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Pulmonary cachexia
International Journal of Cardiology 85 (2002) 101–110 www.elsevier.com / locate / ijcard
Pulmonary cachexia Annemie M.W.J. Schols* Department of Pulmonology, University Maastricht, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands Received 28 January 2002; accepted 6 April 2002
Abstract Weight loss is a frequent complication in patients with chronic obstructive pulmonary disease (COPD) and is a determining factor of functional capacity, health status, and mortality. Weight loss in COPD is a consequence of increased energy requirements unbalanced by dietary intake. Both metabolic and mechanical inefficiency contribute to the elevated energy expenditure during physical activity, while systemic inflammation is a determinant of hypermetabolism at rest. A disbalance between protein synthesis and protein breakdown may cause a disproportionate depletion of fat-free mass in some patients. Nutritional support is indicated for depleted patients with COPD because it provides not only supportive care, but direct intervention through improvement in respiratory and peripheral skeletal muscle function and in exercise performance. A combination of oral nutritional supplements and exercise or anabolic stimulus appears to be the best treatment approach to obtaining significant functional improvement. Patients responding to this treatment even demonstrated a decreased mortality. Poor response was related to the effects of systemic inflammation on dietary intake and catabolism. The effectiveness of anticatabolic modulation requires further investigation. 2002 Published by Elsevier Science Ireland Ltd. Keywords: Pulmonary cachexia; Chronic obstructive pulmonary disease; Involuntary weight loss; Oxygen consumption; Limited ventilatory capacity
1. Introduction Chronic obstructive pulmonary disease (COPD) is a progressive disorder leading to significant debilitation. While traditionally been considered as irreversible lung disease, there is growing evidence that COPD is a multi-organ systemic disease. Parallel to this awareness, the interest for weight loss and muscle wasting in the management of COPD has changed remarkably during the past two decades. Involuntary weight loss is a well-recognized clinical finding and a substantial number of patients suffering from COPD, particularly emphysema, become emaciated during the course of the disease. InterestE-mail addresses: http: / / www.pul.unimaas.nl (A.M.W.J. Schols), [email protected] (A.M.W.J. Schols).
ingly, attempts to classify COPD patients indeed found that body weight might be a discriminating factor. This led to the classical description of the pink puffer (emphysematous type) and the blue bloater (bronchitic type). Initially weight loss was thought to be an epiphenomenonon of severe disease and an adaptive mechanism to decrease oxygen consumption. Potential adverse effects of nutritional support were even highlighted since caloric overload, particularly of carbohydrates might induce CO 2 retention and thus respiratory failure in these patients with limited ventilatory capacity. Recent studies have yet convincingly challenged this viewpoint and shown that weight loss is often associated with elevated oxygen consumption and an independent risk factor for prognosis. Nutritional assessment according to body weight is
0167-5273 / 02 / $ – see front matter 2002 Published by Elsevier Science Ireland Ltd. PII: S0167-5273( 02 )00238-3
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simple but bears important limitations since it provides no qualitative information on body tissues. In contrast to fat accretion as being the main concern in obesity, consequences of weight loss are specifically related to a decrease in body cell mass, even irrespective of the amount of fat tissue. Body cell mass is defined as the active metabolising and contracting tissue. Muscle mass is the largest single tissue component of body cell mass and can be assessed in clinical practice by measurement of fat-free mass. Based on the available evidence I will show here that fat-free mass is a simple screening tool in extrapulmonary COPD management not only to target nutritional interventions, but also pulmonary rehabilitation. Weight loss per se simply refers to a imbalance between dietary intake and energy expenditure. Muscle wasting in chronic disease, however, is a more complex process, being a consequence of changes in the control of both intermediary metabolism (protein synthesis and breakdown) and cell status (proliferation, differentiation, and apoptosis). These processes are regulated by various extrinsic factors (hormones, growth factors and cytokines) and intrinsic factors of the muscle cell (receptors and intracellular signalling mechanisms). Optimal therapeutic intervention in muscle wasting depends on proper insight into the precise mechanisms. While the regulation of energy balance in relation to weight loss has been extensively explored, investigation into intermediary metabolism and molecular mechanisms of muscle wasting is in its infancy in COPD. Nevertheless recent studies show that, besides optimal implementation of nutritional support to reverse weight loss, research into this area may provide a promising therapeutic perspective not only to prevent or treat muscle wasting in COPD, but also to enhance the efficacy of pulmonary rehabilitation.
2. Definition of pulmonary cachexia Traditionally cachexia and starvation are the two paradigms of nutritional depletion. Starvation is characterized by pure caloric deficiency. The organism adapts metabolically to conserve body cell mass and increase fat metabolism while appropriate feeding can reverse the changes. In contrast cachexia is
associated with inflammatory conditions that evoke an acute phase response, including coordinated adaptations in intermediary metabolism, which increase protein degradation in muscle [1]. Feeding alone cannot reverse these aberrations. Either paradigm, however, does not cover the wasting process in COPD patients that I therefore refer to as pulmonary cachexia. Some of the weight-losing COPD patients suffer from pure caloric deficiency [2]. However, in contrast to (semi)-starvation and cachexia, weight loss may also be a consequence of elevated physical activity related energy requirements [3]. One reason for an elevated activity-induced energy expenditure could be a decreased efficiency related to altered pulmonary mechanics [4]. Indirect evidence for this factor in weight loss is provided by a spontaneous weight gain that was observed in patients with emphysema after lung volume reduction surgery (LVRS) [5]. Besides mechanical inefficiency, several recent studies also point towards an inefficient muscle energy metabolism. Using NMR spectroscopy, a severely impaired oxidative phosphorylation during exercise and recovery has been demonstrated, accompanied by an increased and anaerobic metabolism [6]. ATP production by anaerobic pathways is less efficient than ATP production by aerobic metabolism. This shift in cellular energy metabolism has been confirmed in muscle biopsy studies of resting muscle showing decreased levels of aerobic enzymes [7], phosphagens [8] and a fibre type shift towards more type II fibers [9]. Interestingly, two studies revealed that these muscular adaptations were more pronounced in the emphysematous sub-type [8,9]. Dietary assessment studies show that elevated energy requirements are initially met by a high spontaneous dietary intake [2]. When dietary intake is compromised by symptoms such as dyspnea, fatigue and meal related oxygen desaturation [10], a patient starts to loose weight. Since metabolic adaptations to energy deficit per se favour fat oxidation, these patients may already be severely underweight before being significantly debilitated with a poor prognosis. In controlled clinical settings it has been shown that proper timing of nutritional supplements adjusted to daily dietary and activity pattern is able to reverse weight loss in part of the patients [11]. In contrast to an adaptive decrease during starvation, elevated resting metabolic rate is a cardinal
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feature of cachexia [12]. Approximately 25% of the COPD patients are characterized by hypermetabolism at rest, which in accordance to other chronic wasting conditions like HIV infection, cancer and chronic heart failure, is related to presence of a systemic inflammatory response as a hallmark of the cachexia syndrome [13,14]. Hypermetabolism at rest is generally, however, not the direct cause of weight loss in cachexia, since as mentioned above it is associated with an adaptive decrease in activity-induced energy expenditure. This implies that a potential influence of inflammation on a negative energy balance in weightlosing patients could be by altering appetite regulation and dietary intake. Several observations support this hypothesis. There is increasing evidence that, besides local upregulation of inflammatory processes in the lung, COPD is characterized by an elevated systemic inflammatory response as reflected by elevated concentrations of proinflammatory cytokines and acute phase proteins in peripheral blood [15–17]. As in other chronic inflammatory diseases, weight loss has specifically been associated with increased circulating levels of TNFa, initially named cachectin, soluble TNFa receptors and with increased release of TNFa from circulating mononuclear cells [18,19]. Leptin, a 167-amino acid protein synthesized and secreted by white adipose tissue, is a component of a lipostatic signalling pathway that alters energy balance by central and peripheral mechanisms. We investigated the relationship between plasma leptin to both inflammation and energy balance in COPD patients stratified into chronic bronchitis and emphysema by high resolution CT in a cross-sectional and prospective design. As observed in healthy subjects and other chronic diseases, plasma leptin concentration was highly correlated with fat mass and thus (in absolute terms) low in underweight COPD patients [20]. However, after adjustment for the amount of fat mass, a significant correlation was found between leptin and sTNF receptor 55 in COPD [20]. In the prospective study, an inverse relationship between plasma leptin levels, baseline dietary intake and response to nutritional therapy was seen [20]. These results indicate that leptin levels are influenced by inflammatory cytokines and in turn may alter the patient’s ability to respond to nutritional intervention. Proinflammatory cytokines exert a variety of be-
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havioural and physiological effects in addition to their immunological and nutritional functions. To differentiate between effects related to semistarvation versus cachexia, longitudinal information of circulating cytokines and body composition is needed. On the other hand it is also possible that pure semistarvation as described above, may evolve to cachexia because malnutrition-induced immune dysfunction predisposes to infection. Experimental studies have shown that low leptin levels as normal adaptation in underweight COPD patients indeed influence T-cell mediated immunity [21].
