Malnutrition in Children with Cystic Fibrosis: The Energy-Balance Equation

Malnutrition is common in children with cystic fibrosis (CF) (1-4). Early diagnosis and improved treatment (including nutritional management) now ensure that most children with CF survive into adulthood, and it is in the older patients that nutritional deficits are most severe. Results of cross sectional (5-7) and longitudinal (7) studies suggest that progressive or episodic deterioration in growth and nutritional status occurs throughout childhood and adolescence (Fig. 1). Identification of the genetic defect in CF has led to an advance in our understanding of the pathogenesis of the disease but, in the absence of specific treatment, management remains largely supportive. Even with rectification of the basic defect, it will continue to depend on prevention and treatment of the progressive pulmonary disease, malabsorption, and malnutrition. Malnutrition is an adverse prognostic factor in CF (8-10). It probably promotes morbidity and mortality by impairment of lung function and immune function. Malnutrition causes growth failure (5-7) and reduced ability to engage in physical activity (8). A fuller understanding of the cause of malnutrition in CF may provide the means to prevent it, or to delay its progression, and may lead to better nutritional interventions aimed at extending survival and improving quality of life. Although it is well established that negative energy balance is central to the development of malnutrition in CF (1) it is also widely recognized that the etiology of malnutrition in CF is unclear. It is the result of a complex combination of challenges to the maintenance of energy balance that are manifest as decreased energy intake, increased energy expenditure, impaired digestion and absorption, and excessive energy losses. What is unknown, but essential to the design of nutritional intervention strategies in CF, is the relative contribution of each of these factors to the maintenance of energy balance and the link between the main clinical events in CF and the genesis of negative energy balance. It is our contention that optimal management requires identification of the cause(s) of negative energy balance so that nutritional intervention can be targeted effectively. The purposes of this review are to summarize the recent primary literature on energy balance in CF, to consider the relevance to CF management of recent research on energy balance in other diseases characterized by recurrent infection, and to propose priorities for research to explain the development of malnutrition in CF. DISTURBANCES OF ENERGY BALANCE Energy balance may be expressed by the equation: ΔE = (EI) - (TEE + El + Ed) where E is energy balance, EI is energy intake, TEE is total energy expenditure, E1 is energy losses, and Ed is energy deposited. Maintenance of adequate growth and nutritional status in childhood requires a small positive energy balance to meet the energy cost of synthesizing new tissue, and the energy content of the new tissue deposited. We review each of these components of the energy-balance equation to assess their relative contribution to the development of malnutrition in CF. ENERGY INTAKE Chronic Suboptimal Intake There is widespread recognition of the importance of maintaining relatively high EI in CF (11,12), and 120% to 150% of the recommended daily allowance, or estimated average requirement for energy is usually taken as the target (13-15). The clinical impression is that this target seems to be appropriate, but it is not based on firm experimental evidence (e.g., prospective intervention studies). There is considerable evidence that EI rarely meets this target (16-19). Even when free of severe lung disease and acute respiratory exacerbation, many patients with CF fail to consume energy intakes that meet current recommendations (16,17). The etiology of poor EI in CF is complex, multifactorial, and poorly understood, and a full discussion of the topic is beyond the scope of this review. Intakes may be compromised as a result of esophagitis (20), anorexia associated with chronic or acute illness, behavioral and psychological difficulties associated with eating (21), malnutrition per se (22), and dyspnea. The mechanisms underlying anorexia are not well defined, but there is increasing evidence of a role for cytokines (23). Acute Suboptimal Intake Poor EI during (and possibly after) acute respiratory exacerbations may contribute to the development of malnutrition in CF. Adults admitted to hospitals with respiratory infections commonly suffer negative energy balance and consequent deterioration in nutritional status (24), largely as a result of compromised EI during the infection (25). Repeated bouts of anorexia associated with recurrent infection in CF could be mediated by surges of inflammatory activity associated with infection, as has been proposed in emphysema (26). Such episodes contribute to the pathogenesis of malnutrition in chronic obstructive airway disease (27,28), in chronic diarrheal disease (29), and in the malnutrition of old age (24). Repeated episodes of acute diarrhea are associated with step-wise growth-faltering in children in the developing world (29), and evidence is growing that this is caused more by insufficient EI than by excessive fecal losses (29,30). Regarding patients with human