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Effects of disease on desirable protein/energy ratios

N. S. SCRIMSHAW (Chairman), B. R. BISTRIAN, O. BRUNSER, M. ELIA, A.A. JACKSON, Z.-M. JIANG, J.M. KINNEY, I.H. ROSENBERG and R.R. WOLFE


1. Effects of infections on nutritional status
2. Environmental ('tropical') enteritis
3. Other chronic infections
4. Energy vs protein requirements
5. Possible role of specific amino acids
6. Summary
7. Recommendations
References


1. Effects of infections on nutritional status


1.1. Anorexia
1.2. Cultural and therapeutic practices
1.3. Malabsorption
1.4. Catabolic losses
1.5. Anabolic losses
1.6. Fever
1.7. Additional intestinal losses


It is well established that infections worsen nutritional status and that energy balance is decreased, although to a lesser degree than protein balance. However, the extent to which the protein/energy ratio required during treatment and recovery is affected by various diseases is more difficult to specify. This is because multiple mechanisms are involved, some of which affect protein and energy needs differently, and also because there are variations in the impact of various infections depending on their etiology, severity and duration.

By analyzing the ways in which infections worsen nutritional status, their differential effects on protein and energy metabolism can be better understood. These include:

1.1. Anorexia


Experience with nitrogen balance studies that have been disrupted by intercurrent infections reveals a consistent decrease in food intake even when efforts are made to maintain it. This is observed even with asymptomatic infections including live virus immunizations. Not only are protein and energy intakes affected but also those of other nutrients.

1.2. Cultural and therapeutic practices


In the case of young children with diarrhea or febrile infection there is a strong tendency of the mother to withdraw solid food and substitute thin starchy or sugary gruels that are low in protein and caloric density or to offer herbal decoctions of various sorts. In Guatemala, for example, children with measles are frequently given agua de tisana made from a local wild plant.

In field studies it is not possible to separate the effects of anorexia from those of deliberate withdrawal of food for cultural reasons. While consumption of food will be reduced by anorexia, purposeful withholding of food may have much greater impact. The average reduction associated with the presence of specific symptoms of infection in Guatemalan children was approximately 20% at all periods from 15 to 60 weeks of age (MATA et al., 1977; MARTORELL and YARBROUGH, 1983; MARTORELL, RIVERA and LUTTER, 1990).

In Matlab, Bangladesh (HOYLE et al., 1980), caloric intakes in children under five years of age were more than 40% lower during the acute stage of diarrhea than after recovery. The differences were greater with diarrhea caused by rotavirus and E. coli than with cholera and Shigella. In Peru, caloric intake decreased from 10 to 86% among breast-fed children with diarrhea (BENTLEY et al., 1991).

1.3. Malabsorption


The significant decrease in absorption of nutrients with diarrhea is referred to above. In the metabolic studies of INCAP protein absorption was generally reduced 10 to 30% and rarely as much as 40%. However, the frequency of diarrhea! disease in young children makes this a significant contribution to the frequent periods of decreased energy intake in young children due to infections. POWANDA (1977) has summarized additional literature and attempted to quantitate the range of malabsorption of protein, fat and carbohydrate with diarrhea.

Despite the reduced absorption it is important to maintain food intake to the extent possible during bouts of diarrhea. CHUNG and VISCOROVA (1948) reported that the absorption of nitrogen in four children with diarrhea varied from 40 to 74% and that of fat from 39 to 67%. For two similar cases in which food was withheld, absorption percentages were mildly depressed for both nitrogen and fat. Data from ICDDRB for diarrhea due to rotavirus average 43% for nitrogen, 42% for fat, 74% for carbohydrate and 55% for total calories. Corresponding figures for diarrhea due to enteropathogenic E. coli and Shigella were slightly higher (MOLLA et al., 1982).

The range of infections that are associated with malabsorption is wide and most are common in developing countries. They include the bacterial, viral and protozoan enteritides, intestinal parasites such as hookworm, fish tapeworm, ascaris, strongyloides; and systemic disorders such as measles, tuberculosis and streptococcal infections. These infections act by shortening intestinal transit time or by physical blocking of mucosal surfaces.

1.4. Catabolic losses


A catabolic response occurs with all infections even when they are subclinical and not accompanied by infection (BEISEL et al., 1967; BEISEL, 1972; 1975; BEISEL and WANNEMACHER, 1980; KEUSCH and FARTHING, 1986). Under the stimulus of the release of interleukin-1 and tumor necrosis factor by phagocytic cells, endocrine changes are initiated that lead to the mobilization of amino acids from the periphery, primarily from skeletal muscle. Amino acids, such as those of the branched-chain group (BCAAs), are utilized as energy sources leading to the synthesis of alanine or glutamine. BCAAs are rapidly taken up by the liver and utilized for gluconeogenesis, while alanine and glutamine serve as intestinal fuels, for regulation of acid-base and for gluconeogenesis by the kidney.