3. Consequences of weight loss and muscle wasting in COPD Prominent symptoms of COPD are dyspnea and exercise intolerance. Besides airflow obstruction and loss of alveolar structure, skeletal muscle weakness is an important determinant of these symptoms. Body composition studies have convincingly shown that skeletal muscle dysfunction is predominantly determined by skeletal muscle mass in COPD [22,23] and that muscle wasting does not spare the respiratory muscles [24]. Besides effects on muscle strength, muscle mass is also a significant determinant of exercise capacity and exercise response [25,26], implying that functional consequences are not only related to muscle wasting per se, but also to intrinsic alterations in muscle morphology and energy metabolism. Recently Gosker et al. demonstrated that muscle wasting in COPD is fibre type specific affecting type IIx fibres [27]. Whole body fat-free mass was strongly correlated with muscle fibre cross-sectional area [27]. Besides effects on exercise capacity, two studies have shown that FFM depletion as marker of systemic impairment is also related to a decreased health related quality of life measured by the disease-specific St George’s Respiratory Questionnaire (SGRQ) [28,29]. The relationship between weight loss and mortality has been subject of investigation since the 1960s. In the early years a significant association was reported between weight loss and survival [30]. In line, several retrospective studies using different COPD populations from the USA [31], Canada [32], Denmark [33] and The Netherlands [11] reported more recently a
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relationship between low body mass index and mortality independent of disease severity. Remarkably, in all these studies a decreased mortality risk was observed in overweight patients not only compared to underweight patients but also to normal weight subjects. This observation could be related to the fact that depletion of FFM is not only a consequence of weight loss, but may also occur in normal weight patients with a relatively preserved fat mass. The available prevalence studies indicate that depletion of FFM is a significant clinical problem. In stable patients with moderate to severe COPD, depletion of FFM has been reported in 20% of COPD out-patients [34], in 35% of those eligible for pulmonary rehabilitation [35] and even in 45% of lung transplant candidates [36]. Limited data are yet available regarding the prevalence of FFM depletion in representative groups of mild COPD, and on the other side of the spectrum, in patients suffering from acute respiratory failure. Weight loss and a low body mass index are more frequently observed in emphysematous patients compared to chronic bronchitis, but differences in body weight between the two COPD subtypes, if present, merely reflect a difference in fat mass. Depletion of FFM even despite a relative preservation of fat mass also occurs in chronic bronchitis [37]. In fact it has been shown that normal weight patients with depleted fat-free mass are more disabled that underweight patients with preserved fat-free mass [35]. For a differentiation between the contribution of semistarvation and cachexia to muscle wasting and from a therapeutic perspective (to choose priorities between nutritional support and different forms of exercise), we advocate that not only weight changes, but also fat-free mass should be considered in the screening of COPD.
4. Intermediary metabolism in COPD Disproportionate depletion of fat-free mass despite relative or absolute preservation of fat mass in part of the COPD patients points towards alterations in intermediary metabolism. Limited studies have yet investigated intermediary metabolism in COPD. This is surprising since individual effects of several disease characteristics like inflammation, oxidative
stress and hypoxia have been extensively investigated on intermediary metabolism in healthy subjects and in other wasting conditions. One might speculate that COPD is characterised by altered intermediary metabolism shifting body composition towards wasting of fat-free mass, while a sub group of predominantly emphysematous patients is further compromised by loss of weight and fat mass. Insulin has a central role in the regulation of intermediary metabolism. Hyperinsulinemia and to a lesser extent hyperglycemia are commonly seen in COPD [38]. Insulin resistance seems to be at the basis of this metabolic disturbance. Limited information is available, however, on glucose tolerance in chronic lung diseases. This is remarkable since both inflammation and hypoxia influence glucose metabolism in healthy subjects. With chronic altitude exposure basal glucose production is almost twice as great as at sea level. Plasma glucose concentration at high altitude is lower than at sea level, suggesting facilitated tissue uptake [39]. In vitro studies in human muscle have shown that hypoxia stimulates glucose transport, even in insulin-resistant human skeletal muscle [40]. Chronic disease in general can stimulate glucose production and will mostly induce peripheral insulin resistance. The end result of these partly opposite effects on glucose metabolism in (subgroups of) COPD cannot be predicted. Glucose metabolism has hardly been studied in COPD and the three available studies are inconclusive [41–44] probably partly based on differences in patient selection (i.e., range in body mass index and PaO 2 ) . Specifically considering the adverse functional effects of muscle wasting, we investigated the balance between protein synthesis and breakdown in weight stable COPD patients [44]. Whole body protein synthesis and breakdown were elevated compared to a well-matched control group, indicating a disease-related increase in protein turnover. 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 an increased amino acid release from the skeletal muscle compartment resulting in net muscle protein breakdown. Previously Pouw et al. indeed observed an inverse relationship between the acute phase protein LPS binding protein and the total sum of plasma amino acid levels in patients with
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COPD [45]. In another study COPD patients with an acute phase response and elevated resting metabolic rate, were indeed characterized by selective depletion of fat-free mass as hallmark of cachexia [15]. More studies are needed, however, to confirm this hypothesis using advanced techniques to measure (acute phase) protein synthesis and breakdown at the whole body level and across skeletal muscle. These studies are important because they highlight that maintenance of homeostatic regulation of metabolic processes in COPD under certain circumstances is a labile equilibrium between different priorities. Evoked in inflammatory conditions the acute phase response includes the hepatic synthesis of large quantities of proteins with a wide variety of functions to clear tissue debris. This is an energy-intensive process with high rates of hepatic protein synthesis requiring large quantities of essential amino acids. The need for essential amino acids drives the loss of skeletal muscle. The trade off may be viewed as a shift in the body’s priorities from offensive to defensive [1]. This adaptation is effective over the short term because skeletal muscle is replaced rapidly as recovery is completed. Because skeletal muscle depletion significantly contributes to morbidity and mortality, problems ensue when the process is chronic related to continuous low grade inflammation or frequent acute (infectious) exacerbations. It is also important to realize that while this catabolic process is ongoing, anabolic interventions to increase protein synthesis like nutrition and exercise are only partly effective. Based on recent observations in COPD patients showing an altered metabolic response during exercise, one might even speculate that exercise alone may enhance catabolism [46]. The building blocks of proteins are amino acids, playing a pivotal role in intermediary metabolism. Different studies demonstrated consistently decreased levels of the amino acid glutamate (GLU) in peripheral muscle biopsies in patients with COPD [45,47]. Intracellular GLU plays an important role in preserving high-energy phosphates in muscle through different metabolic mechanisms. Intracellular GLU is known as an important precursor for antioxidant glutathione (GSH) and glutamine synthesis in the muscle. Muscle GLU is highly associated with GSH, and Engelen et al. showed that patients with emphysema suffer from decreased muscular GLU and
