Published ahead of print on July 21, 2004, doi:10.1164/rccm.200310-1404OC
© 2004 American Thoracic Society doi: 10.1164/rccm.200310-1404OC Elevated Plasma Ghrelin Level in Underweight Patients with Chronic Obstructive Pulmonary DiseaseDepartment of Internal Medicine, National Cardiovascular Center, and Departments of Biochemistry and of Regenerative Medicine and Tissue Engineering, National Cardiovascular Center Research Institute, Osaka; Second Department of Internal Medicine, Nara Medical University, Nara; and Department of Respiratory Medicine, Chugoku Rousai Hospital, Hiroshima, Japan Correspondence and requests for reprints should be addressed to Noritoshi Nagaya, M.D., Department of Regenerative Medicine and Tissue Engineering, National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan. E-mail: nagayann{at}hsp.ncvc.go.jp
Ghrelin, a novel growth hormone–releasing peptide, has been shown to cause a positive energy balance by reducing fat use and stimulating food intake. This study investigated whether plasma ghrelin is associated with clinical parameters in patients with chronic obstructive pulmonary disease. Plasma ghrelin was measured in 50 patients and 13 control subjects, together with anabolic and catabolic factors. Patients were divided into two groups based on body mass index: underweight patients (n = 26) or normal weight patients (n = 24). Plasma ghrelin was significantly higher in underweight patients than in normal weight patients and healthy control subjects. Circulating tumor necrosis factor-  , interleukin-6, and norepinephrine were significantly higher in underweight patients than in normal weight patients. Plasma ghrelin correlated negatively with body mass index and correlated positively with catabolic factors such as tumor necrosis factor- and norepinephrine. In addition, plasma ghrelin correlated positively with percent predicted residual volume and residual volume-to-total lung capacity ratio. In conclusion, plasma ghrelin was elevated in underweight patients with chronic obstructive pulmonary disease, and the level was associated with a cachectic state and abnormality of pulmonary function.
Key Words: cachexia • ghrelin • hormone • pulmonary disease, chronic obstructive Patients with chronic obstructive pulmonary disease (COPD) often show a certain degree of cachexia. Cachexia is an independent risk factor for mortality in such patients (1–3). Studies have shown that changes in endocrine hormones such as orexin and leptin have close relationships with cachexia associated with COPD (4–6). Growth hormone (GH) and its mediator, insulin-like growth factor (IGF)-I, are anabolic hormones that are essential for skeletal growth and metabolic homeostasis (7, 8). GH treatment has been shown to increase muscle mass in patients with COPD (9), although it has adverse effects including edema and abnormal glucose tolerance. These findings suggest a role of the GH/IGF-I axis in cachexia associated with COPD. Ghrelin, a novel endogenous GH-releasing peptide, was isolated from the stomach (10). Ghrelin stimulates the secretion of GH through a mechanism independent from that of hypothalamic GH-releasing hormone. Ghrelin has been shown to cause a positive energy balance by reducing fat utilization through GH-independent mechanisms (11). In addition, both intracerebroventricular and peripheral administration of ghrelin have been shown to elicit potent, long-lasting stimulation of food intake via activation of neuropeptide Y neurons in the hypothalamic arcuate nucleus in animals (12–14). The plasma ghrelin level has been reported to be elevated in cachectic states (15, 16). However, little information is available regarding the pathophysiology of ghrelin in COPD. Thus, the purposes of this study were to investigate (1) whether the plasma ghrelin level is elevated in patients with COPD, and (2) whether the plasma ghrelin level is related to a cachectic state and pulmonary function in patients with COPD.
Subjects We studied 50 patients with COPD (46 men and 4 women; mean age, 71 years; range, 41 to 83 years). COPD was diagnosed according to Global Initiative for Chronic Obstructive Lung Disease criteria. All patients were clinically stable at the time of evaluation. This study included 13 control subjects who had normal pulmonary function. The age and sex of the control subjects were similar to those of the 50 patients. The Institutional Review Board of Nara Medical University (Nara, Japan) approved this study. All subjects provided informed consent.
Patients with COPD were divided into two groups based on body mass index (BMI): underweight patients (BMI < 20, n = 26), or normal weight patients (BMI
Fat-free mass (lean body mass) was measured by bioelectrical impedance analysis to investigate the relationship between plasma ghrelin and body composition in a subsample of 16 patients (underweight patients, n = 8; normal weight patients, n = 8). Lean body mass was significantly lower in underweight patients than in normal weight patients (39.3 ± 1.4 versus 46.5 ± 2.1 kg, p < 0.05).
Pulmonary Function Testing
Blood Sampling and Analysis
Serum IGF-I was measured by radioimmunoassay (Somatomedin CII Bayer; Bayer Medical, Tokyo, Japan). Serum tumor necrosis factor-
Statistical Analysis
Biochemical Factors Serum total protein and total cholesterol were significantly lower in underweight patients with COPD than in control subjects (Table 2). In addition, serum triglyceride, prealbumin, retinol-binding protein, and transferrin were significantly lower in underweight patients than in normal weight patients and control subjects.
