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Eur Respir J 2003; 22:81s-86s
Copyright ©ERS Journals Ltd 2003

Nutritional and metabolic modulation in chronic obstructive pulmonary disease management

A.M.W.J. Schols

CORRESPONDENCE: A.M.W.J. Schols, Department of Respiratory Medicine, University Hospital Maastricht, P.O. Box 5800, 6202, AZ Maastricht. Fax: 31 433875051. E-mail: a.schols@pul.unimaas.nl

Keywords: body weight, chronic obstructive pulmonary disease, metabolism, muscle, nutrition

Received: June 30, 2003
Accepted June 30, 2003


   ABSTRACT
TOP
 ABSTRACT
Modulation of energy balance
 Modulation of substrate...
 REFERENCES
 
In this paper the perspective for nutritional modulation of systemic impairment in patients with chronic obstructive pulmonary disease (COPD) is discussed. Progressive weight loss is characterised by disease-specific elevated energy requirements unbalanced by dietary intake. Weight gain per se can be achieved by caloric supplementation while future studies may prove efficacy of amino acid modulation to stimulate protein synthesis and enhance muscle anabolism.

Disproportionate muscle wasting resembles the cachexia syndrome as described in other chronic wasting diseases (cancer, chronic heart failure, acquired immunodeficiency syndrome (AIDS)). There is yet no adequate nutritional strategy available to treat cachexia in COPD. Muscle substrate metabolism has hardly been investigated, but the few data available point towards a decreased fat oxidative capacity that may show similarities with the "metabolic syndrome" as described in type II diabetes and obesity and could theoretically benefit from polyunsaturated fatty acid modulation.

To adequately target the different therapeutic options, clearly more clinical (intervention) studies are needed in chronic obstructive pulmonary disease patients that are adequately characterised by local and systemic impairment and in which molecular and metabolic markers are linked to functional outcome.

Nutritional screening and therapy is nowadays considered as an essential component of integrated chronic obstructive pulmonary disease (COPD) management. In particular systemic manifestations of COPD are potential targets for intervention. The present paper aims to present current insight into the efficacy of dietary supplementation to reverse weight loss and muscle wasting in COPD as well as to discuss the perspective for nutritional modulation of altered muscle metabolism. In addition the question will be addressed to what extent these systemic manifestations in COPD should be regarded as disease specific, or represent generalised phenomena of chronic disease.


   Modulation of energy balance
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 ABSTRACT
 Modulation of energy balance
Modulation of substrate...
 REFERENCES
 
Loss of body weight and fat mass
The association between underweight and increased mortality risk has been well established in numerous retrospective studies ranging from selected COPD patients to population-based samples 1–3. Two prospective studies even showed in COPD patients with a body mass index below 25 kg·m–2 that weight gain was associated with decreased mortality risk 2, 4. It is not fully understood why COPD patients become underweight but weight loss and specifically loss of fat mass, is generally the result of a negative energy balance and appears to be more prevalent in patients with emphysema 5. In contrast to an adaptive decreased energy metabolism during (semi) starvation, increased resting energy requirements have been observed in some of the COPD patients, linked to low-grade systemic inflammation 6, 7. Studies in other chronic wasting diseases characterised by hypermetabolism and systemic inflammation (e.g. cancer, chronic heart failure, acquired immunodeficiency disease syndrome (AIDS)) have shown an adaptive decrease in activity-induced energy expenditure so that daily energy expenditure is normal. In contrast, elevated activity induced and daily energy expenditure has been measured in free-living ambulatory COPD patients 8. The cause of this disease-specific increase in energy metabolism is not yet clear. A decreased mechanical efficiency of leg exercise has been described that could result from a decreased efficiency of skeletal muscle energy metabolism. Furthermore some studies reported an increased oxygen cost of respiratory muscle activity due to lung hyperinflation. An obvious choice to improve energy balance might thus be to decrease energy expenditure. However, according to the recent Global Initiative for Obstructive Lung Disease (GOLD) guidelines, pulmonary rehabilitation is evidence based and exercise training a key intervention to improve limited functional abilities and maintain an active lifestyle 9. Since COPD patients may have an elevated energy metabolism and should at the same time be advised to increase exercise, restricting energy output will be hard to realise and may not be desirable. This implies that COPD patients who suffer from weight loss, and even some weight stable patients, should be encouraged to increase their apparently normal energy intake. This could avoid weight loss, specific loss of muscle mass, and a related decrease in functional ability, or could help them regain weight. Besides optimising the treatment of patients who are already underweight, it is therefore important to detect and reverse involuntary weight loss in order to avoid functional decline. This may be achieved by increasing dietary intake per se or by altering dietary habits to include different (energy-dense) foods and optimum timing of meals/snacks in relation to symptoms and activity patterns.