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GSH levels [47]. Moreover, a reduction in muscle GLU was associated with early lactic acidosis during exercise [48]. Besides an already depleted state of some amino acids at rest, sub-maximal exercise at low intensity resulted in increased leakage of amino acids out of muscle as shown by a dramatic decrease of all amino acids in muscle and an increased plasma amino acid level. Abundant evidence from studies in incubated muscles and muscle extracts suggests that the adenosine triphosphate (ATP)-dependent ubiquitin–proteasome pathway is responsible for most of the increased proteolysis in various types of muscle atrophy. In particular, increased levels of ubiquitin-conjugated proteins, and increases in mRNA levels for polyubiquitin, certain proteasome subunits and the ubiquitin conjugating enzyme E2 14K are features found in most atrophying muscles studied so far [49]. Despite these similarities, there are many unanswered questions about the biochemical basis for accelerated proteolysis in muscle atrophy generally, and possible variations in this response in different human conditions like COPD. In addition to catabolic effects of systemic inflammation, tissue hypoxia is known to reduce muscle protein synthesis in experimental conditions [50]. Hypoxia is a hall mark of end stage COPD and a substantial proportion of mainly emphysematous patients exhibit arterial oxygen desaturation during exercise despite normal resting arterial oxygen tension. Presence of tissue hypoxia in COPD and its modulating role in intermediary metabolism under fasting and stressed conditions however remains elusive. In addition to disturbances in energy balance and intermediary metabolism, muscle wasting may be the result of a decreased number of fibres or myofibrillar protein content, consequent to activation of apoptotic pathways, imbalances in protein synthesis and breakdown, and altered regulation of skeletal muscle regeneration. Theoretically, apoptosis of myofibers could result in muscle atrophy. In vitro studies have documented apoptosis in skeletal myoblasts, indicating that myocytes possess the ability to undergo organised cell death. Specifically, the addition of inflammatory mediators like tumor necrosis factor-a (TNFa) and reactive oxygen and nitrogen species to myoblasts resulted in nuclear condensation and DNAladdering [51,52]. In an experimental model of heart
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failure known to result in muscle atrophy, apoptosis in skeletal muscle was correlated with circulating levels of TNFa [53]. A clinical study showed evidence for skeletal myocyte apoptosis in heart failure and its magnitude was associated with the degree of muscle fibre atrophy based on a decreased muscle cross-sectional area [54]. No studies have yet described apoptosis in COPD, but interestingly Gosker et al. [27] showed in muscle biopsies of COPD patients, that severe muscle fibre atrophy at comparable levels was associated with absence of stainable enzyme activity. Other studies have focussed on the activation of pathways by inflammation and oxidative stress that may reduce myofibrillar protein content in skeletal muscle or affect skeletal muscle regeneration. Discussion of these studies is, however, beyond the scope of this review. The studies do suggest, however, that further clinical research should be focussed towards determining the presence of markers of inflammation and oxidative stress in skeletal muscle of COPD patients suffering from muscle wasting.
5. Effects of pulmonary cachexia on the primary organ impairment The effect of pulmonary cachexia in relation to lung function has yet predominantly focussed on ventilatory pump function. Study of the lung parenchyma in humans is difficult. It is possible to obtain lung tissue resected during surgery or whole lungs at autopsy in order to study the influence of weight loss on lung structure and function. Presence of coexisting pathological processes, which would have led to lung resection or death, however, could hinder the study of the effects of nutritional deficiency on lung parenchyma. Recent developments in high resolution CT scanning allow non-invasive measurement of lung mass and density. Such studies, however, have not yet been done in any detailed or systematic fashion. One of the earliest and most dramatic accounts of human starvation was meticulously reported during the second World War. In a total of 370 autopsies in which lungs were examined, 50 cases of emphysema (13.5%) were observed. Of the 50 cases, 14 were reported in individuals under the age of 30 years, and 20 in persons under the age of 40 years. The
pathological features seen in these mostly young adults were similar to those seen in senile emphysema [55]. Almost our entire current knowledge of the effects of malnutrition on lung parenchyma and its structure and function derives from experimental animal studies reported by Sahebjami [56] during the 1980s. These studies have clearly shown that nutritional depletion caused by food deprivation affect lung morphology, biochemistry and mechanics. The most intriguing observation in the lungs of malnourished animals is the remodelling of terminal airspaces in a manner that morphologically and morphometrically is quite similar to those seen in naturally occurring or enzyme-induced emphysema, and partly reversible [56]. The significance of these observations in COPD or other chronic wasting conditions is still unclear, because our current knowledge on the influence of nutrition on normal or diseased human lungs is so limited. It is furthermore important in experimental conditions to distinguish between energy depletion per se versus specific nutrient depletion and from a therapeutic perspective between nutrient repletion and bioactive suppletion. Massaro and Massaro [57] illustrated this issue nicely for vitamin A. Since treatment of normal rats with all-trans-retinoic acid increases the number of alveoli, they tested whether a similar effect would occur in rats with emphysema. Elastase was instilled into rat lungs, producing changes characteristic of human and experimental emphysema: increased lung volume reflecting a loss of lung elastic recoil, larger but fewer alveoli and diminished volume-corrected alveolar surface area due to destruction of alveolar walls. Treatment with all-trans-retinoic acid reversed these changes and the authors suggested that it may even provide nonsurgical remediation of emphysema even in humans.
6. Therapeutic strategy anno 2002: fine tuning of anabolic and anti-catabolic interventions The deleterious effects of weight loss and muscle wasting on morbidity and mortality in COPD provide a strong rationale for nutritional repletion therapy to induce weight gain and exercise or other anabolic stimuli to promote muscle mass and muscle function.
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The efficacy of nutritional intervention per se is not supported by results of a recent meta-analysis [58]. While some studies, particularly those performed in a controlled clinical setting, demonstrated a significant weight gain, others were unsuccessful. Part of a poor treatment response was related to the fact that either the supplementation was insufficient from a caloric viewpoint, or that patients were taking supplements instead of their normal meals. Otherwise, a variable treatment response underlines the complexity of the pathogenesis of nutritional depletion in COPD and indicate that targeted anabolic and anti-catabolic interventions, including nutritional support, should be based on adequate characterization of local and systemic impairment. Some patients may benefit from merely nutritional supplementation to balance dietary intake with elevated energy requirements, while in others additional anabolic stimuli are needed. Furthermore there remains a sub-group of cachectic patients that like in other diseases will hardly improve by the currently available treatment options. Nutrition and ventilation are intrinsically related because oxygen is required for optimal energy exchange. Theoretically, meal-related dyspnea and impaired ventilatory reserves may restrict the energy and carbohydrate content of nutritional support in respiratory disease. Recent short-term studies as well as the available clinical trials, however, did not show significant adverse effects of nutritional supplements on the ventilatory system. Remarkably, at a relatively low energy content, there were even positive effects of a carbohydrate-rich supplement relative to those of a fat-rich diet on lung function and dyspnea sensation [59]. Glucose is a rapidly available substrate. In view of the metabolic adaptations of the peripheral skeletal muscles towards decreased oxidative capacity, carbohydrates are also likely to be preferable above fat as an energy substrate during exercise. There are currently no disease-specific recommendations for protein intake in COPD. Studies in other catabolic conditions as well as in body builders, however, indicate that a protein intake of 1.5 g / kg body weight results in maximal muscle protein synthesis. Vermeeren et al. [60] showed that most patients hospitalised for an acute exacerbation of COPD, did not reach this recommendation during their total stay in the hospital. More studies are needed the assess the appropriate time of nutritional supplementation in