Amino acids, such as phenylalanine and tryptophan, which cannot be metabolized in skeletal muscle, are released in elevated amounts (WANNEMACHER, 1977). Figure 1 shows that in a young man with tularemia more than two thirds of the negative nitrogen balance was due to this metabolic response and the remainder to a spontaneous decrease in food intake (BEISEL et al., 1967). Figure 2 shows that even an individual with completely asymptomatic Q-fever can be in cumulatively increasing negative nitrogen balance for as long as 21 days (BEISEL et al., 1967).

In INCAP experience with metabolic studies in children, infections are always associated with a period of negative nitrogen balance, even in the case of immunization with yellow fever vaccine which provokes no symptoms (GANDRA and SCRIMSHAW, 1961). The response to these asymptomatic infections is qualitatively similar to those with the typical clinical disease.

Figure 1. The components of the negative N balance during the acute phase of tularemia in an adult male subject are shown. The white area represents that proportion resulting from decreased N intake due to anorexia and the shaded area that due to the catabolic response. (From BEISEL et al.,1967)

Figure 2. Nitrogen balance data in a subject who remained asymptomatic despite subclinical Q-fever.

This individual showed neither an elevation of rectal temperature above 100 F nor diminution of dietary intake despite the presence of Coxiella burnetii in the blood over an 8-day period. (From BEISEL, 1977)



1.5. Anabolic losses


During an infection, amino acids are diverted from normal pathways for the synthesis of immunoglobulins, inflammatory cells, acute phase proteins and a variety of other proteins including key liver enzymes (WANNEMACHER, 1977). This would explain the common finding that the extra nitrogen retained during the recovery period in metabolic balance studies substantially exceeds that accounted for by the magnitude of the negative balance during the acute phase of an infection.

1.6. Fever


Whatever its benefits in resisting infection, fever has a metabolic cost. The regulation of normal body temperature within a narrow range is a complex phenomenon that is modified by the endogenous pyrogenic activity of interleukin-1, as well as other cytokines (tumor necrosis factor, interleukin-6, interferon) released by mononuclear leukocytes in response to infection and acting on the hypothalamus. The resulting fever increases BMR by 13% for each 1 C (DuBOIS, 1937).

In some extended infections such as pneumonia and typhoid fever, the elevated temperature is maintained at a higher level with daily variations similar to those in the normal range. Conversely, in malaria there are sudden rises and falls in temperature. During the period of maximum fever, metabolism may increase by nearly one-third. Van't Hoff's law specifies that the coefficients for the increase in the velocity of various chemical reactions with temperature lies between 2 and 3. This means an increase in basal metabolic rate of 30 to 60% for a 3-degree rise from 37 to 40 (DuBOIS, 1936).

Since carbohydrate stores are inadequate to meet the increased energy requirement resulting from fever and the metabolic response to infection (CAHILL, 1970), and since lipid stores are less effectively used in the infected patient (BEISEL and WANNEMACHER, 1980), another source of energy is required. This is mainly through gluconeogenesis from protein. Interleukin-1 releases both insulin and glucagon from the endocrine pancreas and, synergistically with tumor necrosis factor, stimulates muscle breakdown (FLORES et al., 1989), thereby releasing gluconeogenic precursor amino acids into the blood stream. As already noted, the additional depletion of protein must be made up during recovery. It should be emphasized that this process is not dependent on fever, but the energy deficit is increased in proportion to the degree and duration of the fever.

1.7. Additional intestinal losses


Difficult to measure separately from malabsorption, but a significant additional cause of further malnutrition, is the direct loss of nutrients into the gut. Protein-losing enteropathy has been described for measles (AXTON, 1975; DOSSETER and WHITTLE, 1975; SARKER et al., 1986), diarrhea (WALDMAN, 1970; WHO, 1980; RAHMAN and WAHED, 1983) and especially shigellosis (RAHMAN, ALAM and ISLAM, 1974). Alpha 1-antitrypsin is a simple and useful quantitative marker for estimating the loss of protein into the gut in diarrhea! disease (RAHAMAN and WAHED, 1983). It should be used for this purpose with other infections with the potential to cause such losses.

