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Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism (J.M.G., M.G.-T., R.A.H., G.R.C., M.M.), Oncology (D.E.), and Cardiology (D.M.) and the Huffington Center on Aging (J.M.G., G.T., R.G.S.), Baylor College of Medicine, and Michael E. DeBakey Veterans Affairs Medical Center (J.M.G., M.G.-T., R.A.H., G.T., D.E., D.M., G.R.C., M.M.), Houston, Texas 77030
Address all correspondence and requests for reprints to: José M. Garcia, Michael E. DeBakey Veterans Affairs Medical Center, 2002 Holcombe Boulevard, Houston, Texas 77030. E-mail: jgarcia1{at}bcm.tmc.edu.
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Abstract |
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Introduction |
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Various mechanisms have been implicated in the etiology of the cachexia-anorexia syndrome. Individuals with cancer-induced cachexia have decreased food intake (2), increased muscle proteolysis (3), increased adipose tissue lipolysis (4), and increased resting energy expenditure (5). Several gastrointestinal hormones may regulate food intake and energy balance by affecting the arcuate nucleus of the hypothalamus that mediates changes in energy expenditure and appetite. Ghrelin, a 28-amino acid peptide secreted mainly from the stomach, was isolated in 1999 as the endogenous ligand for the GH secretagogue receptor (6, 7). Recently it was unambiguously demonstrated through experiments on GH secretagogue receptor knockout mice that the GH secretagogue receptor mediates ghrelin’s GH-releasing and orexigenic properties (8). The peptide contains an n-octanoyl group on the serine residue in position 3 that appears to be essential for its biological activity (9).
In addition to its GH secretagogue activity (10), ghrelin is thought to be an important orexigenic hormone (11). It reduces fat oxidation and increases adiposity (12). Fasting plasma ghrelin levels are inversely related to body mass index (BMI), and they increase with weight loss induced by caloric restriction (13, 14). Subjects with anorexia nervosa also have substantially elevated fasting levels of ghrelin that return to normal when body weight is normalized (15). Individuals with congestive heart failure (16) or lung cancer-induced cachexia (17) have been reported to have increased levels of total ghrelin, and a ghrelin infusion has been recently shown to increase appetite in subjects with cancer-induced cachexia (18). However, endogenous active ghrelin levels and their relationship with appetite or food intake have not been reported.
Multiple inflammatory cytokines, including IL-6, IL-1ß and TNF
, are also though to contribute to the development of both anorexia and cachexia (19, 20, 21). IL-6 administration reduces body weight, induces lipolysis, and suppresses appetite (22, 23). Intraperitoneal injection of IL-1ß decreases food intake and induces weight loss in mice (24). Ghrelin administration can antagonize the effect of cytokines on appetite and body weight. Intraperitoneal administration of ghrelin blunts the anorectic and weight-reducing effect of IL-1ß administration and induces increase in food intake and body weight in animal models of cancer-induced cachexia (24, 25).
Peptide YY (PYY), a peptide secreted mainly by the endocrine cells lining the mucosa of the distal ileum and colon, has structural resemblance with neuropeptide Y (26). PYY has been postulated to be an anorexigenic signal that stimulates the inhibitory presynaptic Y2 receptor, which decreases food intake in humans and animals (27, 28). However, its anorectic and weight-losing properties in animals recently have been questioned (29). In humans, an iv infusion of PYY decreased ghrelin levels, suggesting another mechanism that can induce suppression of food intake (30). PYY is released postprandially in proportion to the caloric intake (31), and its levels are lower in weight-stable obese subjects when compared with lean individuals. However, its role in the pathogenesis of cancer-induced cachexia syndrome is not known.
Cachexia increases mortality and decreases quality of life in cancer patients (32), and current interventions are suboptimal. A better understanding of the mechanisms controlling appetite in cancer-induced cachexia may help with the development of new therapies that could prolong survival and increase quality of life in these patients. Even when ghrelin appears to have therapeutic potential in this setting (18), the role of endogenous ghrelin and PYY in the pathogenesis of this syndrome has not been well studied. We hypothesize that abnormal endogenous ghrelin and/or PYY levels contribute to cancer-induced cachexia.
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Subjects and Methods |
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The protocol was approved by the Baylor College of Medicine Institutional Review Board and the Research and Development Committee of the Michael E. DeBakey Veterans Affairs Medical Center in Houston, and it was conducted between August 2003 and March 2004. All clinical investigation described in the paper was conducted in accordance with the guidelines in The Declaration of Helsinki.