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relation to daily activities and disease state, to be able to reach a positive energy and protein balance in depleted patients. As described above, future studies may furthermore provide specific recommendations for modulation of metabolic pathways, e.g., energyrich substrates such as creatine, amino acids, antioxidants and other bioactive components in relation to exercise training to improve the efficacy of pulmonary rehabilitation. To enhance muscle gain, anabolic endocrinological therapeutic options are also being considered. Several studies in COPD and other chronic (wasting) conditions have clearly shown that anabolic steroids specifically induce muscle gain [61,62]. Relative to exercise alone, additional effects on muscle function appear limited. Preliminary results by Creutzberg et al. [63], however, point towards a erythropoietic effect of the anabolic steroid nandrolone decanoate, positively influencing exercise capacity. Furthermore, she found a beneficial effect in the sub-group of severe COPD patients on maintenance treatment with low-dose oral glucocorticoids. While these patients poorly responded to exercise alone or (if indicated) combined with nutritional support, anabolic steroid treatment completely reversed these deleterious effects of systemic glucocorticoids. A likely explanation for this effect is probably less related to the anabolic properties per se, but to binding competition of anabolic steroids and glucocorticoids on the glucocorticosteroid receptor, thereby neutralizing deleterious catabolic effects of glucocorticosteroids. Anabolic steroids have a high anabolic / androgenic ratio. Stimulating the androgenic together with the anabolic pathways by testosterone supplementation could, however, also be indicated in COPD since the disease is characterized by a high prevalence of hypogonadism, specifically in patients on systemic glucocorticosteroid treatment [64]. Decreased concentrations of anabolic hormones, like testosterone, might aggravate failure of generating an anabolic response needed for muscle anabolism. Other pharmacological anabolic stimuli to promote protein synthesis in COPD are growth hormone and insulinlike growth factors (IGFs). Although it is yet unclear if growth hormone, IGFs and IGF binding proteins are specifically reduced in patients with COPD, one controlled trial investigated growth hormone supplementation in underweight COPD patients [65]. De-
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spite a significant increase in muscle mass after therapy, no beneficial effects of this treatment have to date been demonstrated on muscle function and even adverse effects were shown on resting metabolic rate and exercise capacity. The latter study clearly indicates a labile balance between anabolic and catabolic processes in cachectic COPD patients. It has been suggested [1] that use of growth hormone can have negative effects in some situations by diverting excess essential amino acids and energy to skeletal muscle from use in the acute phase response, thereby compromising a basic function of host defence. Systemic inflammation is prominently involved in the pathogenesis of cachexia. Elevated levels of proinflammatory cytokines [66] indeed characterised patients poorly responding to nutritional supplementation and anabolic stimulation. Ant-inflammatory therapies may moderate pro-inflammatory cytokine activity. Studies in other chronic wasting conditions like inflammatory bowel disease and cancer have shown encouraging effects of n-3 polyunsaturated fatty acids (PUFAs) on cytokine release, markers of immune function and on body weight [1]. Studies with PUFAs in COPD are currently ongoing. More insight into the molecular mechanisms of pulmonary cachexia may likely boost novel nutritional and pharmacological treatment strategies directed at specifically targeting of crucial mediators of inflammatory signalling cascades and redox imbalances to allow for anabolic stimuli and muscle repair to occur in order to restore muscle mass and function. Meanwhile a stepwise treatment is warranted to treat pulmonary cachexia as integrated part of extra pulmonary COPD management.
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A.M.W. J. Schols / International Journal of Cardiology 85 (2002) 101 – 110 [21] Lord GM, Matarese G, Howard JK, Baker RJ, Bloom SR, Lechler RI. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature 1998;394(6696):897–901. [22] Engelen MP, Schols AM, Does JD, Wouters EF. Skeletal muscle weakness is associated with wasting of extremity fat-free mass but not with airflow obstruction in patients with chronic obstructive pulmonary disease. Am J Clin Nutr 2000;71:733–8. [23] Bernard S, LeBlanc P, Whittom F, Carrier G, Jobin J, Belleau R et al. Peripheral muscle weakness in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998;158:629–34. [24] Murciano D, Pichot MH, Boczkowski J, Sleiman C, Pariente R, Milic Emili J. Expiratory flow limitation in COPD patients after single lung transplantation. Am J Respir Crit Care Med 1997;155(3):1036–41. [25] Baarends EM, Schols AM, Mostert R, Wouters EF. Peak exercise response in relation to tissue depletion in patients with chronic obstructive pulmonary disease. Eur Respir J 1997;10:2807–13. [26] Palange P, Forte S, Onorati P, Paravati V, Manfredi F, Serra P, Carlone S. Effect of reduced body weight on muscle aerobic capacity in patients with COPD. Chest 1998;114(1):12–8. [27] Gosker HR, Engelen MP, van Maameren H, van Dijk PJ, van der Vusse GJ, Wouters EF, Schols AM. Muscle fibre type IIX atrophy is involved in the loss of fat-free mass in chronic obstructive pulmonary disease. Am J Clin Nutr 2002;76:113–9. [28] Shoup R, Dalsky G, Warner S, Davies M, Connors M, Khan M, Khan F, ZuWallack R. Body composition and health-related quality of life in patients with obstructive airways disease. Eur Respir J 1997;10(7):1576–80. [29] Mostert R, Goris A, Weling-Scheepers C, Wouters EFM, Schols AMWJ. Tissue depletion and health related quality of life in patients with chronic obstructive pulmonary disease. Respir Med 2000;9:859–67. [30] Vandenbergh E, Woestijne vdKP, Gyselen A. Weight changes in the terminal stages of chronic obstructive pulmonary disease. Am Rev Respir Dis 1967;95:556–66. [31] Wilson DO, Rogers RM, Wright EC, Anthonisen NR. Body weight in chronic obstructive pulmonary disease. The National Institutes of Health Intermittent Positive-Pressure Breathing Trial. Am Rev Respir Dis 1989;139(6):1435–8. [32] Gray Donald K, Gibbons L, Shapiro SH, Macklem PT, Martin JG. Nutritional status and mortality in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1996;153(3):961–6. [33] Landbo C, Prescott E, Lange P, Vestbo J, Almdal TP. Prognostic value of nutritional status in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999;160(6):1856–61. [34] Engelen MP, Schols AM, Baken WC, Wesseling GJ, Wouters EF. Nutritional depletion in relation to respiratory and peripheral skeletal muscle function in out-patients with COPD. Eur Respir J 1994;7:1793–7. [35] Schols AM, Soeters PB, Dingemans AM, Mostert R, Frantzen PJ, Wouters EF. Prevalence and characteristics of nutritional depletion in patients with stable COPD eligible for pulmonary rehabilitation. Am Rev Respir Dis 1993;147:1151–6. [36] Schwebel C, Pin I, Barnoud D, Devouassoux G, Brichon PY, Chaffanjon P, Chavanon O, Sessa C, Blin D, Guignier M, Leverve X, Pison C. Prevalence and consequences of nutritional depletion in lung transplant candidates. Eur Respir J 2000;16(6):1050–5. [37] Engelen MPKJ, Schols AMWJ, Lamers RJS, Wouters EFM. Different patterns of chronic tissue wasting among patients with chronic obstructive pulmonary disease. Clin Nutr 1999;18:275–80.