Substrate oxidation and ventilation are intrinsically related and theoretically meal-related dyspnoea and impaired ventilatory reserves might restrict the caloric amount and specifically the carbohydrate content of nutritional support in respiratory disease. Earlier studies indeed showed adverse effects of a carbohydrate-rich energy overload on carbon dioxide production and exercise capacity 10, but these results were not confirmed when using a normal energy load 11. In fact even positive effects of a carbohydrate-rich supplement relative to a fat-rich supplement on lung function and dyspnoea sensation were reported 12.

Caloric supplementation versus dietary change
Nutritional interventions for COPD patients have focussed mainly on therapeutic caloric support, but few well-controlled studies (i.e. randomised controlled trials (RCTs)) have so far been conducted. Ferreira et al. 13 have recently reviewed the available studies on therapeutic dietary supplementation in a meta-analysis. They managed to select only six RCTs that were considered to be of sufficient quality, of which two were double-blinded. The pooled effects, based on the analysis of a total of 277 subjects, as well as the results of the individual studies, showed that the effect of nutritional support on anthropometrics was minor at best and generally did not achieve clinical importance or statistical significance. Five of these studies used oral supplementation and four were conducted among outpatients. These results contradict to some extent the results reported by Baldwin et al. 14, who reviewed the literature on dietary advice and supplementation interventions for patients with disease-related malnutrition in general (including COPD). Their conclusion was that dietary supplementation resulted in better effects on body weight than dietary advice. The review by Ferreira et al. 13 made no distinction between what may be called "failure to intervene" on the one hand and "failure of the intervention" on the other. In some of the papers on which the meta-analysis was based, patients took the prescribed dietary supplements to replace regular meals instead of as additional calorie input. In such cases the intervention did not succeed in a relevant increase in energy intake and therefore no weight gain could be expected. In the studies that did accomplish to increase energy intake, functional improvements were also observed. Further, studies investigating the effect of dietary supplementation were often conducted among severe COPD cases, in whom besides a negative energy balance, also a specific negative protein balance is often observed (as discussed below). Nevertheless, the meta-analysis and related studies do show that increasing energy intake among severe COPD cases is difficult to accomplish, and if energy intake is not increased, weight and functionality will certainly not improve. Interventions should also be extended to prevention and early treatment of weight loss, that is, before patients are extremely wasted. This means expanding the target group to include COPD outpatients and primary care patients before they have become underweight, and putting more emphasis on dietary change than on medically prescribed supplementation. Few studies have been published on the possibilities and effects of voluntary dietary change among outpatients. Diet is often part of the focus in self-help or self-management programmes for COPD patients and some of these programmes have been evaluated. However there have not yet been any well-controlled studies of the prevention of weight loss in COPD.


   Modulation of substrate metabolism
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 Modulation of energy balance
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Muscle wasting
Body compositional studies have shown that weight loss is accompanied by significant loss of fat-free mass and that it is specifically the loss of fat-free mass or other measures of muscle mass that are related to impaired skeletal muscle strength and exercise capacity 15, 16. These studies have furthermore shown that muscle wasting may also occur in normal weight stable subjects. A recent study even suggested that muscle mass is a better predictor of survival than body weight 17. Wasting of muscle mass is due to an impaired balance between protein synthesis (anabolism) and protein breakdown (catabolism). Besides nutritional abnormalities and physical inactivity, altered neuro-endocrine response and presence of a systemic inflammatory response may contribute to a negative protein balance in chronic diseases. From a therapeutic perspective it is important to know the relative contribution of these factors to altered protein synthesis and protein breakdown respectively. While increasing dietary intake can compensate elevated energy requirements and vice versa, uncontrolled protein breakdown cannot be overcome by only increasing protein synthesis and vice versa.