The study included three groups: (1) patients with cancer and the anorexia-cachexia syndrome, defined as an unintentional weight loss of at least 5% of their preillness body weight over that of the previous 6 months (n = 21); (2) patients with cancer but without the anorexia-cachexia syndrome, with a stable body weight, matched by age, sex, race, preillness BMI and cancer staging to the previous group (n = 24); (3) subjects without cancer with a stable body weight, matched by age, sex, race, and BMI to the other two groups (n = 23; see Table 1
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The exclusion criteria were: blood malignancies or cancer involving the upper airway or upper gastrointestinal tract; dysphagia; drug or alcohol abuse defined as any use of recreational drugs or more than two drinks per day; presence of congestive heart failure (ejection fraction < 35% on a two-dimensional echocardiogram or clinical signs such as edema, dyspnea, or jugular venous distention); severe liver disease (ascites, lower extremity edema, evidence of cirrhosis on abdominal imaging, elevation on liver enzymes more than twice the upper level of normal); severe chronic obstructive pulmonary disease (severe obstruction on spirometry or use of home O2); diabetes with hemoglobin A1c levels more than 7%; fasting plasma glucose more than 140 mg/dl or random glucose levels more than 200 mg/dl; presence of thyroid disease or renal failure (defined by TSH and/or creatinine values outside the normal range); active infection (temperature 
38.4 C or other signs or symptoms of infection); history of gastrointestinal surgery (except appendectomy); history of neuroendocrine tumor; use of glucocorticoids (7.5 mg of prednisone or equivalent per day for more than 2 wk over the past 6 months except inhaled steroids); use of progesterone, testosterone, or other orexigenic agents (i.e. dronabinol); history of eating disorders or dysphagia; and history of cancer other than nonmelanomatous skin cancer for the control group.
All subjects were patients at the Michael E. DeBakey Veterans Affairs Medical Center and were identified through a search of the computerized medical record system after obtaining permission from the subjects’ primary care providers. Eligible patients after chart review were invited to participate in the study. Among 94 eligible subjects, 68 met the inclusion/exclusion criteria.
The study included an interview focusing on appetite based on visual analog scales (VAS) that ranged from 0 to 100 mm (higher values indicate greater appetite) with words anchored at each end, expressing the most positive and most negative rating (33, 34, 35, 36, 37). The VAS consisted of four questions assessing food intake, appetite changes over the previous 6 months, and hunger. Each question was presented in writing to the patients. To assess perception of food intake, each subject was asked the question "How is your current food intake?" where 0 was "greatly decreased" and 100 was "greatly increased." To assess the changes in appetite, each subject was asked two questions: one was taken from the Edmonton Symptom Assessment System: "How would you describe your appetite?" (where 0 was "no appetite" and 100 was "very good appetite"). The Edmonton Symptom Assessment System VAS for appetite has been used extensively in the setting of cancer-induced cachexia and has been shown to be reliable and correlate well with 1- and 7-d scores in test-retest evaluations (35, 36, 37). A modification of this question, "How would you compare your appetite now to 6 months ago?" (where 0 was "greatly decreased," 50 was "unchanged," and 100 was "greatly increased"), also was included because of the correlation with 6-month weight loss. The question, "How hungry do you feel right now?" (where 0 was "I am not hungry at all" and 100 was "I never been more hungry"), was taken from a previously validated VAS (33, 34). The question was asked at the time of blood collection because ghrelin and PYY are thought to play a role in the acute regulation of appetite.
A blood sample after a 10- to 12-h fast was obtained between 0700 and 0900 h for measurement of a complete blood count, albumin, aspartate aminotransferase (AST), aminotransferase, TSH, creatinine, total and active ghrelin, PYY, glucose, insulin, IL-6, TNF, and IGF-I.
Clinical parameters obtained in the study included age, gender, race, BMI [calculated as weight (kilograms)/height (meters) (2)], appetite, cancer diagnosis and staging, medications, and comorbid conditions.
Insulin sensitivity was assessed using the homeostasis model assessment (HOMA-IR) [HOMA-IR = fasting glucose (millimoles per liter) x fasting insulin (microunits per milliliter)/22.5] as previously described. Estimates of insulin resistance from HOMA correlate well with estimates from the gold standard hyperinsulinemic euglycemic clamp method (r = 0.88, P < 0.0001) (38).
Hormone assays
Blood was collected in EDTA-containing tubes and kept at 4 C during processing. Aprotinin (100 µl containing 0.6 trypsin inhibitor unit per milliliter of blood) was added to one of the tubes and the samples were then centrifuged at 3000 rpm for 30 min. One-milliliter samples were aliquoted into polypropylene vials and stored at –80 C until assayed.
