in life-style

The two major changes occurring at the present time are massive migration from rural areas to towns, and an increasing number of elderly people in all populations. Both effects will in general lead to a reduced level of physical activity. This in turn will lead to a need for the food supply to have an increased nutrient density, i.e., better quality.

7. Infection

7.1. Interactions between energy, protein and amino acid intakes and cytokine responses
7.2. Methods of quantifying losses imposed by infection
7.3. Development of field methods for assessing the severity and intensity of infection
7.4. Interaction of protein-energy status, immunizations and immune status

7.1. Interactions between energy, protein and amino acid intakes and cytokine responses

It has long been known that undernourished subjects show a decreased, negative nitrogen balance in response to injury. They also have lower levels of pyrexia and leucocytosis and a smaller rise in protein turnover. There is also some evidence that in undernutrition the cytokine response is impaired, as if the body were attempting to maintain the integrity of its tissues at the expense of the appropriate response to infection and injury. This is an area where there is a clear need for more fundamental research.

7.2. Methods of quantifying losses imposed by infection

Decreased intake, decreased absorption and catabolic losses all lead to increased requirements for both protein and energy. The extra requirement is relatively greater for protein than for energy (see section on catch-up growth). At the present time the only practicable method of assessing the extent of these losses, apart from metabolic balances, is from the loss of weight. This may give rise to erroneous results in the presence of dehydration, as in cholera. It is difficult to visualize any method other than weight change that could be used in the field for assessing the losses that result from infection. We need much more information on the extent to which weight is lost and regained in a variety of field conditions, and on the time-course of these changes, if realistic estimates are to be made of the effect of infections on energy and protein requirements.

7.3. Development of field methods for assessing the severity and intensity of infection

Estimates of increments in requirement are difficult to make, since infectious stress depends at least in the kind, severity and duration of infection. Some infections which remain asymptomatic nevertheless seem to affect energy and protein metabolism and requirements. It would be desirable to find a simple indicator of infectious stress with predictive value for supplementary energy and protein requirements. Acute phase proteins, c-reactive peptide and alpha-amyloid protein might be indicators to be further explored in that sense, but blood samples need to be taken to assess these. Preferable would be noninvasive methods. The creatinine height index and the nitrogen/creatinine ratio were mentioned as promising examples that need to be further investigated.

7.4. Interaction of protein-energy status, immunizations and immune status

There is limited evidence from both field studies monitoring growth in young children and from metabolic balance studies in young children and adults that immunizations can affect nutritional status even when there are no apparent symptomatic responses. Because of the success of expanded programs of immunization, there is a need for further study of these effects.

There is also a need for further observations on the relationship between nutritional status and vaccine efficacy. There are relatively few previous studies, and the results are variable. In general live vaccines seem better able to produce an immune response than killed vaccines for which the amount of antigenic material is fixed.

Unlike humoral immune response, which is affected to only a limited degree or not at all by mild protein-energy deficiency, cell-mediated immunity seems more responsive and should also be investigated concurrently. Delayed cutaneous hypersensitivity has been used for this purpose in field studies with some success and does not require blood samples. However, there is some conflict of opinion about their value for prognosis in hospitalized patients with secondary malnutrition caused by disease or injury. Where blood can be taken and the necessary laboratory skills are available, a variety of other indices of cell-mediated and non-specific immunity can be used.

8. Functional consequences

A number of functional consequences of undernutrition have already been touched upon. However, we have very little information about the extent to which mild or moderate degrees of deficit affect physical and mental functions, and whether the relationships are linear or have a threshold. In adults, the BMI is increasingly used as a measure of chronic energy deficiency. There is some evidence that when the BMI falls below a level of about 17, functional impairments begin to appear, e.g., increased absenteeism from work, and in women low birth weight of infants. In children we know that severe stunting is accompanied by delays in mental development, but the concomitants of smaller deficits in linear growth have not been studied. This subject presents a major challenge for future work.

9. Variation

Variation in the daily weight gain of children has already been mentioned. It must be emphasized that for every biological function there is a range of variation both within and between subjects of any particular group. The conventional concept of safe level of protein intake recognizes the variability between subjects, but even here the assessment of that variability is based on information derived from quite restricted groups of people, mostly healthy young men.

In all future studies every attempt should be made to assess both within- and between-subject variation, because they have different implications. The former, for example, has been considered important in relation to the BMR and possibilities for adaptation. Perhaps both kinds of variability could be regarded as measures of environmental stress, causing populations to be less homogeneous than they would be in better conditions of nutrition and health.

List of participants

The l/D/E/C/G meeting in Waterville Valley, NH, USA, and these proceedings were funded by the United Nations University, the Nestle Foundation and the Nutricia Company.

This publication is available free of charge from the Secretariat of l/D/E/C/G c/o Nestle Foundation P.O. Box 581 1001 Lausanne Switzerland

Printed in Switzerland ISBN 2-88296-002-6 (c) I/D/E/C/G 1992

Contents - Previous