Protein metabolism
Several studies have investigated in COPD and other chronic wasting disorders the effects of pharmacological anabolic stimuli to promote protein synthesis including anabolic steroids, growth hormone and insulin-like growth factor. Discussion of these studies is beyond the scope of this paper. However the fact that most studies in COPD were able to document a modest but significant gain in muscle mass after intervention 18, 19, illustrates that in some of the patients, stimulation of protein synthesis is an effective therapeutic strategy. No studies have yet specifically investigated the ability to induce or enhance muscle weight gain by nutritional modulation of protein synthesis or protein breakdown rates. Optimising protein intake and essential amino acid intake may stimulate protein synthesis per se, but also enhance efficacy of anabolic drugs 20 as well as physiological stimuli such as resistance exercise 21. Protein requirements in COPD patients and many other chronic diseases are not well established. In normal weight COPD patients, whole body protein synthesis and breakdown rates were elevated compared to a well-matched healthy control group 22. A potential explanation for this elevated protein turnover is thought to be enhanced acute phase protein synthesis, associated with low-grade inflammation. This is balanced by increased amino acid release from the skeletal muscle compartment (ultimately) resulting in net muscle protein breakdown. Indirect support for this hypothesis is given by two studies that demonstrated a specific association between muscle wasting and markers of systemic inflammation in COPD 23, 7 as well as by another study linking hypermetabolism, increased levels of acute phase proteins and decreased plasma amino acid status 24. However these studies were merely descriptive and limited by a cross-sectional study design. Investigating whole body as well as acute phase protein turnover simultaneously 25 may provide more insight into the proposed link between protein metabolism and systemic inflammation in COPD. Skeletal muscle protein turnover has yet been investigated in only one study. Muscle protein synthesis rate was decreased in a group of underweight clinically stable patients with emphysema while protein breakdown rate was normal 26. This observation fits with the observed positive effects of anabolic pharmacological intervention as well as resistance training on muscle mass during rehabilitation. More studies are needed however to test if these results can be extrapolated to patients with disproportionate muscle wasting.

Amino acids
Amino acids are the building blocks of protein and several studies have to date reported an abnormal plasma amino acid pattern in COPD. Of interest are the consistently reduced plasma levels of branched chain amino acids (BCAAs) in underweight COPD patients and in those with low muscle mass 27, 28. There are some indications that low plasma BCAAs in COPD patients are due to specific alterations in leucine metabolism possibly mediated by altered insulin regulation and increased leucine oxidation in skeletal muscle to a noncarbohydrate energy substrate 28. Leucine is an interesting nutritional substrate since it not only serves as precursor, but also activates signalling pathways that enhance activity and synthesis of proteins involved in messenger ribonucleic acid (RNA) translocation to upregulate protein synthesis in skeletal muscle 29.

In addition to fostering a general higher rate of postprandial protein synthesis, increased availability of amino acids also enhances the stimulation of protein synthesis that occurs in response to exercise 21. The magnitude of stimulation however depends on the timing of amino acids administration relative to the period of exercise 30. BCAAs are also important precursors for glutamate (GLU), which is one of the most important non-essential amino acids in muscle. BCAA derived from net protein breakdown and by uptake into the muscle pool, undergo transamination to yield branched-chain keto acid and GLU. Intracellular GLU is involved in numerous metabolic processes including substrate phosphorylation and replenishment of tricarboxylic acid (TCA) intermediates to preserve high-energy phosphates at rest and during exercise. Moreover intracellular GLU is known as an important precursor for antioxidant glutathione (GSH) and glutamine synthesis in muscle 31. Recently, a consistently reduced muscle GLU status of severe COPD patients was reported 31, 24, that further decreased during a submaximal exercise bout 32. While muscle redox potential (glutathione disulphide/GSH) increases after endurance exercise training in healthy subjects, patients with COPD showed a reduced ability to adapt in this way as reflected by a lower capacity to synthesise GSH 33. These observations provide perspective for amino acid supplementation to modulate exercise-induced protein synthesis as well as exercise-induced oxidative stress.

n-3 polyunsaturated fatty acids
Despite anabolic nutritional and/or pharmacological stimulation, (muscle) weight gain is limited in part of the COPD patients. Like in other chronic inflammatory disorders, poor therapeutic response was related to presence of systemic inflammation 34. Disproportionate muscle wasting linked to systemic inflammation and unresponsive to nutritional supplementation is commonly referred to as the cachexia syndrome as recently discussed 35. Current insight into the molecular mechanisms of cachexia indicates a complex interaction between inflammatory mediators, oxidative stress and growth factors, not only involved in an imbalance between muscle protein synthesis and breakdown, but also in processes that govern the maintenance of skeletal muscle and muscle plasticity such as skeletal muscle fibre degeneration, apoptosis and regeneration 35. These experimental studies may provide in the near future novel pharmacological perspective by specifically targeting crucial mediators of the intracellular signalling pathways involved. But to be able to identify applicability of the proposed mechanisms for COPD (subgroups), a challenge for future human research will be to identify and reliably assess critically regulatory molecules of these processes in muscle biopsies or other tissue to be monitored in clinical comparative and intervention studies.