Total ghrelin (the sum of the acylated and deacylated forms of the hormone) has been used in most published studies. However, because the ratio of acylated to total ghrelin was not known in patients with cancer-induced cachexia, both total and active ghrelin were measured. Plasma total ghrelin levels were measured by RIA using kits purchased from Phoenix Pharmaceuticals (Belmont, CA). As suggested by the manufacturer, plasma with aprotinin was used for the assay. This RIA kit uses a polyclonal antibody raised in rabbit against both octanoylated and desoctanoylated ghrelin, and I125-ghrelin as the tracer. The lower and upper detection limits were 80 and 1280 pg/ml, respectively. The intraassay coefficient of variation was 4%. Active ghrelin levels were measured by a commercially available RIA kit from Linco Research (St. Charles, MO) in plasma treated with hydrochloric acid 1 N and phenylmethylsulfonyl fluoride added immediately after collection. This RIA kit uses an antibody raised in guinea pig against octanoylated ghrelin and I125-octanoylated ghrelin as the tracer. This assay has been found to be highly specific for active ghrelin with less than 0.1% cross-reactivity for desoctanoyl ghrelin, and no cross-reactivity with ghrelin 14–28, motilin-related peptide, leptin, insulin, glucagon, or glucagon-like peptide 7–36. The lower and upper detection limits were 10 and 2000 pg/mL, respectively. The intraassay coefficient of variation was 5.3%.
PYY levels were measured by a commercially available RIA kit from Linco Research that recognizes the two biologically active forms of the hormone: PYY 1–36 and 3–36. As recommended by the manufacturer, we used plasma treated with aprotinin added immediately after collection. This RIA kit uses an antibody raised in guinea pig against PYY and I125-PYY (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36) as the tracer. The lower and upper detection limits were 20 and 1280 pg/ml, respectively. The intraassay coefficient of variation was 5%.
The measurements of circulating levels of IL-6 and TNF were performed in the Cardiac Cytokine Laboratory at the Michael E. DeBakey Houston Veterans Affairs Medical Center using commercially available ELISA kits from R&D Systems (Minneapolis, MN) as described previously (39, 40).
Insulin levels were measured by a RIA kit purchased from Linco Research. IGF-I levels were extracted using acid-methanol and measured by a RIA kit from Nichols Laboratories (San Juan Capistrano, CA).
For all hormones, plasma from an equal number of subjects from each group was included in the first assay, and the remaining samples were assayed in a second assay to minimize interassay variability in hormone levels between groups.
Statistical analysis
SPSS (version 9.00 software for Windows; SPSS Inc., Chicago, IL) and SAS (version 8.3 Software; SAS Institute Inc., Cary, NC) were used for statistical analysis. Quantitative parameters were expressed as mean ± SD for baseline characteristics and mean ± SE for the rest of the data. Categorical parameters were expressed as percentages. Statistical comparisons among the groups were performed using the Fisher’s exact test or 
2 test for categorical data and t test for quantitative data. Pearson’s correlations, or nonparametric Spearman’s correlation when the data were not normally distributed, were obtained between continuous variables, and one-way ANOVA was used for continuous dependent variables and independent categorical variables. For multiple comparisons, the Tukey test was used. P 
0.05 was considered statistically significant.
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Results |
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The two cancer groups had a different composition in terms of cancer diagnosis, and there was a trend toward a more advanced stage in the cachectic group, although it did not reach statistical significance (see Table 2). The two groups were comparable regarding the proportion of subjects receiving chemotherapy and the proportion of subjects receiving agents that cause androgen blockade because hypogonadism is known to be associated with low ghrelin levels (41).
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Active ghrelin levels were significantly elevated in cachectic subjects, compared with noncachectic cancer controls and noncancer controls (141 ± 12, 91 ± 11, and 78 ± 11 pg/ml, respectively, P ANOVA = 0.001) (see Fig. 1A). The ratio of active to total ghrelin was higher in cachectic, compared with noncachectic cancer and noncancer controls (33 ± 3, 21 ± 3, and 24 ± 3, respectively, P ANOVA = 0.032) (see Fig. 1B).
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). These differences in ghrelin levels between groups persisted, even after adjusting for cancer diagnosis and staging.
PYY levels
PYY levels were not significantly different in cachectic, noncachectic, or noncancer controls (137 ± 9, 155 ± 8, and 140 ± 8 pg/ml, respectively, P ANOVA = 0.26) (see Fig. 2). There was no correlation between PYY levels and BMI at the time of recruitment (R2 = 0.01, P = 0.41) or with weight loss over the previous 6 months (R2 = 0.02, P = 0.28) (not shown).