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[38] Engelen M, Wouters E, Deutz N, Menheere P, Schols A. Factors contributing to alterations in skeletal muscle and plasma amino and profiles in patients with chronic pulmonary disease. Am J Clin Nutr 2000;72(6):1480–7. [39] Brooks GA, Butterfield GE, Wolfe RR, Groves BM, Mazzeo RS, Sutton JR, Wolfel EE, Reeves JT. Increased dependence on blood glucose after acclimatization to 4,300 m. J Appl Physiol 1991;70:919–27. [40] Azevedo Jr. JL, Carey JO, Pories WJ, Morris PG, Dohm GL. Hypoxia stimulates glucose transport in insulin-resistant human skeletal muscle. Diabetes 1995;44:695–8. [41] Hjalmarsen A, Aasebo U, Birkeland K, Sager G, Jorde R. Impaired glucose tolerance in patients with chronic hypoxic pulmonary disease. Diabetes Metab 1996;22:37–42. [42] Jakobsson P, Jorfeldt L, von Schenck H. Fat metabolism and its response to infusion of insulin and glucose in patients with advanced chronic pulmonary disease. Clin Physiol 1995;15:319–29. [43] Jakobsson P, Jorfeldt L, von Schenck H. Insulin resistance is not exhibited by advanced chronic pulmonary disease patients. Clin Physiol 1995;15:547–55. [44] Engelen MPKJ, Deutz NEP, Wouters EFM, Schols AMWJ. Enhanced levels of whole-body protein turnover in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;162:1488–92. [45] Pouw EM, Schols AM, Deutz NE, Wouters EF. Plasma and muscle amino acid levels in relation to resting energy expenditure and inflammation in stable chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998;158:797–801. [46] Engelen MPKJ, Wouters EFM, Deutz NEP, Does JD, Schols AMWJ. Effects of exercise on amino acid metabolism in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;163:859–64. [47] Engelen MPKJ, Schols AMWJ, Does JD, Deutz NEP, Wouters EFM. Altered glutamate metabolism is associated with reduced muscle glutathione levels in patients with emphysema. Am J Respir Crit Care Med 2000;161:98–103. [48] Engelen MPKJ, Schols AMWJ, Does JD, Gosker HR, Deutz NEP, Wouters EFM. Exercise-induced lactate increase in relation to muscle substrates in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;162:1697–704. [49] Jagoe RT, Goldberg AL. What do we really know about the ubiquitin-proteasome pathway in muscle atrophy? Curr Opin Clin Nutr Metab Care 2001;4:183–90. [50] Preedy VR, Sugden PH. The effects of fasting or hypoxia on rates of protein synthesis in vivo in subcellular fractions of rat heart and gastrocnemius muscle. Biochem J 1989;257(2):519–27. [51] Meadows KA, Holly JMP, Stewart CEH. J Cell Physiol 2000;183:330–7. [52] Stangel M, Zettl UK, Mix E, Zielasek J, Toyka KV, Hartung HP, Gold R. H 2 O 2 and nitric oxide-mediated oxidative stress induce apoptosis in rat skeletal muscle myoblasts. J Neuropathol Exp Neurol 1996;55(1):36–43. [53] Dalla Libera L, Sabbadini R, Renken C, Ravara B, Sandrini M, Betto R, Angelinin A, Vescovo G. Apoptosis in the skeletal muscle of rats with heart failure is associated with increased serum levels of TNF-alpha and sphingosine. J Mol Cell Cardiol 2001;33(10):1871– 8. [54] Vescovo G, Volterrani M, Zennaro R, Sandri M, Ceconi C, Lorusso R, Ferrari R, Ambrosio GB, Dalla Libera L. Apoptosis in the skeletal muscle of patients with heart failure: investigation of clinical and biochemical changes. Heart 2000;84(4):431–7.
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[55] American Joint Distribution Committee. Maladie de famine. Recherches cliniques sur la famine executees dans le ghetto de Varsovie en 1942. Varsovie, 1946. [56] Sahebjami. Nutrition and lung structure and function. Exp Lung Res 1993;19(2):105–24. [57] Massaro GD, Massaro D. Retinoic acid treatment abrogates elastaseinduced pulmonary emphysema in rats. Nat Med 1997;3(6):675–7. [58] Ferreira IM, Brooks D, Lacasse Y, Goldstein RS. Nutritional support for individuals with COPD: a meta-analysis. Chest 2000;117(3):672–8. [59] Vermeeren MAP, Wouters EFM, Nelissen LH, van Lier A, Hofman Z, Schols AM. Acute effects of different nutritional supplements on symptoms and functional capacity in patients with chronic obstructive pulmonary disease. Am J Clin Nutr 2001;73:295–301. [60] Vermeeren MA, Schols AM, Wouters EF. Effects of an acute exacerbation on nutritional and metabolic profile of patients with COPD. Eur Respir J 1997;10:2264–9. [61] Ferreira IM, Verreschi IT, Nery LE, Goldstein RS, Zamel N, Brooks D, Jardim JR. The influence of 6 months of oral anabolic steroids on body mass and respiratory muscles in undernourished COPD patients. Chest 1998;114(1):19–28.
[62] Schols AM, Soeters PB, Mostert R, Pluymers RJ, Wouters EF. Physiologic effects of nutritional support and anabolic steroids in patients with chronic obstructive pulmonary disease. A placebocontrolled randomized trial. Am J Respir Crit Care Med 1995;152(4 Pt 1):1268–74. [63] Creutzberg EC, Wpouters EFM, Mostert R, Pluymers RJ, Schols AMWJ. A role for anabolic steroids in the rehabilitation of patients with chronic obstructive pulmonary diseases? A placebo controlled randomized trial. Chest 2002;in press. [64] Kamischke A, kemper DE, Castel MA, Luthke M, Rolf C, Behre HM, Magnussen H, Nieschlag E. Testosterone levels in men with chronic obstructive pulmonary disease with and without glucocorticoid therapy. Eur Respir J 1998;11:41–5. [65] Burdet L, de Muralt B, Schutz Y, Pichard C, Fitting JW. Administration of growth hormone to underweight patients with chronic obstructive pulmonary disease. A prospective, randomized controlled study. Am J Respir Crit Care Med 1997;156:1800–6. [66] Creutzberg EC, Schols AM, Weling Scheepers CA, Buurman WA, Wouters EF. Characterization of nonresponse to high caloric oral nutritional therapy in depleted patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;161:745–52.
Pulmonary cachexia Annemie M.W.J. Schols* Department of Pulmonology, University Maastricht, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands Received 28 January 2002; accepted 6 April 2002
Abstract Weight loss is a frequent complication in patients with chronic obstructive pulmonary disease (COPD) and is a determining factor of functional capacity, health status, and mortality. Weight loss in COPD is a consequence of increased energy requirements unbalanced by dietary intake. Both metabolic and mechanical inefficiency contribute to the elevated energy expenditure during physical activity, while systemic inflammation is a determinant of hypermetabolism at rest. A disbalance between protein synthesis and protein breakdown may cause a disproportionate depletion of fat-free mass in some patients. Nutritional support is indicated for depleted patients with COPD because it provides not only supportive care, but direct intervention through improvement in respiratory and peripheral skeletal muscle function and in exercise performance. A combination of oral nutritional supplements and exercise or anabolic stimulus appears to be the best treatment approach to obtaining significant functional improvement. Patients responding to this treatment even demonstrated a decreased mortality. Poor response was related to the effects of systemic inflammation on dietary intake and catabolism. The effectiveness of anticatabolic modulation requires further investigation. 2002 Published by Elsevier Science Ireland Ltd. Keywords: Pulmonary cachexia; Chronic obstructive pulmonary disease; Involuntary weight loss; Oxygen consumption; Limited ventilatory capacity
1. Introduction Chronic obstructive pulmonary disease (COPD) is a progressive disorder leading to significant debilitation. While traditionally been considered as irreversible lung disease, there is growing evidence that COPD is a multi-organ systemic disease. Parallel to this awareness, the interest for weight loss and muscle wasting in the management of COPD has changed remarkably during the past two decades. Involuntary weight loss is a well-recognized clinical finding and a substantial number of patients suffering from COPD, particularly emphysema, become emaciated during the course of the disease. InterestE-mail addresses: http: / / www.pul.unimaas.nl (A.M.W.J. Schols), [email protected] (A.M.W.J. Schols).