The fatty acid composition of inflammatory and immune cells is sensitive to change according to the fatty acid composition of the diet. The n-3 polyunsaturated fatty acids (PUFA) eicopentanaenoic acid (EPA) and docosahexaenoic acid are found in high proportions in oily fish and fish oils. The n-3 PUFA are structurally and functionally distinct from the n-6 PUFA. Typically human inflammatory cells contain high proportions of the n-6 PUFA, arachidonic acid and low proportions of n-3 PUFA. The significance of this difference is that arachidonic acid is the precursor of 2-series prostaglandines and 4-series leukotrienes, which are highly-active mediators of inflammation. Feeding fish oil results in partial replacement of arachidonic acid in inflammatory cell membranes by EPA. This change leads to decreased production of arachidonic acid-derived mediators. This response alone is a potentially beneficial anti-inflammatory effect of PUFA. Supplementation of the diet of healthy volunteers with fish oil-derived n-3 PUFA resulted in decreased monocyte and neutrophil chemotaxis and decreased production of pro-inflammatory cytokines 36. Clinical studies have reported that fish oil supplementation has beneficial effects on the systemic inflammatory response and disease activity in conditions such as rheumatoid arthritis and inflammatory bowel disease 36. In patients with cancer cachexia encouraging effects of PUFA supplementation were shown in terms of a decreased systemic inflammatory response and body weight gain 37. The latter may be related to other effects of n-3 PUFA which occur downstream of altered eicosanoid production or might be independent of this activity. Nuclear factor kappa B (NF-{kappa}B) is a critical mediator of the intracellular signalling events triggered by tumour necrosis factor (TNF)-{alpha} and other inflammatory cytokines including skeletal muscle specific gene expression 35. Recent studies have shown that n-3 PUFA can down-regulate the activity of NF-{kappa}B. The interaction of n-3 PUFA and cytokine biology is however complex. In healthy volunteers the sensitivity of a person to the suppressive effects of n-3 PUFA on TNF-{alpha} production is linked to the inherent level of production of the cytokines by cells from the person before supplementation and genetic variation encoded by, or associated with the TNF-{alpha} –308 and lymphotoxin a +252 single nucleotide polymorphisms 38. Some studies suggest that TNF-{alpha} levels are particularly increased in COPD patients with weight loss and/or muscle wasting 23. Therapeutic effects of n-3 PUFA in COPD have yet to be determined. In this context it may be relevant to note that TNF-{alpha} –308 polymorphism has been associated with the presence of COPD 39 and even specifically with the extent of emphysematous changes in these patients 40.

Muscle morphology and metabolism
Independent of muscle wasting, intrinsic abnormalities in peripheral skeletal muscle morphology and metabolism have been described in COPD patients, pointing towards a decreased oxidative capacity. These abnormalities include muscle fibre type shifts from the oxidative type I fibres towards the glycolytic type IIx fibres 41, accompanied by a decrease in oxidative enzymes involved in carbohydrate and fatty acid oxidation 42. As reviewed elsewhere striking similarities have been observed in these abnormalities between patients with COPD and chronic heart failure 43. Detailed information of substrate metabolism on whole-body and skeletal muscle level in these diseases is lacking. Nevertheless, the metabolic adaptations have clinical consequence as illustrated e.g. by a decreased mechanical efficiency 44 and enhanced lactic acid production during exercise 45 relative to healthy control subjects. In addition nuclear magnetic resonance studies using single limb exercise models showed a rapid decline and impaired recovery of phosphocreatine stores 46. Three studies indicated that the decreased oxidative capacity may be more pronounced in patients with emphysema, possibly related to altered oxygen availability 41, 47, 48.

