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Published ahead of print on July 21, 2004, doi:10.1164/rccm.200310-1404OC
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American Journal of Respiratory and Critical Care Medicine Vol 170. pp. 879-882, (2004)
© 2004 American Thoracic Society
doi: 10.1164/rccm.200310-1404OC

Elevated Plasma Ghrelin Level in Underweight Patients with Chronic Obstructive Pulmonary Disease

Takefumi Itoh, Noritoshi Nagaya, Masanori Yoshikawa, Atsuhiko Fukuoka, Hideaki Takenaka, Yoshito Shimizu, Yoshinori Haruta, Hideo Oya, Masakazu Yamagishi, Hiroshi Hosoda, Kenji Kangawa and Hiroshi Kimura

Department 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


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
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-{alpha}, 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-{alpha} 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.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
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 >= 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 (Table 1). The mean smoking history was significantly higher in patients with COPD than in control subjects.


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  		TABLE 1. Patient characteristics

 
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
Lung volumes were measured by the helium gas dilution method, and forced expiratory flow rates were measured with a mass flow anemometer (FUDAC 70; Fukuda Denshi, Tokyo, Japan). Carbon monoxide transfer factor was measured by the single-breath method. Pulmonary function values were expressed as a percentage of predicted values (17). Arterial blood gases were measured at rest with a blood gas analyzer (ABL 720; Radiometer, Brønshøj, Denmark).

Blood Sampling and Analysis
Blood samples were taken from the antecubital vein in the morning between 7:00 and 8:00 A.M. after an overnight fast. The blood was centrifuged immediately at 4°C and stored at –80°C. Plasma ghrelin was measured by radioimmunoassay as described previously (18).

Serum IGF-I was measured by radioimmunoassay (Somatomedin CII Bayer; Bayer Medical, Tokyo, Japan). Serum tumor necrosis factor-{alpha}, interleukin-6, and insulin were measured by enzyme immunoassay (Quantikine HS [R&D Systems, Minneapolis, MN]; TFB kit [TFB, Tokyo, Japan]; and AIA-PACK IRI [Tosoh, Tokyo, Japan], respectively). Plasma epinephrine and norepinephrine were measured by high-performance liquid chromatography (HLC8030; Tosoh). Serum testosterone in male subjects was measured by radioimmunoassay (DPC testosterone kit; DPC, Los Angeles, CA). Serum prealbumin, retinol-binding protein, and transferrin were measured by nephelometry (Dade Behring, Deerfield, IL).

Statistical Analysis
Data are expressed as means ± SEM. Comparisons of parameters between the two groups were made by Fishes exact test or unpaired Student t test. Comparisons of parameters among three groups were made by one-way analysis of variance followed by the Scheffé multiple comparison test. Five groups (control subjects and patients with Stage I, II, III, and IV COPD) were compared by one-way analysis of variance followed by the Scheffé multiple comparison test. Independent relations between plasma ghrelin and pulmonary function parameters were examined by multivariate regression analyses. A p value less than 0.05 was considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
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.


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  		TABLE 2. Circulating levels of hormonal and biochemical factors

 
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.



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  		Figure 1. Plasma level of ghrelin in control subjects (Control), normal weight patients with chronic obstructive pulmonary disease (COPD) (NW), and underweight patients with COPD (UW).

 


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  		Figure 2. Correlation between plasma ghrelin level and body mass index in patients with COPD. Patients with COPD were divided into two groups: normal weight patients (NW-COPD) and underweight patients (UW-COPD). r = –0.38, p < 0.01.

 
Circulating levels of catabolic factors such as tumor necrosis factor-{alpha} 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-{alpha} (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
The plasma ghrelin level was higher in COPD patients with Stage IV disease than in control subjects (283 ± 31 versus 157 ± 10 fmol/ml, p < 0.05; Figure 3). Plasma ghrelin level tended to correlate negatively with percent predicted forced expiratory volume in one second (r = –0.28, p = 0.07), although the correlation did not reach statistical significance. Interestingly, plasma ghrelin level correlated positively with percent predicted residual volume (r = 0.34, p < 0.05) and residual volume-to-total lung capacity ratio (r = 0.33, p < 0.05) (Figure 4). Multiple regression analysis demonstrated that percent predicted residual volume or the residual volume-to-total lung capacity ratio was an independent determinant of plasma ghrelin level (each p < 0.05) even after adjustment for age, sex, and BMI. On the other hand, the plasma ghrelin level did not significantly correlate with any other pulmonary function parameters.



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  		Figure 3. Plasma ghrelin level in patients with COPD according to disease severity based on Global Initiative for Chronic Obstructive Lung Disease guidelines. *p < 0.05 versus control.

 


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  		Figure 4. Correlations between plasma ghrelin level and percent predicted residual volume (RV, left), and between plasma ghrelin level and residual volume-to-total lung capacity ratio (RV/TLC, right) in patients with COPD. NW-COPD indicates normal weight patients with COPD; UW-COPD, underweight patients with COPD.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
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-{alpha} 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-{alpha}, interleukin-6, and norepinephrine were significantly higher in underweight patients than in normal weight patients, whereas anabolic factors including IGF-I and insulin were significantly lower in underweight patients than in normal weight patients. The plasma ghrelin level correlated positively with catabolic factors such as tumor necrosis factor-{alpha} and norepinephrine. Considering the positive energy effects induced by ghrelin, increased ghrelin may represent a compensatory mechanism under catabolic–anabolic imbalance in cachectic patients with COPD. Unexpectedly, the serum IGF-I level was significantly higher in normal weight patients than in control subjects. Catabolic factors including tumor necrosis factor-{alpha} and norepinephrine were significantly higher in normal weight patients than in control subjects, although the increases were marked in underweight patients. These findings raise the possibility that increased IGF-I in normal weight patients may represent a compensatory mechanism under conditions of energy imbalance.

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.


   FOOTNOTES
 
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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