ingly, attempts to classify COPD patients indeed found that body weight might be a discriminating factor. This led to the classical description of the pink puffer (emphysematous type) and the blue bloater (bronchitic type). Initially weight loss was thought to be an epiphenomenonon of severe disease and an adaptive mechanism to decrease oxygen consumption. Potential adverse effects of nutritional support were even highlighted since caloric overload, particularly of carbohydrates might induce CO 2 retention and thus respiratory failure in these patients with limited ventilatory capacity. Recent studies have yet convincingly challenged this viewpoint and shown that weight loss is often associated with elevated oxygen consumption and an independent risk factor for prognosis. Nutritional assessment according to body weight is
0167-5273 / 02 / $ – see front matter 2002 Published by Elsevier Science Ireland Ltd. PII: S0167-5273( 02 )00238-3
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simple but bears important limitations since it provides no qualitative information on body tissues. In contrast to fat accretion as being the main concern in obesity, consequences of weight loss are specifically related to a decrease in body cell mass, even irrespective of the amount of fat tissue. Body cell mass is defined as the active metabolising and contracting tissue. Muscle mass is the largest single tissue component of body cell mass and can be assessed in clinical practice by measurement of fat-free mass. Based on the available evidence I will show here that fat-free mass is a simple screening tool in extrapulmonary COPD management not only to target nutritional interventions, but also pulmonary rehabilitation. Weight loss per se simply refers to a imbalance between dietary intake and energy expenditure. Muscle wasting in chronic disease, however, is a more complex process, being a consequence of changes in the control of both intermediary metabolism (protein synthesis and breakdown) and cell status (proliferation, differentiation, and apoptosis). These processes are regulated by various extrinsic factors (hormones, growth factors and cytokines) and intrinsic factors of the muscle cell (receptors and intracellular signalling mechanisms). Optimal therapeutic intervention in muscle wasting depends on proper insight into the precise mechanisms. While the regulation of energy balance in relation to weight loss has been extensively explored, investigation into intermediary metabolism and molecular mechanisms of muscle wasting is in its infancy in COPD. Nevertheless recent studies show that, besides optimal implementation of nutritional support to reverse weight loss, research into this area may provide a promising therapeutic perspective not only to prevent or treat muscle wasting in COPD, but also to enhance the efficacy of pulmonary rehabilitation.
2. Definition of pulmonary cachexia Traditionally cachexia and starvation are the two paradigms of nutritional depletion. Starvation is characterized by pure caloric deficiency. The organism adapts metabolically to conserve body cell mass and increase fat metabolism while appropriate feeding can reverse the changes. In contrast cachexia is
associated with inflammatory conditions that evoke an acute phase response, including coordinated adaptations in intermediary metabolism, which increase protein degradation in muscle [1]. Feeding alone cannot reverse these aberrations. Either paradigm, however, does not cover the wasting process in COPD patients that I therefore refer to as pulmonary cachexia. Some of the weight-losing COPD patients suffer from pure caloric deficiency [2]. However, in contrast to (semi)-starvation and cachexia, weight loss may also be a consequence of elevated physical activity related energy requirements [3]. One reason for an elevated activity-induced energy expenditure could be a decreased efficiency related to altered pulmonary mechanics [4]. Indirect evidence for this factor in weight loss is provided by a spontaneous weight gain that was observed in patients with emphysema after lung volume reduction surgery (LVRS) [5]. Besides mechanical inefficiency, several recent studies also point towards an inefficient muscle energy metabolism. Using NMR spectroscopy, a severely impaired oxidative phosphorylation during exercise and recovery has been demonstrated, accompanied by an increased and anaerobic metabolism [6]. ATP production by anaerobic pathways is less efficient than ATP production by aerobic metabolism. This shift in cellular energy metabolism has been confirmed in muscle biopsy studies of resting muscle showing decreased levels of aerobic enzymes [7], phosphagens [8] and a fibre type shift towards more type II fibers [9]. Interestingly, two studies revealed that these muscular adaptations were more pronounced in the emphysematous sub-type [8,9]. Dietary assessment studies show that elevated energy requirements are initially met by a high spontaneous dietary intake [2]. When dietary intake is compromised by symptoms such as dyspnea, fatigue and meal related oxygen desaturation [10], a patient starts to loose weight. Since metabolic adaptations to energy deficit per se favour fat oxidation, these patients may already be severely underweight before being significantly debilitated with a poor prognosis. In controlled clinical settings it has been shown that proper timing of nutritional supplements adjusted to daily dietary and activity pattern is able to reverse weight loss in part of the patients [11]. In contrast to an adaptive decrease during starvation, elevated resting metabolic rate is a cardinal
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feature of cachexia [12]. Approximately 25% of the COPD patients are characterized by hypermetabolism at rest, which in accordance to other chronic wasting conditions like HIV infection, cancer and chronic heart failure, is related to presence of a systemic inflammatory response as a hallmark of the cachexia syndrome [13,14]. Hypermetabolism at rest is generally, however, not the direct cause of weight loss in cachexia, since as mentioned above it is associated with an adaptive decrease in activity-induced energy expenditure. This implies that a potential influence of inflammation on a negative energy balance in weightlosing patients could be by altering appetite regulation and dietary intake. Several observations support this hypothesis. There is increasing evidence that, besides local upregulation of inflammatory processes in the lung, COPD is characterized by an elevated systemic inflammatory response as reflected by elevated concentrations of proinflammatory cytokines and acute phase proteins in peripheral blood [15–17]. As in other chronic inflammatory diseases, weight loss has specifically been associated with increased circulating levels of TNFa, initially named cachectin, soluble TNFa receptors and with increased release of TNFa from circulating mononuclear cells [18,19]. Leptin, a 167-amino acid protein synthesized and secreted by white adipose tissue, is a component of a lipostatic signalling pathway that alters energy balance by central and peripheral mechanisms. We investigated the relationship between plasma leptin to both inflammation and energy balance in COPD patients stratified into chronic bronchitis and emphysema by high resolution CT in a cross-sectional and prospective design. As observed in healthy subjects and other chronic diseases, plasma leptin concentration was highly correlated with fat mass and thus (in absolute terms) low in underweight COPD patients [20]. However, after adjustment for the amount of fat mass, a significant correlation was found between leptin and sTNF receptor 55 in COPD [20]. In the prospective study, an inverse relationship between plasma leptin levels, baseline dietary intake and response to nutritional therapy was seen [20]. These results indicate that leptin levels are influenced by inflammatory cytokines and in turn may alter the patient’s ability to respond to nutritional intervention. Proinflammatory cytokines exert a variety of be-
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havioural and physiological effects in addition to their immunological and nutritional functions. To differentiate between effects related to semistarvation versus cachexia, longitudinal information of circulating cytokines and body composition is needed. On the other hand it is also possible that pure semistarvation as described above, may evolve to cachexia because malnutrition-induced immune dysfunction predisposes to infection. Experimental studies have shown that low leptin levels as normal adaptation in underweight COPD patients indeed influence T-cell mediated immunity [21].
3. Consequences of weight loss and muscle wasting in COPD Prominent symptoms of COPD are dyspnea and exercise intolerance. Besides airflow obstruction and loss of alveolar structure, skeletal muscle weakness is an important determinant of these symptoms. Body composition studies have convincingly shown that skeletal muscle dysfunction is predominantly determined by skeletal muscle mass in COPD [22,23] and that muscle wasting does not spare the respiratory muscles [24]. Besides effects on muscle strength, muscle mass is also a significant determinant of exercise capacity and exercise response [25,26], implying that functional consequences are not only related to muscle wasting per se, but also to intrinsic alterations in muscle morphology and energy metabolism. Recently Gosker et al. demonstrated that muscle wasting in COPD is fibre type specific affecting type IIx fibres [27]. Whole body fat-free mass was strongly correlated with muscle fibre cross-sectional area [27]. Besides effects on exercise capacity, two studies have shown that FFM depletion as marker of systemic impairment is also related to a decreased health related quality of life measured by the disease-specific St George’s Respiratory Questionnaire (SGRQ) [28,29]. The relationship between weight loss and mortality has been subject of investigation since the 1960s. In the early years a significant association was reported between weight loss and survival [30]. In line, several retrospective studies using different COPD populations from the USA [31], Canada [32], Denmark [33] and The Netherlands [11] reported more recently a
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relationship between low body mass index and mortality independent of disease severity. Remarkably, in all these studies a decreased mortality risk was observed in overweight patients not only compared to underweight patients but also to normal weight subjects. This observation could be related to the fact that depletion of FFM is not only a consequence of weight loss, but may also occur in normal weight patients with a relatively preserved fat mass. The available prevalence studies indicate that depletion of FFM is a significant clinical problem. In stable patients with moderate to severe COPD, depletion of FFM has been reported in 20% of COPD out-patients [34], in 35% of those eligible for pulmonary rehabilitation [35] and even in 45% of lung transplant candidates [36]. Limited data are yet available regarding the prevalence of FFM depletion in representative groups of mild COPD, and on the other side of the spectrum, in patients suffering from acute respiratory failure. Weight loss and a low body mass index are more frequently observed in emphysematous patients compared to chronic bronchitis, but differences in body weight between the two COPD subtypes, if present, merely reflect a difference in fat mass. Depletion of FFM even despite a relative preservation of fat mass also occurs in chronic bronchitis [37]. In fact it has been shown that normal weight patients with depleted fat-free mass are more disabled that underweight patients with preserved fat-free mass [35]. For a differentiation between the contribution of semistarvation and cachexia to muscle wasting and from a therapeutic perspective (to choose priorities between nutritional support and different forms of exercise), we advocate that not only weight changes, but also fat-free mass should be considered in the screening of COPD.