In ICDDRB studies, nearly two-thirds of patients with enterotoxigenic E. coli and 40% of those with rotavirus diarrhea were also associated with excessive loss of protein in the feces. Between 100 and 500 mL of serum were lost with feces each day in patients with shigellosis due to protein-losing enteropathy.

Bleeding into the intestine, from Schistosoma mansoni or hookworm, also represents a loss of nutrients. BRISCO (1979) found that each adult hookworm causes the loss of about 1 kcal/d. For an estimated average hookworm load of 100 worms in ICDDRB studies this would amount to an energy loss equivalent of 5 % of adult caloric in takes. For mild-to-moderate infections, most of the protein and about half of the iron loss due to bleeding into the intestinal tract is reabsorbed. However, protein absorption is significantly reduced with severe infections (DRAKE, 1959). Some individuals may have as many as 500 worms.

2. Environmental ('tropical') enteritis


The prevalence of environmental enteropathy varies with the access of infectious agents to the gastrointestinal tract. Between 30 to nearly 100% of individuals living in an unsanitary environment experience chronic changes in the intestinal epithelium that includes blunting of the villi and increased numbers of lymphocytes in the lamina propria progressing to a flat mucosa that resembles celiac disease (BAYLESS, SWANSON and WHEBY, 1971; LINDENBAUM, HARMON and GERSON, 1972). It has been reported for local populations in Haiti (KLIPSTEIN et al., 1968), India (BAKER, 1972; GORBACH et al., 1970), Thailand (SPRINZ et al., 1962; KEUSCH, 1972), Bangladesh (LINDENBAUM, GERSON and KENT, 1971), Colombia (MAYORAL et al., 1967; GHITIS, TRIPATHY and MAYORAL, 1967), Puerto Rico (LUGO-DE-RIVERA, RODRIGUES and TORRES-PENEDO, 1972) and undoubtedly occurs in most developing countries. ROSENBERG, SOLOMONS and SCHNEIDER (1977) showed that most rural Guatemalans had reduced absorption of both protein and carbohydrate.

The acquired nature of the condition attracted considerable attention when it was identified in returning US Peace Corps volunteers, missionaries, and other expatriates who had lived in unsanitary environments (KLIPSTEIN and FALAIYE, 1969). Some individuals required up to a year for full recovery. Xylose and lactose malabsorption were later found in American military and Peace Corps personnel in Thailand (KEUSCH, PLAUT and TRONCALE, 1970).

In Chile, BRUNSER et al. (1970) reported a fecal nitrogen loss in young adults with mild environmental enteropathy of 16 mg/kg per day when subjects were receiving an egg diet providing 0.8 g of protein/kg, and the loss increased to 20 mg/kg when the diet provided 1 g of protein/kg per day. Both diets provided 20 g of insoluble fiber. A period of 3 months in a metabolic unit with strict sanitation restored normal mucosa morphology.

3. Other chronic infections


Most acute infections are self-limiting, and specific antimicrobial therapy now exists for most infectious illnesses. For some diseases, however, clinical recovery may be delayed and nutritional support becomes a significant consideration. Persistant diarrhea, i.e., episodes lasting longer than 15 days, follows from 10 to 20% of acute episodes depending on the location (WHO, 1980).

The majority of these episodes do not have a dramatic symptomatology but are nevertheless associated with severe weight loss and malnutrition. Such individuals have considerable limitation in their capacity to digest and absorb nutrients, and some may require parenteral nutrition to stabilize and improve their nutritional status. However, it is important to feed them as much as possible by mouth, if necessary using predigested formulas or continuous tube feeding. The aim is to provide adequate nourishment to facilitate prompt recovery of the intestinal mucosa.

A certain proportion of children with acute diarrhea! disease of nonspecific cause have persistent carbohydrate intolerance and develop a much more severe and prolonged nutritional deficit (ROSENBERG and SCRIMSHAW, 1972).

There are some infections for which specific therapy is not effective and which have long-term and sometimes severe consequences for nutritional status. Most prominent of these is the current pandemic of Acquired Immunodeficiency Syndrome (AIDS). The malnutrition of AIDS has multiple etiologies. AIDS is a viral infection producing a systemic response that includes anorexia, fever and weight loss that initially responds to specific retroviral therapy with azothymidine (AZT) or dideoxyinosine (DDI). In addition to the adverse impact of the systemic response on nutritional status, involvement of the gastrointestinal mucosa with the virus may contribute further to the malnutrition (HUANG et al., 1988).

Patients with AIDS develop superimposed infections that do not normally produce symptoms in immunocompetent hosts. Gastrointestinal infections such as with Isospora Microsporidia, Mycobacterium avium intracellulare or cryptosporidia produce severe diarrhea and malnutrition in AIDS for which antimicrobial therapy is of limited effectiveness. A limited number of such patients (usually less than 10%) may benefit from home enteral or parenteral feeding (KOTLER et al., 1989; 1991).

