Pulmonary cachexia

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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.

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. Interestingly, 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 CO2 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 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 extra-pulmonary 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.

Section snippets

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].

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

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

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

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. 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

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