Basic concepts in nutrition: Energy and protein balance

Jens Kondrup

Nutrition Unit-5711, Rigshospitalet University, 9 Blegdamsvej, 2100 Copenhagen, Denmark

Received 5 February 2008; accepted 8 February 2008

Learning objectives

- To know basic concepts in energy and nitrogen balance during health and disease

- To be familiar with terms homeostasis, homeorhesis,adaptation and accommodation.

Basic concepts

- Homeostasis refers to the metabolic regulatory mechanisms that act to keep the body in a    

  constant condition with respect to physiologic function and reserves of energy and other

  nutrients.

- Homeorhesis refers to regulatory mechanisms that allow the body to change from one  

  homeostatic, stable condition to another in a programmed fashion, e.g. growth during childhood

  or the onset of lactation.

The concept can be extended to weight gain after a period of weight loss, and perhaps also to weight loss itself, as far as it follows a programmed pattern. Mild disturbances of homeostasis

or homeorhesis lead to adaptation, without loss of function, e.g. the decrease in resting energy expenditure during starvation, while more severe disturbances lead to accommodation, changes in function, e.g. the reduction in physical activity during prolonged semi-starvation, with the aim of maintaining other more vital functions.

Much is known about the homeostatic regulatory mechanisms, which govern the transition between the fasted and fed states, although less is known about homeorhetic mechanisms. Short term experiments or a prolonged mild disturbance lead mainly to adaptation. More severe stimuli lead to breakdown of these mechanisms causing accommodation, and resulting in disease or aggravation of disease as a consequence of loss of physiological function.

Components of energy balance

Total energy expenditure (TEE) in healthy subjects consists  mainly of resting energy expenditure (REE: about 60% of TEE) and activity induced energy expenditure (AEE: about 30% of TEE). In addition, diet induced energy expenditure (DEE) is about 10% of TEE. REE is the result of homeostatic reactions such as maintaining ion gradients across cell membranes and of substrate cycling, e.g. the constant synthesis and breakdown of protein, glycogen, adipose tissue and intermediates in gluconeogenesis. These cycles serve the purpose of maintaining an alert state of metabolism enabling rapid reactions to external stimuli. If a reaction is simultaneously running in the forward direction at a rate of 100 units and backwards at a rate of

99 units, a regulation by 10% in each direction (up- and down-regulation) will have a 210 times larger effect than a 10% stimulation of a single forward reaction running at a rate of 1 unit.

REE is a product mainly of the metabolism of lean body mass and is therefore dependent on variables related to it, e.g. body weight, height, sex, age. Injury and infection increase REE via neural and cytokine stimuli to the hypothalamus and changes in catecholamine and neurotransmitter secretion. In most cases, the increase is modest and largely offset by immobility. AEE is highly variable, depending on the amount of physical activity, of course, but also on physical capacity since a training paraplegic patient, for instance, may have several fold higher energy expenditure during a specific activity compared to a healthy person.

A fixed value for TEE, e.g. 30 kcal/kg, is useful for clinical purposes as an initial estimate, but it is obvious from the discussion above that this value will vary according to circumstances. One must be prepared, therefore, to adjust the energy intake according to monitoring measures.   

The energy content of food ingested is determined either by bomb calorimetric analyses of foods, or by measuring it’s content of fat, nitrogen (protein), water and ashes and obtaining carbohydrate content by difference. The calorimetric values of fat, nitrogen and carbohydrate are then measured in representative samples of pure macronutrients. By subtracting fecal energy, also measured by bomb calorimetry, the absorption of energy from various foods can be obtained, usually around 95%. The metabolizable energy refers o the actual energetic gain by the organism after absorption. This is different from absorbed energy particularly in the case of protein, since the main product of nitrogen oxidation is urea, which has higher energy content than the bomb calorimetric products (H2O, CO2, N2).

