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Plasma Ghrelin Concentrations, Food Intake, and Anorexia in Liver Failure

Unit of Metabolic Diseases (G.M., N.V.), Department of Internal Medicine and Gastroenterology, and Unit of Internal Medicine (G.B., M.Z), Department of Internal Medicine, Cardioangiology, Hepatology, "Alma Mater Studiorum" University of Bologna, I-40138 Bologna, Italy; and Department of Internal Medicine (P.L., P.D.F.), Section of Internal Medicine, Endocrine and Metabolic Sciences, University of Perugia, I-06126 Perugia, Italy

Address all correspondence and requests for reprints to: Professor Giulio Marchesini, M.D., Unit of Metabolic Diseases, "Alma Mater Studiorum" University of Bologna, Via Massarenti 9, I-40138 Bologna, Italy. E-mail: giulio.marchesini{at}unibo.it.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
Ghrelin is related to feeding behavior and nutrition in several physiological and pathological conditions. We tested the hypothesis that the anorexia and the decreased food intake of advanced liver failure might be associated with hyperghrelinemia. Fasting ghrelin was measured in 43 cirrhotic patients, food intake was self-assessed using the Corli score and a 3-d dietary record (n = 25), and anorexia/hunger was tested by a Likert scale. Fifty healthy subjects, matched for age and body mass index, served as controls. Ghrelin levels were not systematically increased in cirrhosis (414 ± 164 vs. 398 ± 142 pmol/liter in controls) but increased with decreasing Corli score (P = 0.014) and along the scale of anorexia/hunger (P = 0.0001), which were both related to the 3-d dietary record (P = 0.009 and P < 0.0001, respectively). Logistical regression confirmed that high ghrelin (>500 pmol/liter) was significantly associated with a low calorie intake [odds ratio (OR), 3.03 for any 100-calorie reduced intake; P = 0.015], a reduced Corli score (OR, 3.09; P = 0.031), and the anorexia score (OR, 3.37; P = 0.009), after adjustment for body mass index. The study confirms the previously observed relationship of fasting ghrelin with food intake in disease-associated malnutrition. In the presence of anorexia, hyperghrelinemia might indicate a compensatory mechanism trying to stimulate food intake, which is nonetheless ineffective in the physiological range.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
GHRELIN IS A recently identified enteric hormone involved in food intake. Circulating ghrelin levels rise shortly before expected food intake and fall shortly after every meal (1, 2). Ghrelin administration increases subjective hunger and voluntary food intake (3). In anorexia nervosa, in which food intake is voluntarily restricted, ghrelin levels are doubled compared with levels in constitutionally thin subjects with normal feeding behavior (4) and normalize after renutrition (4, 5). Similarly, in cancer anorexia, ghrelin levels are increased in subjects with cachexia and further increase with decreased food intake after chemotherapy (6). Also, in the cachexia associated with chronic heart failure, ghrelin levels are significantly elevated (7). Because of its orexigenic properties, the hormone may be teleologically aimed at regulating food intake to compensate for malnutrition, and its clinical use to stimulate food intake might be tested in therapeutic trials (3).

Anorexia is a problem of paramount importance in patients with advanced cirrhosis, contributing to malnutrition. The reasons for reduced food intake include hepatocellular failure to tense ascites, causing mechanical difficulties in feeding; poor palatability of a low-sodium diet; and, finally, increased brain tryptophan availability for serotonin synthesis (8). In turn, malnutrition is a risk factor for the development of life-threatening complications and increased mortality (9, 10), and any effort to promote regular feeding should be encouraged. Very recently, Tacke et al. (11) reported that ghrelin levels are elevated in cirrhosis compared with healthy controls and that there is a dependence of ghrelin on the severity of liver disease, but the potential role of the decreased food intake was not considered.