immunodeficiency virus (HIV) infection, there has been considerable interest in the cause of wasting and in the possible role of energy expenditure in contributing to weight loss, which it has been proposed is progressive (the result of chronic hypermetabolism) or episodic (the result of acute hypermetabolism associated with recurrent infection). Ingenious measurements of total and resting energy expenditure, with simultaneous measurement of energy intake during periods of weight stability and weight loss, have recently established that reduced energy intake is the main cause of wasting in HIV infection. Wasting is caused by the profound anorectic effect of infective episodes (31). Could such a process be operating during acute respiratory exacerbations in CF (32)? The clinical impression is that appetite is suppressed early in acute exacerbation (often some time before treatment of the infection has started), but we have found only two published studies in which EI during acute pulmonary exacerbations in CF was measured (33,34), in both cases by a household measures record (35). In results of both studies EI was low initially when resting metabolic rate (RMR) was elevated. Patients failed to compensate for negative energy balance early in the episode by increased energy intake as respiratory symptoms improved (33,34). The evidence reviewed here suggests that chronic suboptimal EI is common in children with CF and may worsen as the disease progresses. Intake may be compromised further by the anorectic effects of acute pulmonary exacerbation. The ability of patients to achieve positive energy balance by increasing EI after acute exacerbations may also be limited. In summary, suboptimal EI probably makes a major contribution to growth failure and malnutrition in CF. Short periods of very low intake, superimposed on prolonged poor intake, may be the main reason why malnutrition develops in CF, as in HIV infection and chronic diarrheal disease. This implies that nutritional intervention should be targeted at improving EI between acute episodes in CF, and particularly after episodes of acute pulmonary infection. ENERGY LOSSES Energy Losses From Malabsorption and Maldigestion Energy is lost in the stool as lipid or carbohydrate, as intestinal mucus, bile and epithelial cells, and as bacteria. It can also be lost in the urine (glycosuria) in patients in whom endocrine pancreatic function is compromised, and in sputum (36). Fecal energy loss (E1) in CF is caused largely by pancreatic enzyme (principally lipase) deficiency, as well as by decreased bicarbonate and bile acid secretion. Dietary triglyceride is not hydrolyzed, gastric acid is not neutralized in the duodenum, lipase reaching the small intestine is inactivated, and bile salts are precipitated, leading to steatorrhea and fecal E1. Pancreatic hypofunction is progressive, and when more than 90% of secretory function is lost steatorrhea occurs. In untreated CF up to 80% of ingested fat may be lost in the feces. However even when pancreatic enzyme supplements are given to children with CF, fat absorption does not return completely to normal (37). Murphy et al. (37) calculated, using balance studies, that in a group of 20 children (mean age, 11 years) with CF, studied when well and taking regular pancreatic enzyme supplements, that stool E1 averaged 11% of gross EI. Up to 20 g/day of fat (160 kJ/day) was lost in the stools of some children-approximately three times the gross E1 of healthy children. Data in several other studies have confirmed similarly high stool energy, fat, and protein losses, particularly in untreated patients or in patients with inadequate control of pancreatic insufficiency (38,39). Morrison et al. (16) found that the mean digestibility coefficient for energy of 50 children with CF (mean age 10 years) studied when well, was 0.89. Parsons et al. (18) showed that normal growth was maintained in children with CF only when energy absorbed reached 100% to 110% of estimated requirements. Energy absorbed is the difference between energy ingested and energy lost in the stool. All energy in the stool is not the product of dietary maldigestion and malabsorption: Bacteria represent around 55% of the total dry weight of stools of healthy adults (40) and around 34% in children with CF (37). In addition to this mucus, bile and epithelial cells will contribute to total stool energy. Fermentation of carbohydrate and the resultant production of short-chain fatty acids in the colon, which are easily and rapidly absorbed, promoting water absorption, is a well-established mechanism of water conservation and energy salvage in healthy individuals (41,42). Under normal circumstances approximately 7% of daily energy may derive from short-chain fatty acids produced in the colon (43). This amount may be increased in circumstances where a higher amount of carbohydrate reaches the colon. In children with CF malabsorption in the small intestine, even with enzyme supplementation, increases the amount of carbohydrate and fat reaching the colon. Much of this carbohydrate should be salvageable. However, the use of antibiotics both prophylactically and in increased doses for acute infection, is likely to severely reduce the ability of the colonic microflora to ferment carbohydrate, which could result in loss of salvageable energy and increased risk of diarrhea