Components of nitrogen balance

The recommended daily intake of protein (0.8 g/kg per day) is based on long-term nitrogen balance studies and consists of three components:

- the average amount of high quality protein needed to maintain nitrogen balance (0.6 g/kg)

- safety factor to ascertain that 95% of the healthy population is covered (0.15 g/kg)

- allowance for the usual intake of proteins that are not entirely high quality protein (0.05 g/kg)

The general acceptance of nitrogen balance as a criterion for adequate intake is only due the lack of a more specific test. Adequacy for several other essential nutrients is based on treatment or prevention of specific disease states (e.g. scurvy and vitamin C) but such a specific abnormality associated with inadequate protein intake is not known. Nitrogen balance is measured by collection of nitrogen losses in urine, feces, skin and miscellaneous losses (sweat,

secretions, etc) and subtracting these losses from measured nitrogen content of protein intake. For determination of requirement, these balances are measured at several levels of protein intake from inadequacy to well above estimated adequacy with the intercept corresponding to zero balance being determined. Each level of intake is tested over several days to assure a metabolic steady state at each intake. Due to the technical problems involved, it is understandable that only few studies are available that have performed such complete analyses, and no lege artis studies have in fact been performed in patients. However, a number of modified procedures have been undertaken in various patient groups giving useful results. From the studies available in healthy subjects, the following values can be derived:

- At an intake of 1 g protein/kg per day, the nitrogen loss in urine will correspond to, approximately, 0.85 g/kg, the loss in feces will be equivalent to 0.1 g/kg per day and the loss from skin and miscellaneous sources will be equivalent to 0.03 g/kg per day.

With varying intakes, the loss in urine will vary while the losses in feces and skin, etc., will not vary substantially on an ordinary Western diet in a temperate climate. Fecal loss, however, is dependent on the fibre content of the diet, since a high fibre content will increase colonic bacterial flora and thereby increase the bacterial nitrogen content of feces. In addition, protein in foods of low digestibility will increase fecal nitrogen losses. Protein of low biological value will also increase urinary nitrogen loss.Digestibility and biological value are combined in the Net Protein Utilization (NPU), which is the fraction of protein retained in the body with an increase in intake of a specific dietary protein.

The amount of protein required to maintain nitrogen balance consists of two major components: essential amino acids (EAA) and essential nitrogen. The latter consists of any form of nitrogen that can enter ammonium metabolism in the body and be incorporated into amino acids by amination or transamination. The amount of essential amino acids required in adult healthy subjects corresponds to about 10% of total protein requirement, while in children it is close to 40% (2 g/kg per day). This reflects that the nitrogenrequirement of the growing subject is largely determined by the EAA composition of the growing tissues, while in the adult depends on the needs for protein turnover of lean tissue, the synthesis of essential compounds such as hormones, as well as the increased requirements for wound healing or response to disease.

In the diseased subject, synthetic reactions require yet another pattern of amino acids, e.g. proline for collagen synthesis, aromatic amino acids for synthesis of antibodies and acute phase proteins, and glutamine for rapidly dividing cells. In such conditions, amino acids that are not usually essential can become conditionally essential due to limited synthetic capacity, e.g. glutamine in the severely ill patient. Similarly, in patients with decreased liver function, cysteine may not be produced in sufficient quantities from methionine, and therefore the requirement for sulphur containing amino acids in these patients may not be covered by provision of methionine alone. In addition, after a period of weight loss, the adult subject may have a requirement for EAA esembling that of a growing child due to the needs for rebuilding of tissue.

The amount and composition of protein required to maintain nitrogen balance in patients may therefore differ substantially from that in healthy subjects. During acute illness, the short term goals of feeding are to restore and maintain function, while limiting further loss of lean tissue. During the weeks of convalescence, the aim is to restore lean mass as well as function. Nitrogen balance may be indicative of loss or gain of body protein but is not a goal in itself. Nonetheless, in the absence of specific tests for adequacy of protein intake, some measure of nitrogen balance is useful in various clinical settings, since a prolonged state of a negative nitrogen balance is not compatible with life.