The present study tested the hypothesis that, also in advanced liver diseases, plasma ghrelin concentrations might be regulated by anorexia and decreased food intake.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
Patients

Fasting ghrelin levels were assayed in 43 patients with liver cirrhosis (29 males, 14 female, aged 39–76 yr, median 61 yr; body mass index (BMI), 23.8 ± SD 3.2 kg/m²) with a wide range of hepatocellular dysfunction, as assessed by the Child-Pugh classification (12) on the basis of albumin, prothrombin, and bilirubin levels and the presence or severity of ascites and encephalopathy (Table 1). In ascitic patients, the calculation of BMI was based on the weight before the development of ascites or on body weight after therapeutic paracentesis. Causes of the liver cirrhosis were as follows: in 11 patients, alcohol was the primary cause of disease; in 27 patients, the cause was viral hepatitis (hepatitis B in three cases; hepatitis C in 24); and in five patients, the cirrhosis was of varying etiology (cryptogenic, three cases; primary biliary cirrhosis, one case; secondary biliary cirrhosis, one case). At the time of the study, patients with alcoholic liver disease had been abstaining from alcohol for 6 months or more. No patients had laboratory (-fetoprotein) or ultrasonographic evidence of hepatocellular carcinoma.

Most patients were being treated with proton pump inhibitors, diuretics, and/or nonabsorbable disaccharides, and five were being treated with intermittent antibiotics (ciprofloxacin) to prevent spontaneous bacterial peritonitis. No patients were on oral amino acid nutritional supplementation.

A group of 50 subjects, free of hepatic disease, diabetes, and endocrine diseases, was used as control. Control subjects ranged in age from 35–79 yr (median, 52 yr; BMI, 25.2 ± 3.0 kg/m²).

Blood samples for ghrelin concentrations were collected between 0800 and 0900 h in the morning, after an overnight fast. Plasma was immediately separated and stored at –80 C until analysis.

All subjects gave their informed consent to blood sampling and agreed to fill in the questionnaires. All other investigations were carried out during regular follow-up, according to specific protocols. The study was approved by the Saint Orsola University Hospital senior staff committee, a board regulating noninterventional studies, comparable to an institutional review board.

Methods

Plasma immunoreactive ghrelin levels were measured in duplicate using a commercial RIA that uses ¹²⁵I-labeled bioactive ghrelin as a tracer and a rabbit polyclonal antibody raised against full-length octanoylated human ghrelin (Phoenix Pharmaceuticals, Belmont, CA) that recognizes both acylated and des-acylated ghrelin. The intraassay coefficient of variation is less than 10% (14).

The self assessment of food intake was scored according to Corli et al. (15), with minor modifications. Patients were invited to score the amount of food ingested during the previous week, compared with their usual food intake, as normal (score 0), more than normal (score +1), less than normal (score –1), or much less than normal (score –2). The final value is therefore skewed, favoring the assessment of a reduced food intake. In 25 cases with cirrhosis and in 30 controls, a 3-d dietary record of ingested food was completed in the 3 d preceding ghrelin measurement, and a registered dietitian calculated the reported calorie intake.

Anorexia was tested in the fasting state by a visual analogical scale, modified from Raben et al. (16). The scale provides a self-determined evaluation of anorexia/hunger on a 90-mm scale [from –45 mm (severe anorexia) to +45 mm (severe hunger)], the norm (0 mm) lying in the middle. In the course of a previous study (17), we found that the use of the analogical scale may be difficult, particularly for most severely anorexic patients. For this reason, the scale was transformed into 7-point Likert scale, having severe (–3), moderate (–2), and mild anorexia (–1) on the left side, and mild, moderate, and severe hunger (graded from 1–3) on the right side.

Statistical analysis

Data were processed on a personal computer and analyzed using StatView 5.0 (SAS Institute Inc., Cary, NC). Patients were grouped according to categorical variables (sex, Child-Pugh class, class of BMI, presence/absence of ascites, encephalopathy). Ghrelin concentrations were tested for significance using unpaired t test (two-tail), whereas food intake and anorexia scores were tested using nonparametric analysis (Mann-Whitney U test or Kruskal-Wallis test). Contingency test and Fisher’s exact test were also used, whenever appropriate, to compare prevalence. Logistical regression analysis also was used to associate high ghrelin levels with reduced food intake and anorexia. For this purpose, the Corli and the anorexia scores were rotated, higher values indicating lower food intake and higher grades of anorexia. All data in the text and in the tables are given as means ± SD when not otherwise indicated.