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levels
IL-6 levels were significantly higher in the group with cachexia, compared with the group of individuals with cancer without cachexia and the noncancer control group (23 ± 4, 8 ± 4, and 3 ± 4 pg/ml, respectively, P ANOVA = 0.001). IL-6 levels were inversely correlated with BMI at the time of recruitment (R = –0.32, P = 0.008) and directly correlated with weight loss over the previous 6 months (R = 0.35, P = 0.001) (see Fig. 3, A and C). After adjusting for groups, no correlation was found between the IL-6 and active ghrelin levels (P > 0.1).
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showed a trend toward being elevated only in cachectic subjects but did not reach significance when compared with cancer and noncancer controls (1.98 ± 0.28, 1.66 ± 0.26, 1.23 ± 0.25 pg/ml, respectively, ANOVA P = 0.17) (see Fig. 3B). TNF levels were not correlated with BMI (R2 = 0.02, P = 0.31) or 6-month weight changes (R2 = 0.004, P = 0.6) (not shown). Albumin levels
Serum albumin, a marker of nutritional status, was lower in cachectic and intermediate in noncachectic cancer controls when compared with noncancer controls, (3.3 ± 0.9, 3.6 ± 0.8, and 3.9 ± 0.9 g/dl, respectively; ANOVA P < 0.001). Albumin also directly correlated with BMI (R2 = 0.15, P = 0.001) and weight change in the previous 6 months (R2 = 0.29, P < 0.001) (data not shown).
Appetite scores
The VAS was correlated with weight loss, active ghrelin, PYY, IL-6, TNF, and albumin levels. Responses to the question "How is your current food intake?" as measured by the VAS were compared among groups and were found to be lower in cachectic, compared with noncachectic cancerous patients and noncancer controls (34 ± 3, 43 ± 3, and 43 ± 3, respectively, ANOVA P = 0.036). There was no correlation between this VAS and active ghrelin (R2 = 0.03, P < 0.18) or TNF levels (R2 = 0.02, P = 0.28), but there was an inverse correlation with IL-6 (R2 = 0.16, P = 0.001) and a direct correlation with albumin (R2 = 0.13, P = 0.004) and PYY (R2 = 0.06, P = 0.04).
Responses to the question "How would you describe your appetite?" were compared among groups, and the score was decreased in cachectic subjects when compared with cancer controls (21 ± 11, 66 ± 10, and 49 ± 10, respectively, ANOVA P = 0.02). Responses as measured by this VAS were not correlated with active ghrelin (R2 = 0.02, P = 0.24), PYY (R2 = 0.008, P = 0.46), TNF levels (R2 = 0.01, P < 0.4), or IL-6 (R2 = 0.05, P < 0.067). Scores for the question "How would you compare your appetite now with 6 months ago?" were compared among groups and no differences were noted (35 ± 3, 42 ± 3, and 44 ± 2, respectively, ANOVA P = 0.2). Scores were not correlated with active ghrelin (R2 = 0.007, P = 0.5), PYY (R2 = 0.02, P = 0.31), or TNF levels (R2 = 0.002, P < 0.71), but there was an inverse correlation with IL-6 (R2 = 0.2, P < 0.001) and direct correlation with albumin (R2 = 0.06, P = 0.044).
For responses to the question "How hungry do you feel right now?" no significant differences in group scores were noted (40 ± 6, 53 ± 6, and 43 ± 5, respectively, ANOVA P = 0.16). There was no correlation between the mean response and active ghrelin (R2 = 0.01, P = 0.3), PYY (R2 < 0.01, P = 0.74), albumin (R2 = 0.01, P < 0.4), or TNF levels (R2 < 0.01, P = 0.9), but there was an inverse correlation with IL-6 (R2 = 0.08, P = 0.02) (see Fig. 4 and Table 3).
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Glucose, insulin, and insulin resistance
Insulin resistance, as measured by the euglycemic hyperinsulinemic clamp, has been reported in cancer patients (42, 43). We measured glucose and insulin levels on the same fasting blood specimens. The number of diabetics in each group was similar (ANOVA P = 0.65), and none required insulin therapy. Fasting glucose levels in the groups were similar (110 ± 6, 110 ± 6, and 103 ± 6 mg/dl, respectively, ANOVA P < 0.63). Insulin levels were elevated in noncachectic cancer patients when compared with cachectics and noncancer controls; however, there was no difference between noncancer controls and cachectic patients (28 ± 3, 17 ± 3, and 19 ± 3 mU/ml, respectively, ANOVA P < 0.05). After adjusting for the presence of diabetes mellitus, HOMA-IR values were also significantly elevated in noncachectic cancer patients, compared with the other two groups (8.5 ± 0.94, 4.67 ± 0.94, and 5.22 ± 0.92%, respectively, ANOVA P < 0.02) (see Fig. 5A).