from the osmotic action of unabsorbed carbohydrate. Antibiotics have been shown to decrease the fermentation capacity of the colonic microflora (42) and to increase stool output in normal adults (43), and antibiotic associated diarrhea is well described (44). There have been few studies of colonic fermentation in children with CF. In one study of fecal short-chain fatty acids (45), findings revealed no differences between patients and control subjects, but those with CF were well and the effect of antibiotics on the microflora is likely to be greatest during acute infection when antibiotics are prescribed. Results of a study comparing the in vitro fermentation capacity of children with CF (46), which included children with increased antibiotic use, demonstrated a decreased ability of the fecal of these children to ferment and complex carbohydrate when with of the It that even with optimal doses of pancreatic enzyme supplements, fat digestion is and stool lipid losses in children with CF between and 20 g/day This a loss of around 11% of the gross energy intake of a normal In addition to carbohydrate, during periods of antibiotic is likely to to fecal E1. ENERGY of It is to that TEE is up of three energy on physical metabolic rate or resting metabolic rate In most healthy children the relative contribution of each to TEE is as shown in energy on or resting metabolic From a of is relatively to particularly with the widespread of TEE and the energy on physical activity in children has only possible in recent with the of the of the of this and its relatively high use of is energy expenditure studies of patients with CF are largely based on measurements of and energy requirement is to be to It is to that TEE is the of three components (Fig. and an increased TEE be demonstrated to a In many diseases is but this is of or no there is a in activity and no effect on HIV infection is a of this (31). metabolic rate is the energy cost of maintaining tissue and is a function of (the amount of tissue to have specific metabolic at and at and the rate of metabolic which (e.g., protein and the activity of in the There is a considerable of evidence that suggests that is increased in patients with CF relative to in control This has the of why is increased has a of and the more of increased by increasing and energy This has relatively but is central to the of energy expenditure to in CF. 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We have found only two published of in patients with CF during the of acute pulmonary exacerbations (33,34). Results in both studies in of that can be as increases in in but not in patients early in the for to 10 and by the of with treatment of the infection. The in during the of the exacerbation was not to in lung function. This may be evidence for the contribution of than respiratory to increased in CF and the of the of the link between lung function and nutritional status to exacerbations cause periods of that contribute to the development of malnutrition in CF by the effect of episodes of negative energy balance. in and its to clinical during acute exacerbation, has even led to the that may be a clinical patients with to severe lung disease, episodes of acute hypermetabolism be superimposed on the chronic hypermetabolism to It is possible that these episodes also be mediated by surges of inflammatory activity associated with acute pulmonary exacerbations (26). for hypermetabolism is a cause of and growth failure in CF, TEE be in patients with CF, relative to control subjects, or TEE associated with acute that negative energy balance. increases in for most patients are relatively well and have lung function are and so hypermetabolism in CF can be only in acute exacerbations in patients with to severe lung disease. We have also established even when is it is only of TEE is increased there are no in the other two components of TEE (Fig. Even in acute when is by there is usually a in the energy on physical activity patients are and have reduced physical activity is evidence that this occurs in CF In that the energy on physical activity is a and of TEE (Fig. this in activity compensate for increased associated with an acute respiratory exacerbation. loss during infections in immune can be by reduced EI and hypermetabolism during these it not the cause of weight this we to the between TEE and weight loss in patients with HIV infection (Fig. TEE is low in patients with the most caused by physical energy expenditure is in those patients This may in a positive between activity and It is likely that the in acute pulmonary exacerbations in CF is in that may be but energy on physical activity is This requires by studies of TEE of patients with CF and after acute pulmonary exacerbation. Data in such studies or the that acute hypermetabolism to malnutrition in CF the were on more EI. The of the that hypermetabolism does not in HIV infection has been to clinical management and research on dietary intake and to reduce the on and with CF have to severe lung disease have of in physical activity by such patients to suggest that it is reduced relative to healthy the patients are and this to the of increased However, the of the increases in in these patients is such that it may not be by reduced physical patients suffer from a chronic but this experimental of Energy The energy on activity is not a