There are a number of illnesses commonly seen in AIDS patients for which chemotherapy is more effective such as Pneumocystis carini, toxoplasmosis, cytomegalovirus, herpes simplex and tuberculosis. In these diseases the treatment in the hospital may be sufficiently long and difficult that enteral or parenteral alimentation may become necessary. This is especially likely in the patient who has an altered state of consciousness or requires mechanical ventilation.

A second common clinical syndrome is that of nosocomial pneumonias or intra-abdominal infections that develop in critically ill patients following surgery or other critical conditions such as pneumonia, major gastrointestinal bleeding, trauma, acute inflammatory disease of the intestine and pancreas or chronic organ insufficiency (liver, heart, lung, kidney). The organisms often found in these situations are or become resistant to multiple antibiotics. In such patients the clinical course may be quite prolonged and the septic syndrome can be profoundly catabolic. This general category of patient is the most common indicator for parenteral and enteral nutrition in the hospital setting.

4. Energy vs protein requirements


In a previous IDECG monograph, SRIMSHAW (1990) reviewed the available information on the impact of infection on energy requirements. The protein losses of 0.6 to 1.2 g of protein per kg of body weight described by POWANDA (1977) would account for a concurrent energy loss of 7 kcal to nearly 30 kcal per kg of body weight. Reduced food intake would further deplete an individual with acute infection, and the consequences might be greater for protein than for total dietary energy, because the diet is so often altered to one of lower protein value during an infection.

The difficulty with such calculations is that they do not include the energy and protein expended for the multiple anabolic processes associated with an infection. Balance studies suggest that these must be substantial, but there are no quantitative estimates. The best guide may be the relative amounts of protein and energy required for catch-up growth following severe depletion. For a 7 kilo child (UNU, 1979) this ranges from 5.6% of protein calories for a 10 g weight gain per day to 9.l% for a 90 g gain. For a similar child with both infection and severe depletion, the P/E ratios were calculated in the UNU report to be from 9 to 13% higher than for nutritional depletion alone, depending on the assumed rate of repletion.

5. Possible role of specific amino acids


5.1. Branched-chain amino acids
5.2. Glutamine
5.3. Cancer


5.1. Branched-chain amino acids


Studies suggesting that branched-amino acids (BCAAs) may promote tissue anabolism have led to considerable interest in the provision of BCAAs in total parenteral nutrition (TNP). Their metabolic role as precursors for the synthesis of muscle glutamine has also stimulated interest in their use. Interactions between BCAAs and aromatic amino acids in their transport into the brain, and the indication that they may decrease brain tryptophan uptake and serotonin production, has led to the suggestion that they may be of therapeutic value. For example, they may be able to stimulate the respiratory center and aid patients with sleep apnea.

Specific trials of TPN solutions enriched with BCAAs have shown the following relationships. In patients with hepatic-failure-induced encephalopathy, improvement of mental function is observed, but benefits over administration of similarly low amounts of regular amino acid mixtures are uncertain (NAYLOR et al., 1989). Trials of their influence on nitrogen balance in patients fed varying intakes of protein have shown:

(a) limited effects with intakes greater than 70 g,
(b) improvement at intakes between 40 and 70 g,
(c) no effect of intakes at less than 40 g, where other amino acids may be limiting.

In renal failure, where lowering blood urea levels is desirable, enriched mixtures containing 40 to 70 g total amino acids have been useful in treatment.

5.2. Glutamine


Interest in glutamine has developed over the last few years subsequent to developments in two areas:

(a) the understanding of the metabolic importance of glutamine as a fuel for lymphocytes, macrophages and other rapidly dividing cells,

(b) understanding of the importance and regulation of the skeletal muscle glutamine pool.

Thus, as a potential fuel for the immune system, concern has been expressed that inadequate provision of glutamine from skeletal muscle as a result of stress from infections and burns may be deleterious (FURST, ALBERS and STEHLE, 1987; JEPSON et al., 1988; NEWSHOLME et al., 1988). Concern has also been expressed that the ability of the gut mucosa to act as a barrier to pathogens in sepsis or trauma may be limited by inadequate mucosal synthesis subsequent to reduced availability of glutamine (WILMORE et al., 1988; LACEY and WILMORE, 1990). Finally, the suggestion that glutamine in skeletal muscle may act to regulate protein balance in this tissue has also led to attempts to limit the negative nitrogen balance in trauma by the provision of glutamine (ABUMRAD et al., 1989; HAMMARQVIST et al., 1989).