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
On average, fasting ghrelin concentrations did not differ between control subjects (range, 220–751 pmol/liter) and patients with cirrhosis (range, 201–949 pmol/liter; Table 1). In cirrhotic patients, there were no differences in fasting ghrelin levels in relation to gender, severity of liver failure (Child-Pugh class), and BMI class, whereas in the control group the subjects in the overweight class had lower ghrelin levels compared with normal-weight cases. In addition, a correlation between ghrelin and BMI was observed in controls (r_s = –0.712; P < 0.0001), but not in patients with cirrhosis (r_s = –0.002; P = 0.989; Fig. 1). Also, excluding patients with ultrasound-detectable ascites, no correlation was present between ghrelin and BMI in cirrhosis (r_s = –0.020; P = 0.943).

View larger version (21K): [in this window] [in a new window]   FIG. 1. Correlation of plasma ghrelin concentration with BMI in control subjects (open circles) and patients with cirrhosis (closed circles). The dotted line in the scattergram is the regression line in controls (rs = –0.712; P < 0.0001); the continuous line is the regression in patients with cirrhosis (rs = –0.002; P = 0.989).

Only four patients scored their food intake as more than normal, and 18 scored it as normal. Of the remaining 21 patients, 15 scored their food intake as lower than normal and six as much less than normal. Also, the anorexia/hunger scale was skewed to the left. Eleven patients scored their desire for food as mild hunger, and 13 scored this as zero, whereas anorexia was reported as mild in nine cases and as moderate in 10. No patients complained of severe anorexia. The scale of anorexia/hunger did not show systematic differences in the distribution according to the severity of liver failure (², 7.45; P = 0.681). The score of food intake was significantly associated with the Likert scale of anorexia/hunger (², 18.87; P = 0.026).

Recorded food intake was on average 1700 ± 289 kcal (range, 1165–2244 kcal) in patients with cirrhosis and 1960 ± 293 (range, 1510–2520 kcal) in controls (P = 0.0047, Mann-Whitney U test). When expressed per kilogram of ideal body weight, calorie intake was on average 21.1 ± 3.6 kcal in cirrhosis and 24.4 ± 3.6 kcal in controls (P = 0.0047; Mann-Whitney U test). In cirrhosis, recorded food intake was significantly associated with the Corli score (r_s = 0.534; P = 0.009) and with the anorexia/hunger scale (r_s = 0.929; P < 0.0001; Spearman rank correlation). In particular, calorie counting was on average 1970 ± 249 kcal/d (24.5 ± 3.1 kcal/kg ideal body weight) in overweight cirrhosis patients (n = 8), 1637 ± 181 kcal/d (20.3 ± 2.2 kcal/kg ideal body weight) in normal-weight patients (n = 13), and only 1367 ± 186 kcal/d (17.0 ± 2.3 kcal/kg ideal body weight) in the four cases with severe cachexia (P = 0.0013; Kruskall-Wallis test).

Ghrelin was very high in the few patients who scored their food intake as much less than usual (524 ± 223 pmol/liter) and decreased with increasing food intake (461 ± 183 pmol/liter, 356 ± 103 pmol/liter), finally decreasing to 332 ± 115 pmol/liter in the four patients who scored their food intake as more than normal (P = 0.108; Kruskal-Wallis test; Fig. 2). Similarly, plasma ghrelin decreased progressively along the scale of anorexia/hunger (P < 0.0001; Kruskal-Wallis test; Fig. 3), being more than twice as high in the 10 patients who had very little desire for food (moderate anorexia, 607 ± 173 pmol/liter) compared with subjects with mild hunger (297 ± 56 pmol/liter). A significant correlation was present between plasma ghrelin and the score of food intake (r_s = –0.377; P = 0.014; Spearman rank correlation), the score of the anorexia/hunger scale (r_s = –0.399; P = 0.0001), as well as the 3-d calorie record (r_s = –0.658; P = 0.0013; Fig. 4). In controls, the relationship between fasting ghrelin and the calorie intake was not statistically significant (r_s =–0.357; P = 0.054; Fig. 4).