4. Intermediary metabolism in COPD Disproportionate depletion of fat-free mass despite relative or absolute preservation of fat mass in part of the COPD patients points towards alterations in intermediary metabolism. Limited studies have yet investigated intermediary metabolism in COPD. This is surprising since individual effects of several disease characteristics like inflammation, oxidative
stress and hypoxia have been extensively investigated on intermediary metabolism in healthy subjects and in other wasting conditions. One might speculate that COPD is characterised by altered intermediary metabolism shifting body composition towards wasting of fat-free mass, while a sub group of predominantly emphysematous patients is further compromised by loss of weight and fat mass. Insulin has a central role in the regulation of intermediary metabolism. Hyperinsulinemia and to a lesser extent hyperglycemia are commonly seen in COPD [38]. Insulin resistance seems to be at the basis of this metabolic disturbance. Limited information is available, however, on glucose tolerance in chronic lung diseases. This is remarkable since both inflammation and hypoxia influence glucose metabolism in healthy subjects. With chronic altitude exposure basal glucose production is almost twice as great as at sea level. Plasma glucose concentration at high altitude is lower than at sea level, suggesting facilitated tissue uptake [39]. In vitro studies in human muscle have shown that hypoxia stimulates glucose transport, even in insulin-resistant human skeletal muscle [40]. Chronic disease in general can stimulate glucose production and will mostly induce peripheral insulin resistance. The end result of these partly opposite effects on glucose metabolism in (subgroups of) COPD cannot be predicted. Glucose metabolism has hardly been studied in COPD and the three available studies are inconclusive [41–44] probably partly based on differences in patient selection (i.e., range in body mass index and PaO 2 ) . Specifically considering the adverse functional effects of muscle wasting, we investigated the balance between protein synthesis and breakdown in weight stable COPD patients [44]. Whole body protein synthesis and breakdown were elevated compared to a well-matched control group, indicating a disease-related increase in protein turnover. 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 an increased amino acid release from the skeletal muscle compartment resulting in net muscle protein breakdown. Previously Pouw et al. indeed observed an inverse relationship between the acute phase protein LPS binding protein and the total sum of plasma amino acid levels in patients with
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COPD [45]. In another study COPD patients with an acute phase response and elevated resting metabolic rate, were indeed characterized by selective depletion of fat-free mass as hallmark of cachexia [15]. More studies are needed, however, to confirm this hypothesis using advanced techniques to measure (acute phase) protein synthesis and breakdown at the whole body level and across skeletal muscle. These studies are important because they highlight that maintenance of homeostatic regulation of metabolic processes in COPD under certain circumstances is a labile equilibrium between different priorities. Evoked in inflammatory conditions the acute phase response includes the hepatic synthesis of large quantities of proteins with a wide variety of functions to clear tissue debris. This is an energy-intensive process with high rates of hepatic protein synthesis requiring large quantities of essential amino acids. The need for essential amino acids drives the loss of skeletal muscle. The trade off may be viewed as a shift in the body’s priorities from offensive to defensive [1]. This adaptation is effective over the short term because skeletal muscle is replaced rapidly as recovery is completed. Because skeletal muscle depletion significantly contributes to morbidity and mortality, problems ensue when the process is chronic related to continuous low grade inflammation or frequent acute (infectious) exacerbations. It is also important to realize that while this catabolic process is ongoing, anabolic interventions to increase protein synthesis like nutrition and exercise are only partly effective. Based on recent observations in COPD patients showing an altered metabolic response during exercise, one might even speculate that exercise alone may enhance catabolism [46]. The building blocks of proteins are amino acids, playing a pivotal role in intermediary metabolism. Different studies demonstrated consistently decreased levels of the amino acid glutamate (GLU) in peripheral muscle biopsies in patients with COPD [45,47]. Intracellular GLU plays an important role in preserving high-energy phosphates in muscle through different metabolic mechanisms. Intracellular GLU is known as an important precursor for antioxidant glutathione (GSH) and glutamine synthesis in the muscle. Muscle GLU is highly associated with GSH, and Engelen et al. showed that patients with emphysema suffer from decreased muscular GLU and
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GSH levels [47]. Moreover, a reduction in muscle GLU was associated with early lactic acidosis during exercise [48]. Besides an already depleted state of some amino acids at rest, sub-maximal exercise at low intensity resulted in increased leakage of amino acids out of muscle as shown by a dramatic decrease of all amino acids in muscle and an increased plasma amino acid level. Abundant evidence from studies in incubated muscles and muscle extracts suggests that the adenosine triphosphate (ATP)-dependent ubiquitin–proteasome pathway is responsible for most of the increased proteolysis in various types of muscle atrophy. In particular, increased levels of ubiquitin-conjugated proteins, and increases in mRNA levels for polyubiquitin, certain proteasome subunits and the ubiquitin conjugating enzyme E2 14K are features found in most atrophying muscles studied so far [49]. Despite these similarities, there are many unanswered questions about the biochemical basis for accelerated proteolysis in muscle atrophy generally, and possible variations in this response in different human conditions like COPD. In addition to catabolic effects of systemic inflammation, tissue hypoxia is known to reduce muscle protein synthesis in experimental conditions [50]. Hypoxia is a hall mark of end stage COPD and a substantial proportion of mainly emphysematous patients exhibit arterial oxygen desaturation during exercise despite normal resting arterial oxygen tension. Presence of tissue hypoxia in COPD and its modulating role in intermediary metabolism under fasting and stressed conditions however remains elusive. In addition to disturbances in energy balance and intermediary metabolism, muscle wasting may be the result of a decreased number of fibres or myofibrillar protein content, consequent to activation of apoptotic pathways, imbalances in protein synthesis and breakdown, and altered regulation of skeletal muscle regeneration. Theoretically, apoptosis of myofibers could result in muscle atrophy. In vitro studies have documented apoptosis in skeletal myoblasts, indicating that myocytes possess the ability to undergo organised cell death. Specifically, the addition of inflammatory mediators like tumor necrosis factor-a (TNFa) and reactive oxygen and nitrogen species to myoblasts resulted in nuclear condensation and DNAladdering [51,52]. In an experimental model of heart
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failure known to result in muscle atrophy, apoptosis in skeletal muscle was correlated with circulating levels of TNFa [53]. A clinical study showed evidence for skeletal myocyte apoptosis in heart failure and its magnitude was associated with the degree of muscle fibre atrophy based on a decreased muscle cross-sectional area [54]. No studies have yet described apoptosis in COPD, but interestingly Gosker et al. [27] showed in muscle biopsies of COPD patients, that severe muscle fibre atrophy at comparable levels was associated with absence of stainable enzyme activity. Other studies have focussed on the activation of pathways by inflammation and oxidative stress that may reduce myofibrillar protein content in skeletal muscle or affect skeletal muscle regeneration. Discussion of these studies is, however, beyond the scope of this review. The studies do suggest, however, that further clinical research should be focussed towards determining the presence of markers of inflammation and oxidative stress in skeletal muscle of COPD patients suffering from muscle wasting.