Energy loss or gain

In the transition from the fed state to starvation, e.g. an over-night fast, energy requirements will be covered mainly by breakdown of glycogen. This is regulated by decreasing plasma insulin (decreasing glycogen synthesis) and rising glucagon (stimulating glycogenolysis). During a more prolonged period of starvation (2e4 days), glycogen stores fall and gluconeogenesis increases. This is accomplished by hepatic formation of glucose from amino acids originating from skeletal muscle, intestine and skin. This process is still governed by low insulin and increased glucagon (promoting gluconeogenesis), but now accompanied by increases in cortisol (stimulating gluconeogenesis and increasing protein breakdown) and growth hormone (increasing gluconeogenesis).

With starvation for longer than 72 h, causing elevated blood ketones, the brain adapts to obtaining 60% of its energy from this source instead of the usual glucose. At the same time, the resting energy expenditure begins to decrease. These changes result not only from the hormonal

changes described above, but are probably also due to decreased concentrations of triiodothyronine (T3) with a rise in the inactive reverse T3. In addition, physical activity isreduced and in more advanced states this is associated with a state of apathy. Muscle function is reduced due to increased relaxation time in neuromuscular function tests, and this is related to decreased electron transport and oxidative phosphorylation in mitochondria. During long-term weight gain, the cost of adding 1 kg body weight is, approximately, 7500 kcal while the energy yield from 1 kg body tissue is, approximately, 5200 kcal. The difference reflects the cost of building lean body mass and adipose tissue. The proportional formation of lean body mass relative to fat mass is dependent on the initial nutritional status. When the subject is underweight,

the main part of tissue gained is lean body mass while it is mainly adipose tissue if the subject is of normal weight. Since the energy cost of gaining adipose tissue is much larger than that of gaining lean body mass, the cost of gaining 1 kg body weight depends on the initial body weight.

The values given above refer to a condition of moderate underweight.

Protein loss or gain

In the transition from the fed to the postabsorptive state, protein degradation increases while protein synthesis largely remains unaffected. The higher the habitual protein intake, the larger is the increase in protein degradation. When no protein is given for a prolonged period, the loss of nitrogen from the healthy subject decreases from, approximately, 1 g/kg per day to 0.4 g/kg per day, as an adaptation to insufficient intake. This is in part due to the switch to fatty acid oxidation mentioned above, but it is also due to an adaptive down-regulation of hepatic degradation pathways of amino acids including EAA. After a brief period of starvation, the body reutilises about 60% of the EAA liberated by protein degradation but the reutilizations increases to about 80% during prolonged starvation. In the patient in intensive care, this loss can be increased to 1- 2 g/kg per day when no protein is given. Immobilization by itself leads to wasting of muscle tissue. In experimental studies of long-term immobilization (with intact innervation), the loss of nitrogen from the body corresponds to only 0.05 g protein/kg per day and therefore the massive loss of nitrogen seen in patients in intensive care, and to lesser extents in other patient categories, is mainly due to the metabolic disturbances associated with disease processes.

Eventually, loss of protein will severely affect the function of a number of organs including muscle, intestine, skin, immune cells, and liver. With the knowledge available, however, the effect of protein deficit per se versus the effect of energy and other deficits cannot be distinguished with certainty. From data available, it appears that immune function is relatively spared compared to physical activity/ muscle function, suggesting that unknown regulatory mechanisms are responsible for a programmed loss of function during starvation alone, although such adaptive mechanisms may be impaired in the presence of illness.

During long-term weight gain, the positive nitrogen balance in undernourished but otherwise healthy adult subjects corresponds to about 40% of the intake at an intake of 1.5 g protein/kg per day. Expressed in another way, nearly 75% of an incremental increase in protein intake is retained in the body. This is not very far from the corresponding figures in infants, suggesting that the efficiency of rebuilding lean body mass is close to that of early growth. The regulation of this programmed change is also not known in detail, but sustained high levels of plasma amino acids and insulin

may play central roles. This rebuilding is an energy demanding process, since protein degradation as well as protein synthesis is increased during recovery, reflecting constant remodeling of the tissues being restructured.

Summary

We describe basic principles of energy and nitrogen balances together with principles of homeostatic and homeorhetic changes of organism. Daily energy and protein balances are supposed to be 30 kcal/kg and 1 g/kg, respectively. However, these can be extended, especially in the condition, when body weight is gained after period of weight loss (e.g. disease related).