In parenteral nutrition solutions, the instability of glutamine during autoclaving has resulted in its omission from such solutions. Several authors have suggested the inclusion of glutamine containing dipeptides in TPN solutions. The suggestion has been made that enteral provision of glutamine could also be advantageous. To date there is no quantitative information about the dose-response of either immune function or gut-mucosal function to provide a basis for recommendations.

5.3. Cancer


Malnutrition occurs commonly as a consequence of cancer and represents an important prognostic sign. Response to treatment and survival are inversely correlated to the degree of weight loss, although intestinal obstruction may contribute to weight loss in some cancers. In most instances, the development of malnutrition in cancer is a systemic response to the tumor and is principally due to anorexia and reduced intake rather than through changes in energy expenditure. Therefore, protein and energy are more equally depleted than with infection. However, similar to infection (STREAT et al., 1987), nutritional repletion is ineffective in cancer cachexia that develops as a systemic reponse (NIXON et al., 1981).

The usual chemotherapy regimen for most tumors is of short duration, and although anorexia and weight loss commonly occur, chemotherapy does not elicit a severe catabolic response. Thus, it is not surprising that data from a number of randomized clinical trials investigating the role of invasive nutritional support during chemotherapy did not identify a net benefit (KLEIN et al., 1986).

In bone marrow transplantation, however, the chemotherapy regimens are much more aggressive and prolonged, and malnutrition resulting from these regimens can be clinically important. Nutritional support under these circumstances has been shown to benefit morbidity, mortality and treatment outcome (WEISDORF et al., 1987). A corollary finding in many of the randomized clinical trials was that infectious morbidity was greater in the fed group due to poor management. Excess carbohydrate calories that produce significant hypoglycemia or excess parenteral fat administered too rapidly have been shown to diminish immune function. These findings emphasize that nutritional support therapies must be provided in an expert manner with attention to an appropriate P/E ratio. This becomes critical with parenteral alimentation. Nutritional support has the potential to cause complications and worsen outcomes if not done well.

Radiation therapy is usually longer than chemotherapy and can lead to significant anorexia. Nutritional support to the malnourished may be more likely to improve outcome when intense radiotherapy courses are provided that include the abdomen in the radiated field. However, there are insufficient data to recommend routine adjuvant nutritional support during radiotherapy.

With gastrointestinal cancer, where local obstructive symptoms may commonly be a cause of malnutrition (i.e., cancer of the esophagus), nutritional support can replete lean tissue and will improve nutritional status prior to the planned stress of major surgery as well as improve outcome (MULLER et al., 1982).

When malnutrition develops from the metabolic response to injury or inflammation as seen in trauma, infection, inflammatory disease, and cancer, nutritional therapy adequate in terms of protein and energy may reduce the rate of tissue loss. However, it will not replete lean tissue during the acute phase, although fat gain can be achieved (STREAT et al., 1987; NIXON et al., 1981).

6. Summary


For recovery from most infections, P/E ratios in the range of those proposed to allow for catch-up growth of severely malnourished individuals should be adequate. For chronic infections there is so much variation with the nature and duration of the disease that no generalizations can be made. In the absence of other data, the same P/E ratios as for recovery from acute infections should be followed in dealing with recovery from chronic infections depending on the degree of depletion and the rate of recovery. There is no evidence of an increase in the desirable P/E ratio in the treatment of cancer, except when recovery from depletion is occuring as the result of remission or of successful therapy.

7. Recommendations


1. Because infections always result in the depletion of lean body mass, it is important that the diet be adequate in protein and energy during the recovery period for the repletion of adults and for both the repletion and catch-up growth of children.

2. An adequate diet should continue to be fed during diarrhea. After an acute diarrhea! episode, additional food with an increased protein content should be provided for repletion and catch-up growth of children and for the restoration of the lean body mass of adults.

3. During persistent diarrhea, patients should receive as much nourishing food as they can tolerate. If depletion becomes clinically important, this may need to be supplemented by parenteral feeding.

4. The long-term approach to the prevention of environmental enteropathy is environmental sanitation and hygiene to ensure safe water and food supplies. Until the condition can be prevented, its adverse effect on the absorption of nutrients must be taken into consideration, given the wide prevalence but modest severity of malabsorption in the individual case. An additional allowance of 10% is likely to be sufficient to compensate for the effect of this condition on intestinal function.

5. The effects of intestinal parasites on the absorption of protein, fat and other nutrients depend on the kind of parasite and the severity of the infection. Severe parasitism will continue to impair absorption until treated.


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