5. Effects of pulmonary cachexia on the primary organ impairment The effect of pulmonary cachexia in relation to lung function has yet predominantly focussed on ventilatory pump function. Study of the lung parenchyma in humans is difficult. It is possible to obtain lung tissue resected during surgery or whole lungs at autopsy in order to study the influence of weight loss on lung structure and function. Presence of coexisting pathological processes, which would have led to lung resection or death, however, could hinder the study of the effects of nutritional deficiency on lung parenchyma. Recent developments in high resolution CT scanning allow non-invasive measurement of lung mass and density. Such studies, however, have not yet been done in any detailed or systematic fashion. One of the earliest and most dramatic accounts of human starvation was meticulously reported during the second World War. In a total of 370 autopsies in which lungs were examined, 50 cases of emphysema (13.5%) were observed. Of the 50 cases, 14 were reported in individuals under the age of 30 years, and 20 in persons under the age of 40 years. The
pathological features seen in these mostly young adults were similar to those seen in senile emphysema [55]. Almost our entire current knowledge of the effects of malnutrition on lung parenchyma and its structure and function derives from experimental animal studies reported by Sahebjami [56] during the 1980s. These studies have clearly shown that nutritional depletion caused by food deprivation affect lung morphology, biochemistry and mechanics. The most intriguing observation in the lungs of malnourished animals is the remodelling of terminal airspaces in a manner that morphologically and morphometrically is quite similar to those seen in naturally occurring or enzyme-induced emphysema, and partly reversible [56]. The significance of these observations in COPD or other chronic wasting conditions is still unclear, because our current knowledge on the influence of nutrition on normal or diseased human lungs is so limited. It is furthermore important in experimental conditions to distinguish between energy depletion per se versus specific nutrient depletion and from a therapeutic perspective between nutrient repletion and bioactive suppletion. Massaro and Massaro [57] illustrated this issue nicely for vitamin A. Since treatment of normal rats with all-trans-retinoic acid increases the number of alveoli, they tested whether a similar effect would occur in rats with emphysema. Elastase was instilled into rat lungs, producing changes characteristic of human and experimental emphysema: increased lung volume reflecting a loss of lung elastic recoil, larger but fewer alveoli and diminished volume-corrected alveolar surface area due to destruction of alveolar walls. Treatment with all-trans-retinoic acid reversed these changes and the authors suggested that it may even provide nonsurgical remediation of emphysema even in humans.
6. Therapeutic strategy anno 2002: fine tuning of anabolic and anti-catabolic interventions The deleterious effects of weight loss and muscle wasting on morbidity and mortality in COPD provide a strong rationale for nutritional repletion therapy to induce weight gain and exercise or other anabolic stimuli to promote muscle mass and muscle function.
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The efficacy of nutritional intervention per se is not supported by results of a recent meta-analysis [58]. While some studies, particularly those performed in a controlled clinical setting, demonstrated a significant weight gain, others were unsuccessful. Part of a poor treatment response was related to the fact that either the supplementation was insufficient from a caloric viewpoint, or that patients were taking supplements instead of their normal meals. Otherwise, a variable treatment response underlines the complexity of the pathogenesis of nutritional depletion in COPD and indicate that targeted anabolic and anti-catabolic interventions, including nutritional support, should be based on adequate characterization of local and systemic impairment. Some patients may benefit from merely nutritional supplementation to balance dietary intake with elevated energy requirements, while in others additional anabolic stimuli are needed. Furthermore there remains a sub-group of cachectic patients that like in other diseases will hardly improve by the currently available treatment options. Nutrition and ventilation are intrinsically related because oxygen is required for optimal energy exchange. Theoretically, meal-related dyspnea and impaired ventilatory reserves may restrict the energy and carbohydrate content of nutritional support in respiratory disease. Recent short-term studies as well as the available clinical trials, however, did not show significant adverse effects of nutritional supplements on the ventilatory system. Remarkably, at a relatively low energy content, there were even positive effects of a carbohydrate-rich supplement relative to those of a fat-rich diet on lung function and dyspnea sensation [59]. Glucose is a rapidly available substrate. In view of the metabolic adaptations of the peripheral skeletal muscles towards decreased oxidative capacity, carbohydrates are also likely to be preferable above fat as an energy substrate during exercise. There are currently no disease-specific recommendations for protein intake in COPD. Studies in other catabolic conditions as well as in body builders, however, indicate that a protein intake of 1.5 g / kg body weight results in maximal muscle protein synthesis. Vermeeren et al. [60] showed that most patients hospitalised for an acute exacerbation of COPD, did not reach this recommendation during their total stay in the hospital. More studies are needed the assess the appropriate time of nutritional supplementation in
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relation to daily activities and disease state, to be able to reach a positive energy and protein balance in depleted patients. As described above, future studies may furthermore provide specific recommendations for modulation of metabolic pathways, e.g., energyrich substrates such as creatine, amino acids, antioxidants and other bioactive components in relation to exercise training to improve the efficacy of pulmonary rehabilitation. To enhance muscle gain, anabolic endocrinological therapeutic options are also being considered. Several studies in COPD and other chronic (wasting) conditions have clearly shown that anabolic steroids specifically induce muscle gain [61,62]. Relative to exercise alone, additional effects on muscle function appear limited. Preliminary results by Creutzberg et al. [63], however, point towards a erythropoietic effect of the anabolic steroid nandrolone decanoate, positively influencing exercise capacity. Furthermore, she found a beneficial effect in the sub-group of severe COPD patients on maintenance treatment with low-dose oral glucocorticoids. While these patients poorly responded to exercise alone or (if indicated) combined with nutritional support, anabolic steroid treatment completely reversed these deleterious effects of systemic glucocorticoids. A likely explanation for this effect is probably less related to the anabolic properties per se, but to binding competition of anabolic steroids and glucocorticoids on the glucocorticosteroid receptor, thereby neutralizing deleterious catabolic effects of glucocorticosteroids. Anabolic steroids have a high anabolic / androgenic ratio. Stimulating the androgenic together with the anabolic pathways by testosterone supplementation could, however, also be indicated in COPD since the disease is characterized by a high prevalence of hypogonadism, specifically in patients on systemic glucocorticosteroid treatment [64]. Decreased concentrations of anabolic hormones, like testosterone, might aggravate failure of generating an anabolic response needed for muscle anabolism. Other pharmacological anabolic stimuli to promote protein synthesis in COPD are growth hormone and insulinlike growth factors (IGFs). Although it is yet unclear if growth hormone, IGFs and IGF binding proteins are specifically reduced in patients with COPD, one controlled trial investigated growth hormone supplementation in underweight COPD patients [65]. De-
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spite a significant increase in muscle mass after therapy, no beneficial effects of this treatment have to date been demonstrated on muscle function and even adverse effects were shown on resting metabolic rate and exercise capacity. The latter study clearly indicates a labile balance between anabolic and catabolic processes in cachectic COPD patients. It has been suggested [1] that use of growth hormone can have negative effects in some situations by diverting excess essential amino acids and energy to skeletal muscle from use in the acute phase response, thereby compromising a basic function of host defence. Systemic inflammation is prominently involved in the pathogenesis of cachexia. Elevated levels of proinflammatory cytokines [66] indeed characterised patients poorly responding to nutritional supplementation and anabolic stimulation. Ant-inflammatory therapies may moderate pro-inflammatory cytokine activity. Studies in other chronic wasting conditions like inflammatory bowel disease and cancer have shown encouraging effects of n-3 polyunsaturated fatty acids (PUFAs) on cytokine release, markers of immune function and on body weight [1]. Studies with PUFAs in COPD are currently ongoing. More insight into the molecular mechanisms of pulmonary cachexia may likely boost novel nutritional and pharmacological treatment strategies directed at specifically targeting of crucial mediators of inflammatory signalling cascades and redox imbalances to allow for anabolic stimuli and muscle repair to occur in order to restore muscle mass and function. Meanwhile a stepwise treatment is warranted to treat pulmonary cachexia as integrated part of extra pulmonary COPD management.
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