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IGF-I levels were significantly decreased in cachectic subjects, compared with noncachectic cancer patients and noncancer controls (96 ± 13, 127 ± 12, and 143 ± 12 ng/ml, respectively, ANOVA P = 0.039) (See Fig. 5B). One cachectic subject who had renal cell carcinoma [a cancer associated with increased IGF-I levels (44)] and an IGF-I value of 492.1 ng/ml (more than 5 SD beyond the mean for the group) was excluded from the statistical analysis.
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Discussion |
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This is the first report of elevated active ghrelin levels in the setting of cancer-induced cachexia. Whereas other investigators have reported elevated total ghrelin levels in patients with lung cancer (17), we found significant increases in active ghrelin and active to total ghrelin ratio in patients with various cancer diagnoses and staging, suggesting that this increase in ghrelin is inherent to the cachexia syndrome and not restricted to a specific type or stage of cancer. Alterations in the active to total ghrelin ratio also have been reported in renal failure (46) and obesity (47), but this is the first report of an altered active to total ghrelin ratio in the setting of cancer-induced cachexia.
We postulate that the lack of increased appetite and the weight loss could be due to a resistance to the orexigenic effects of increased endogenous ghrelin levels. In a recent report, ghrelin administration to a group of cachectic and noncachectic cancer patients induced a 30% increase in appetite and food intake (18). If we assume that in these patients weight loss was associated with elevated preinfusion levels of ghrelin, as shown by others (17) and by us in this study, further elevation in ghrelin levels (3- to 4-fold from baseline) may be able to increase appetite and food intake. Thus, the resistance must be partial. We postulate that the ghrelin resistance observed in patients with cancer-induced cachexia may be analogous to the insulin resistance state seen in type 2 diabetes mellitus, which is overcome by using high doses of insulin.
The increase in the active to total ghrelin ratio observed in cancer-induced cachexia cannot be explained simply by an increase in ghrelin secretion and suggests that other mechanisms, such as a decreased inactivation, may also play a role. The pathways leading to inactivation or activation of ghrelin and their regulation remain largely unknown, and their importance in determining ghrelin levels is unclear.
The role of PYY on food intake and body weight is still controversial (27, 29, 30). In our study, PYY levels were not increased in cachectic subjects despite having a significantly lower BMI when compared with cancer and noncancer controls. We did not find an inverse correlation between PYY and BMI as previously reported (30). Further studies on the role of PYY in the regulation of body weight are needed to clarify this topic.
We observed insulin resistance, as measured by HOMA-IR, in the noncachectic cancer patients but not in the cancer-cachexia group when compared with noncancer controls. We postulate that the cancer-associated insulin resistance can be at least partially reversed by the weight loss. Additional studies are needed to prove this hypothesis.
Cytokines and ghrelin have opposite effects on body weight and appetite, and recent data suggest that cytokines may directly decrease ghrelin production (24) and that ghrelin itself may suppress IL-6 and TNF production (48). Despite human and animal data suggesting that TNF plays a role in cachexia by inducing lipolysis (49, 50) and muscle proteolysis (51), plasma levels of TNF were not significantly elevated in our cachectic patients, and no correlation was found between TNF and weight loss or appetite scores. This may be due to the fact that TNF works more as paracrine rather than endocrine molecule and that plasma values may not truly represent tissue concentrations. Given the complexity of the interaction between ghrelin and cytokines, further studies are needed to clarify this issue.
The increase in active ghrelin was not sufficient to increase IGF-I levels, even though ghrelin is a powerful GH secretagogue. Cachexia has been described as a GH-resistant state with high GH levels but low IGF-I (45). Whether exogenous ghrelin administration in this setting will increase IGF-I levels remains to be determined.
There is an urgent need for new and effective therapies for the prevention and treatment of the cachexia-anorexia syndrome. It affects quality of life and survival, and it represents a significant burden to the patients and their families.
Clinical trials with ghrelin or its analogs and evaluation of appetite, body weight, quality of life, and survival may provide new approaches for managing patients with anorexia.
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Footnotes |
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First Published Online February 15, 2005
Abbreviations: AST, Aspartate aminotransferase; BMI, body mass index; HOMA-IR, insulin sensitivity assessed using the homeostasis model assessment; PYY, peptide YY; VAS, visual analog scale.
Received September 10, 2004.
Accepted February 3, 2005.
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