Plasma Ghrelin and Cachectic State in Patients with COPD The plasma ghrelin level was significantly higher in patients with COPD than in control subjects (237 ± 13 versus 157 ± 10 fmol/ml, p < 0.01). In particular, the plasma ghrelin level was higher in underweight patients than in normal weight patients and control subjects (272 ± 20 versus 195 ± 11 and 157 ± 10 fmol/ml, respectively, p < 0.01; Figure 1). The level did not significantly differ between normal weight patients and control subjects. The plasma ghrelin level correlated negatively with BMI (r = –0.38, p < 0.01; Figure 2). In addition, plasma ghrelin level correlated negatively with fat-free mass (lean body mass) (r = –0.49, p < 0.05) in a subsample of 16 patients.
Circulating levels of catabolic factors such as tumor necrosis factor- and norepinephrine were significantly higher in both COPD groups than in control subjects (Table 2). Furthermore, the increases in these catabolic factors were marked in underweight patients compared with normal weight patients. On the other hand, circulating levels of anabolic factors such as IGF-I and insulin were significantly lower in underweight patients than in normal weight patients, although these anabolic factors in normal weight patients ware increased (IGF-I) or unchanged (insulin) compared with those in control subjects. The plasma ghrelin level correlated positively with serum tumor necrosis factor- (r = 0.47, p < 0.01) and plasma norepinephrine (r = 0.40, p < 0.01), but not serum IGF-I (r = 0.12, p = 0.83) and insulin (r = –0.25, p = 0.27). The plasma ghrelin level did not significantly differ between COPD patients with (n = 15) and without (n = 35) corticosteroid therapy (255 ± 27 versus 225 ± 14 fmol/ml, p = NS).
Plasma Ghrelin and Pulmonary Function in Patients with COPD
In the present study, we demonstrated that (1) the plasma ghrelin level was elevated in underweight patients with COPD, and that (2) plasma ghrelin correlated negatively with BMI and correlated positively with circulating levels of tumor necrosis factor- and norepinephrine. We also demonstrated that (3) the plasma ghrelin level was associated with indexes of hyperinflation including percent predicted residual volume and residual volume-to-total lung capacity ratio.
Ghrelin strongly stimulates GH release through a mechanism independent from that of hypothalamic GH-releasing hormone (10). Ghrelin has also been shown to cause a positive energy balance by reducing fat utilization and stimulating food intake (11–14). These findings suggest that ghrelin induces anabolic effects through GH-dependent and independent mechanisms. Thus, we investigated the pathophysiological significance of ghrelin in pulmonary cachexia. In the present study, we defined underweight as BMI < 20 kg/m2. Some nutritional parameters including serum triglyceride, prealbumin, retinol-binding protein, and transferrin were also lower in underweight patients than in normal weight patients. These results suggest that "underweight" defined in the present study is accompanied by malnutrition. We demonstrated that plasma ghrelin level was higher in underweight patients than in normal weight patients. Furthermore, the plasma ghrelin level correlated negatively with BMI and lean body mass. These results suggest that the plasma ghrelin level is elevated in response to a cachectic state. Earlier studies have shown that hormonal changes and cytokine activation induce a catabolic state in patients with COPD, resulting in the development of cachexia (4–6, 19). In fact, some catabolic factors such as tumor necrosis factor- In the present study, the plasma ghrelin level showed significantly positive correlation with indexes of hyperinflation such as percent predicted residual volume and residual volume-to-total lung capacity ratio. In addition, the plasma ghrelin level tended to correlate negatively with percent predicted forced expiratory volume in 1 second. Thus, elevated ghrelin may be associated with abnormality of pulmonary function in patients with COPD. Because GH secretagogues receptor, a receptor for ghrelin, is expressed in the lung (20), further studies are to investigate a role of ghrelin in the lung. Although the present study demonstrated that body composition and indexes of hyperinflation were among the determinants of the plasma ghrelin level, further work will be required to determine the factors that contribute to the wide range of ghrelin levels among underweight patients with COPD. In conclusion, the plasma ghrelin level was elevated in underweight patients with COPD, and the level was associated with a cachectic state and abnormality of pulmonary function.
Supported by the Mochida Memorial Foundation for Medical and Pharmaceutical Research and by grants from the Japan Cardiovascular Research Foundation, the New Energy and Industrial Technology Development Organization (NEDO), the Organization for Pharmaceutical Safety and Research (OPSR) of Japan (Promotion of Fundamental Studies in Health Science), and the Research Committee, Intractable Respiratory Failure, Ministry of Health, Labor, and Welfare of Japan. Conflict of Interest Statement: T.I. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; N.N. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; M.Y. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; A.F. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; H.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; Y.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; Y.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; H.O. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; M.Y. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; H.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; K.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; H.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. Received in original form October 14, 2003; accepted in final form July 20, 2004
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ABSTRACT
METHODS
20, n = 24). There was no significant difference in age, sex, smoking history, disease severity, or medication use between underweight and normal weight patients with COPD (