Positive effects of pulmonary rehabilitation, in particular of endurance exercise training, illustrate that decreased muscle oxidative capacity in COPD is at least partly reversible 46, although again detailed information on the effect of endurance training on substrate metabolism in COPD is lacking. While overall effects of endurance type exercise are positive, the available studies also clearly show that it is difficult to enhance this response by modulating exercise type and intensity only 49, 50. It is therefore tempting to explore the potential of nutritional modulation on muscle substrate metabolism to enhance improvement of exercise capacity in COPD.

Muscle substrate metabolism
The muscle fibre type shift from type I to type IIx together with the enhanced lactic acid production during exercise points towards a decreased oxidative capacity for specifically fatty acids. This suggestion is consistent with the finding that 3-hydroxyacyl-coenzyme A dehydrogenase (HADH) (an enzyme involved in the β-oxidation of fatty acids) was shown to be decreased in COPD 42, whereas cytochrome C oxidase (an enzyme of the respiratory chain) as well as phosphofructokinase (a glycolytic enzyme) was found to be increased in some studies 51, 52. Disturbances in fat oxidative capacity have also been found in other diseases such as obesity and type 2 diabetes mellitus. These disturbances can be located at the levels of cellular fatty acid uptake, mitochondrial fatty acid uptake and/or fatty acid oxidation. The uptake of fatty acids from the blood into the muscle cell is facilitated by the fatty acid transporters fatty acid translocase (FAT)/CD36 and fatty acid binding protein (FAPBpm) 53. Impaired expression of fatty acid transporters have indeed been suggested to be involved in the decreased fat oxidative capacity observed in type 2 diabetes mellitus, but data in COPD is lacking 54. However, it could explain the beneficial effects of endurance training in COPD, as exercise training is able to increase the protein content of FAT/CD36 55. Once taken up into the muscle cell, fatty acids need to be taken up into the mitochondria before they can undergo β-oxidation. Mitochondrial fatty acid uptake is accomplished by carnitine-palmitoyl-transferase-1, the activity of which is under the control of malonyl coenzyme A (malonyl-CoA), the latter being formed out of acetyl-CoA by the enzyme acetyl-CoA carboxylase-2 (ACC2) 56. It is generally assumed that the mitochondrial uptake of fatty acids is a rate-limiting step in fatty acid oxidation. Endurance training is known to increase fat oxidative capacity and recent data show that ACC2 might be a key factor involved, as endurance training rapidly down-regulates ACC2, allowing increased fat oxidation 57. Once taken up into the mitochondria, fatty acids can undergo β-oxidation. The key-enzyme in the β-oxidation of fatty acids is HADH, which is decreased in skeletal muscle of COPD 42. The acetyl-CoA formed from the degradation of fatty acids, subsequently enters the TCA cycle, in which the rate-limiting step is the enzyme citrate synthase, which was also shown to be lower in COPD 42. Future studies are clearly needed to further explore the presence and mechanisms of decreased fat oxidative capacity in COPD. Moreover, these studies may be a further trigger to explore the potential of nutritional modulation on muscle substrate metabolism to enhance improvement of exercise capacity.

Polyunsaturated fatty acids
Polyunsaturated fatty acids, particularly those of the (n-3) family and to a lesser extent of the (n-6) family, have been shown to specifically alter expression of genes involved in substrate metabolism. They may upregulate the expression of genes encoding proteins involved in fatty acid oxidation while simultaneously down-regulate genes encoding proteins of lipid synthesis 58. Therefore polyunsaturated fatty acids can be of potential interest in improving oxidative capacity in chronic obstructive pulmonary disease. Polyunsaturated fatty acids govern oxidative gene expression by activation of the transcription factor peroxisome proliferator activated receptor {alpha} 59. This is also the basis for the use of peroxisome proliferator activated receptor agonists in overcoming disturbances in substrate metabolism in insulin resistant disorders (i.e. the metabolic syndrome). The decreased fat oxidative capacity in chronic obstructive pulmonary disease can also be explained by the shift in muscle fibre type. In this context, it is very interesting to note that it was very recently shown that overexpression of the peroxisome proliferator activated receptor gamma-coactivator-1 in mice resulted in a complete shift in muscle fibre type from IIx to I 60. Moreover, endurance training was shown to increase peroxisome proliferator activated receptor gamma-coactivator-1 expression 61. It is therefore tempting to speculate that peroxisome proliferator activated receptor gamma-coactivator-1 expression might be altered in chronic obstructive pulmonary disease, although no data is yet available.


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