View larger version (15K): [in this window] [in a new window]   FIG. 2. Box plot representation of plasma ghrelin concentrations in patients with cirrhosis, grouped according to self-assessed food intake. In these "box and whiskers" plots, the bar within each column represents the median value, the upper and lower borders of the box are the quartiles, and the whiskers (error bars) at the extremities indicate the 10th and the 90th percentiles. Closed circles indicate individual outliers. For trend, P = 0.014.

View larger version (17K): [in this window] [in a new window]   FIG. 3. Box plot representation of plasma ghrelin concentrations in patients with cirrhosis, grouped according to the Likert scale of anorexia/hunger. For trend, P = 0.001. See also legend to Fig. 2.

View larger version (20K): [in this window] [in a new window]   FIG. 4. Correlation of plasma ghrelin concentration with average daily calorie intake per kilogram of ideal body weight (3-d record) in control subjects (open circles) and patients with cirrhosis (closed circles). The dotted line in the scattergram is the regression line in controls (rs = –0.357; n = 30; P = 0.054); the continuous line is the regression in patients with cirrhosis (rs = –0.658; n = 25; P = 0.001). i.b.w., Ideal body weight.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
The study confirms that ghrelin levels are elevated in a subgroup of patients with cirrhosis and identifies decreased food intake and malnutrition, a common finding in advanced disease, as the cause of hyperghrelinemia.

We used self-assessed methods to score food intake and anorexia. These methods are useful and validated in pathological conditions but cannot be used in healthy subjects with normal weight and regular food intake, for whom total calories are mainly regulated by physical activity. The method for food intake was developed in cancer patients (15) and correctly quantified the undernutrition of terminally ill patients and the effects of care programs. The validity of the method is strongly supported by the correlation we found between the Corli score, as well as the anorexia score, and the 3-d diary food records, assessed by a registered dietitian in a subgroup of 25 patients. In particular, the Corli method does not score the amount of ingested food according to "normal" food intake of healthy subjects. Comparison is made with the "usual" food intake of individual patients. Changes in food intake (3) and weight gain (5) are reported to produce significant effects on circulating ghrelin levels. Accordingly, a significant, inverse correlation was observed between food intake and ghrelin, suggesting a normal response of the orexigenic hormone to reduced energy supply. The relationship was not maintained in controls, for whom food intake, both total and per kilogram of ideal body weight, may be extremely variable due to the variable amount of physical activity.

We also tested the subjective rating of anorexia/hunger by a visual analogical scale, which also correlates with recorded food intake. The method was previously shown to correlate with fasting ghrelin in the Prader-Willi syndrome, characterized by hunger, hyperphagia, and obesity (18). In this condition, inappropriate ghrelin secretion might be the pathogenic link to hyperphagia. In our study, the association of anorexia/hunger rating with plasma ghrelin was negative; the more severe the anorexia, the higher were fasting ghrelin levels. Similar data were reported in anorexia nervosa, characterized by higher-than-normal (4) and nonsuppressible (19) ghrelin levels, in the presence of a low BMI. However, although in anorexia nervosa, food intake is voluntarily reduced, in advanced cirrhosis, reduced food intake is the effect of anorexia. In both conditions, the final goal is not reached: ghrelin, in physiological amounts, is ineffective in normalizing food intake.

The dependence of fasting ghrelin on previous food intake is probably a general phenomenon, present in any physiological and pathological condition. High ghrelin levels were recently reported in undernourished old subjects, in whom anorexia was suggested as a link to malnutrition (20), and in patients with cancer anorexia, in whom ghrelin is high but food intake is nonetheless reduced (6). Cirrhosis-associated anorexia has features common to cancer anorexia. Interestingly, previous data have suggested that a common pathogenic mechanism is responsible for the anorexia of both liver failure and cancer (21). In both conditions, increased ghrelin might represent a compensatory mechanism trying to overcome the anorexia, a mechanism that remains nonetheless ineffective. Further studies are needed to clarify the reasons for this sort of "ghrelin resistance." Impaired ghrelin receptor signaling, hyperleptinemia contrasting ghrelin action (22, 23), and increased levels of TNF- and of soluble TNF receptor (24) remain the likely candidates.

