© 2006 American Thoracic Society doi: 10.1164/rccm.2510003
Muscle Wasting in Chronic Obstructive Pulmonary DiseaseTo Bother and to Measure!University of Maastricht, Maastricht, The Netherlands Chronic obstructive pulmonary disease (COPD) is characterized by a range of pathologic changes contributing to a highly variable clinical presentation and extensive heterogeneity among patients with this pulmonary problem. The consequences of COPD experienced by the patient include exercise intolerance, exacerbations, weight loss, impaired health status, and finally, death. The complexity of the disease is often underestimated by our traditional approach that focuses on the presence of chronic airflow limitation and frequently limits therapeutic interventions to relief of airflow limitation. Survival studies in selected groups of patients with COPD and in population-based studies have consistently shown higher COPD-related mortality rates in underweight and normal-weight patients than in overweight and even obese patients (1–3). This relation is different from the U-shaped survival curve that is commonly reported for body mass index (BMI) in larger population studies. The discrepancy may be attributed to specific effects of metabolically and functionally active fat-free mass (FFM) on mortality in these patients that is not reflected in BMI. It was demonstrated, for example, that small midthigh cross-sectional area, as measured with computed tomography scan, was associated with increased mortality risk during a 3-year follow-up period (4). In this issue of the Journal (pp. 79–83), Vestbo and coworkers (5) explored the association of low FFM with prognosis in a population-based cohort of 1,898 patients with COPD in whom FFM was measured using bioelectrical impedance analysis. Patients were followed for a mean of 7 years. The authors report that BMI and FFMI (FFM corrected for height squared) are significant predictors of mortality, independent of covariates such as sex, smoking, and lung function. Remarkably, FFMI is also a predictor of overall mortality when analyses are restricted to subjects with normal BMI, indicating that FFMI provides information in addition to BMI of use in assessing prognosis in patients with COPD. These results fit very well with recent data reported by Schols and colleagues (6). They examined the association between body composition, as measured by bioelectrical impedance, and mortality in 412 patients with clinically stable COPD screened on admission to a rehabilitation program. BMI, FFMI, fat mass index, and skeletal muscle index were calculated for these patients. Patients were stratified by body composition into four categories: cachexia (low BMI, low FFMI), semistarvation (low BMI, normal FFMI), muscle atrophy (normal BMI, low FFMI), and patients with no impairment (normal BMI, normal FFMI). The authors reported that FFMI was an independent predictor of survival, but not fat mass index. In the same study, survival of patients suffering from cachexia or muscle atrophy did not differ significantly. The authors concluded that FFMI provides information concerning prognosis that is beyond that provided by BMI. Slinde and colleagues recently reported similar findings in a smaller sample of 86 patients with COPD (7). On the basis of these studies, measurement of FFM should be considered in the routine assessment of patients with COPD. Bioelectrical impedance analysis was applied as an easy, safe, noninvasive, and convenient method of measuring lean and fat body compartments (5). This technique has been validated extensively in COPD and other chronic wasting conditions, where high correlations have been demonstrated between FFM assessed by bioelectrical impedance and that measured by reference methods such as magnetic resonance imaging or deuterium dilution (8). Gosker and colleagues (9) showed in patients with COPD that FFM assessed by bioelectrical impedance was significantly related to muscle fiber cross-sectional area using biopsy of muscle tissue from the vastus lateralis, indicating that whole-body FFM also reflects lower-limb muscle atrophy in this chronic disease condition. The study of Vestbo and coworkers (5) also demonstrated that a low FFMI is a common problem in patients with COPD with all Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages of COPD and that the risk of a low FFMI increased with increasing severity of COPD. Muscle atrophy in the presence of normal or even increased body weight was reported in 13.1% of the cohort population. Among subjects in GOLD stages 3 and 4 with normal BMI, approximately 50% had low FFMI. In the study of Schols and coworkers, semistarvation and muscle atrophy were equally distributed among disease stages, but the prevalence of cachexia was highest in GOLD stage 4 patients (6). These data clearly indicate that body composition assessment cannot be replaced by simple measurement of body weight in clinical practice. Assessment of body composition can be very helpful for better understanding the heterogeneity in clinical manifestations of COPD. FFM is a strong predictor of peripheral skeletal muscle weakness of upper and lower extremities (10), of exercise capacity (11), and reduced health status (12). Others reported an associated loss of FFM and bone mineral density in patients with COPD; both important problems were related and occurred commonly in the course of the disease (13). Besides the impact of loss of peripheral muscle mass on morbidity and prognosis in patients with COPD, there is also growing attention to the qualitative changes in the muscles of these patients. In particular, quadriceps muscle biopsies have demonstrated that fiber atrophy is mainly confined to the type IIA/IIX and IIX fibers, and also that activity of aerobic enzymes is decreased (9, 14). It has been recently reported that these metabolic and muscle features can influence the susceptibility of patients with COPD to fatigue. A significant relationship could be demonstrated between the fall in quadriceps twitch force, a marker of contractile fatigue, and lactate dehydrogenase activity, capillary/fiber ratio, and blood lactate levels, suggesting that changes in muscle enzymatic profile and capillary supply, with a greater reliance on glycolytic metabolism, are associated with contractile fatigue in patients with COPD (15). Previously, it was reported that muscle oxidative stress was associated with a reduced quadriceps endurance (16). The underlying mechanisms contributing to depletion of skeletal muscle still remain unclear. Associations between various circulating markers of inflammation and the loss of muscle mass have been made in chronic inflammatory disease conditions, including COPD. However, the elucidation of the mechanisms responsible for wasting of skeletal muscle in these conditions may be very complicated, as the depletion of skeletal muscle mass is assumed to progress very slowly. Besides imbalances in protein metabolism and possible cytokine-driven increases in protein degradation, involving the ubiquitin–proteasome pathway, deregulation of muscle homeostasis, involving muscle fiber apoptosis and regeneration, should be explored. Better understanding of signaling pathways in skeletal muscle may help in developing future interventions for muscle wasting. Given the fact that a cure for COPD is far away, better medical care can help patients to enjoy a longer and better life. Assessment of muscle mass needs to be a part of the evaluation of our patients suffering from COPD. Addressing alterations in skeletal muscle function should clearly be an important part in our management of patients with COPD. FOOTNOTES Conflict of Interest Statement: E.F.M.W. is a member of the scientific advisory boards of GlaxoSmithKline (GSK), Boehringer Ingelheim, AstraZeneca, and Numico. He has received lecture fees from GSK, AstraZeneca, and Boehringer Ingelheim. He has received research grants between 2002 and 2004 from GSK, AstraZeneca, Boehringer Ingelheim, Centocor, and Numico. REFERENCES
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