function of the amount and of activity but the energy cost of each In some diseases energy cost of activity has been to but this does not to be the in children and with CF There is no evidence on in CF, but in that this is a small of is largely and it is probably of of Energy It should be that be the for measurement of TEE in individuals can provide of TEE that are on a group and the relatively recent development of the seems but at the evidence on TEE in CF in results of studies using There are now two published studies, in which that TEE is not in CF in studied with and in patients to with lung disease, studied when well by In results of the study by et al. CF patients to for increased by reduced in physical activity so that their estimated TEE was to that of control There are two that that TEE may be in CF. et al. measured TEE using in than with CF chronic lung disease and the results with from healthy and for TEE on higher in the patients than in the but this may be largely by differences in between the two of and control for the increase in TEE of with CF It could be that there is no hypermetabolism in with CF, but an is that such are only when to the of in TEE during remains et al. measured the using of children with CF lung and nutritional and the results with those of healthy children. energy expenditure was to higher for weight in the caused by increased and by increased energy on physical energy expenditure was only in patients for the There was no difference in energy expenditure between patients for the and control Although this could be as evidence for hypermetabolism in children with CF are relatively well and free of lung disease, an is that the is the result of relatively in physical activity in a small group of children with CF were relatively The mean of of physical in the 10 patients with the was which is not from published The that hypermetabolism is now established in CF is but the of hypermetabolism is and can be using that is now OF the current of of energy balance in CF, reviewed the link between energy balance and deterioration in nutritional status in CF requires on the of the energy-balance equation shown as in the with CF is relatively well, with lung function and control of malabsorption, or positive energy balance can be (Fig. 1). Such a can with increases in fecal which are relative to that of control subjects, even with as as EI is only suboptimal and TEE is Acute pulmonary exacerbations represent a more to the maintenance of positive or energy balance. exacerbations EI is and the may be further compromised by increased E1. rate can be but this causes negative energy balance on the of the in physical activity 1). most research on energy balance in CF has on children are well, the and of from negative energy balance associated with acute respiratory exacerbations is unclear. The effect of acute exacerbations on nutritional status is likely to be and probably increases with the of lung disease and increasing and of acute In the older with more severe lung disease it is well established that positive energy balance is to status and growth (Fig. leading to deterioration that may in reduce the ability to energy balance on the components of energy balance in this group is 1). There are few on the EI of these and no measurements of However, it is that is increased as lung function (Fig. The of the increase in is such that reduced physical activity is to Such patients may suffer from a hypermetabolism with episodes of negative energy balance associated with acute pulmonary but this has to be on the is well, and on components of energy balance energy intake or has been in the and of the in energy balance shown in However, further in our understanding of the pathogenesis of malnutrition in CF will on the in our In measurements of energy balance in children are acute exacerbations and in children with severe lung are so that the clinical events can be more to deterioration in nutritional should be given to the measurement of the components in the energy-balance equation in the are now that this This has now and the cause of weight loss in patients (31). of differences is also In both nutritional status and survival are better in with CF than The reason is but does not to be to differences in EI longitudinal studies in which components of energy balance are measured a of the three clinical in the periods in the development of malnutrition to be Data from a recent longitudinal study of in in patients with CF have most described growth in and revealed a possible link between impaired development of the and deterioration in lung function the cause(s) of negative energy balance in CF will nutritional management of the disease by to on those components that are to the deterioration and to those that are the between the main clinical events and in energy balance will also provide the for more of nutritional to deterioration in CF, as in other diseases an understanding of the causes of negative energy balance in CF has the to lead to treatment strategies that the quality of and the survival of patients with CF. The for this and and the for their on growth expressed as in children with CF mean at each from et al. of total energy expenditure in healthy children et al. pulmonary function in with CF from et energy expenditure by and weight loss in adults with HIV infection = from et (31).