In advanced liver disease, also, the association of ghrelin levels with BMI is disrupted. In normal subjects, this association is well-known (25) and was confirmed in our control population free of hepatic diseases. It possibly stems from the link between hunger and/or food intake and obesity, which, according to our results, might also be responsible for the age dependence of ghrelin, variably reported in the literature (26, 27). However, the association with BMI is not the rule in disease states (28). In advanced cirrhosis, the measurement of BMI is subject to errors: the volume of ascites and edema may be difficult to estimate, and increased body water may be present also in the absence of overt ascites (29). In patients with ascites, we calculated BMI after paracentesis and/or considering body weight before the development of ascites, but this value may overestimate true body weight due to rapid loss of lean body mass in catabolic conditions. However, the random scattering of the relationship between BMI and ghrelin concentrations, also in subjects without ascites, suggests that ghrelin secretion does not primarily depend on BMI but probably depends on nutrition and/or central signals related to food intake, which may in turn modify BMI. This mechanism might be operative in normal subjects too. Interestingly, ghrelin concentrations were not systematically increased in patients who felt a sense of mild anorexia, but increased to a large extent only in the presence of moderate anorexia (Fig. 3).

In a recent study in subjects with liver disease, Tacke et al. (11) suggested a dependence of hyperghrelinemia on liver function on the basis of a progressive hormone increase from mild liver disease to advanced cirrhosis, but also pointed out a possible relationship with the anorexia-cachexia syndrome. In our series, limited to patients with cirrhosis, we were unable to confirm a role of liver function, although a possible type II error cannot be ruled out in smaller groups of patients. Ghrelin levels were moderately higher in Child-Pugh class C cases (+25%), but in a few patients, normal ghrelin concentrations were demonstrated also in the presence of severe hepatocellular failure. Also, the average ghrelin concentrations were no longer different from those of age-, sex-, and BMI-matched control subjects when patients with negative ratings of anorexia/hunger were excluded from analysis. Our study definitely favors a pathogenic role of anorexia and decreased food intake in hyperghrelinemia.

It might be argued that cirrhosis-related gastropathy might affect ghrelin concentrations. An association of atrophic gastritis with primary biliary cirrhosis was reported (30), but in cirrhosis of different etiology the gastric mucosa is not systematically altered (31, 32). Although mucosal biopsies were not routinely performed, at endoscopy no subjects had signs suggestive of chronic atrophic gastritis. Only one case of primary biliary cirrhosis was included in the present analysis, but ghrelin levels were normal (431 pmol/liter). The large majority of our patients (89%) had signs of portal hypertensive gastropathy, reflecting a selection bias favoring subjects with advanced disease (33), but high ghrelin levels were not systematically associated with portal hypertensive gastropathy.

In summary, the study points to a fine regulation of ghrelin levels by food intake and anorexia in patients with advanced liver disease. Ghrelin was proposed as a therapeutic option to stimulate appetite and food intake for the prevention and treatment of malnourished states (34). In cirrhosis-associated malnutrition, the resulting hyperghrelinemia might be insufficient when compared with the increase observed in normal subjects in response to starvation, as also observed in cancer cachexia (35). Wasting syndrome in prolonged critical illnesses, after severe trauma or acute life-threatening diseases, is characterized by negative protein balance and associated with reduced pulsatile GH secretion (36) and low circulating IGF-I concentrations (37). It has been shown that treatment with synthetic GH secretagogues (GH releasing peptide 2) is able to correct the low activity of the somatotropic axes (38, 39). Similarly, ghrelin administration in pharmacological amounts might be potentially useful to ameliorate these conditions as well as to overcome anorexia and protein wasting of patients with cirrhosis.

	Footnotes

 
This work was supported by a grant from the University of Bologna, Fondi Ricerca Istituzionale, 2002.

Abbreviations: BMI, Body mass index; OR, odds ratio.

Received October 9, 2003.

Accepted January 27, 2004.

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