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ORIGINAL ARTICLES |
From the Departments of Neurologic and Psychiatric Sciences (A.F., P.S.), Clinical Medicine (L.C.), and Pediatrics (A.B.), University of Padua, Padua, Italy.
Address reprint requests to: Prof. Paolo Santonastaso, Clinica Psichiatrica, Dip. Scienze Neurologiche e Psichiatriche, Via Giustiniani, 3 35128 Padova, Italy. Email: santopla{at}ux1.unipd.it
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ABSTRACT |
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METHODS: The total amount of tryptophan and the ratio between tryptophan and other large neutral amino acids (TRP/LNAA) were assessed in a sample of 16 starving anorexic patients. Body weight and composition and energy intake were evaluated in all patients. All subjects also completed self-reported questionnaires such as the Hopkins Symptom Checklist and Eating Disorders Inventory (EDI).
RESULTS: The TRP/LNAA ratio seems to be higher in patients with a more severe catabolic status. It is, in fact, significantly inversely correlated with body mass index, body fat, muscle mass, daily energy intake, and daily tryptophan intake. The TRP/LNAA ratio also correlates with growth hormone and the EDI drive for thinness. Patients who exercise excessively had significantly higher TRP/LNAA ratios.
CONCLUSIONS: In starving anorexic patients, the TRP/LNAA ratio does not seem to be determined by the content of tryptophan in the diet, but it correlates with measures of catabolism. The relationship of the TRP/LNAA ratio to excessive exercise and starvation indicates the importance of further investigations exploring the role of tryptophan availability in maintaining anorexia nervosa.
Key Words: anorexia nervosa • tryptophan • serotonin • hyperactivity • starvation
Abbreviations: AN = anorexia nervosa; BMI = body mass index; DSM-IV= Diagnostic and Statistical Manual of Mental Disorders,fourth edition; EDI = Eating Disorders Inventory; GH = growthhormone; HSCL = Hopkins Symptom Checklist; LNAA = largeneutral amino acids; MAC = mid-upper arm circumference; MAMC= midarm muscle circumference; TRP = tryptophan; TSF =triceps skinfold; 5-HT = 5-hydroxytryptamine.
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INTRODUCTION |
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The effects of intense physical activity on plasma TRP and on serotonin synthesis are less well known. In normal-weight subjects and athletes, the TRP/LNAA ratio seems to increase during prolonged exercise because of the increase in the oxidation rates of skeletal muscle LNAA (9). The ratio tends to normalize after exercise, but the absence of a preexercise meal seems to be associated with an additional increase of the TRP/LNAA ratio during recovery from exercise (9). No study to date has evaluated the effects of exercise on plasma amino acids in subjects with AN. The literature reports that a high percentage of AN subjects exercise extensively during the acute phase of the disorder (10). Animal models show that strenuous exercise increases 5-HT synthesis and turnover and that this increase is greater in a semistarved condition (11). Food restriction may cause an increase in physical activity that is perhaps mediated by endogenous opioid peptides (12). An increase in 5-HT levels due to overexercise will further suppress appetite, creating a weight-loss cycle that may cause or maintain AN.
The study reported here examined the relationship between the TRP/LNAA ratio and nutritional status, energy intake, and excessive exercise in starving anorexic patients.
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METHODS |
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All patients gave informed consent. They were evaluated by means of a semistructured interview and self-reported questionnaires: the EDI (13) and HSCL (14). All subscales of the EDI and the somatization, obsessive-compulsive, depression, anxiety, and hostility subscales of the HSCL were investigated. Diagnosis of eating disorder and current axis I psychiatric disorders were evaluated by means of the Structured Clinical Interview for DSM-IV (15). Only one patient reported a history of previous psychiatric treatment. She also reported previous use of antidepressants. Excessive exercise was defined as at least 1 hour of intensive physical activity per day.
A blood sample was taken between 8:30 and 9:30 AM after an overnight fast. Total TRP and LNAA levels were assayed, and the ratio of TRP concentrations to LNAA concentrations was calculated. TRP and LNAA concentrations were determined by ion exchange chromatography (16) (Beckmann 6300 amino acid analyzer, Palo Alto, CA). Serum GH was determined by radioimmunoassay. Anthropometric and biochemical parameters were evaluated on the same day. Anthropometric evaluation included measurements of body weight and height and skinfold anthropometry. Skinfold measurements were made at four sites: the triceps, biceps, and subscapular and suprailiac areas, as described by Durnin and Womersley (17). All measurements were made on the nondominant side of the body by the same experienced observer using a Holtain caliper (Holtain Ltd, Crymych, UK). Measurements were taken to the nearest 3.0 mm, and a mean result was calculated from three or four readings. Percentage of body fat was calculated using the method of Durnin and Womersley (17). MAMC, an index of muscle mass, was calculated with use of the following formula: MAMC (cm) = MAC (cm) - 0.314 x TSF (mm). MAC was measured with a tape at the same site of the TSF measurement. Observed MAMC values were normalized to the percentage of the 50th percentile, which was derived from the same tables (MAMC%).
Energy and nutrient intake were calculated from one or three consecutive 24-hour dietary recalls by means of a computer-assisted interview. A program provided with food pictures was used to estimate portion sizes and for calculations (Winfood 1.5, Medimatica srl, Martinsicuro, Italy). Because all patients with binge eating/purging–type AN vomited after binging, their energy intake was calculated using information from 3 separate days when they neither binged nor purged (the frequency of this behavior ranged from two to five times per week). A 3-day food record was also obtained in patients whose diet was not "typical" the day before the interview. Daily intake was calculated as the mean of the three records.
Because of the small size of our sample, we used nonparametric statistical tests, such as the Mann-Whitney U test and Spearman’s rank-order correlation coefficient.
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RESULTS |
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Five patients reported excessive exercise (ie, at least 1 h/d). These patients had significantly higher TRP/LNAA ratios than patients who did not exercise (0.11 ± 0.02 vs. 0.085 ± 0.01, U = 8.00, z = 2.22, p < .03). In a partial correlation analysis in which the effect of BMI was removed, correlations between TRP/LNAA ratio and excessive exercise (r = 0.60, p < .02) and energy intake (r = -0.60, p < .02) were still significant.
No correlation was found between TRP/LNAA ratios and the HSCL and EDI subscales (Table 2) except for a positive correlation with the EDI drive for thinness subscale (r = 0.60, p < .03).
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DISCUSSION |
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It might seem contradictory to find that a low BMI is associated with a high TRP/LNAA ratio considering that previous studies (6) linked dieting with lower TRP/LNAA ratios. Thus, we expected to find increasingly lower TRP/LNAA ratios with greater dietary restraint. But our patients are not of normal weight, and a catabolic process is under way. In the presence of low body fat (and therefore probably depleted glycogen and fat stores) and insufficient energy intake, energy may be provided by release of amino acids from skeletal muscle. This release may be enhanced in anorectic patients who exercise intensively because physical activity further increases energy requirements. In addition, in our sample the TRP/LNAA ratio seemed to be correlated with the depletion of muscle mass and with GH, which is considered an index of hypercatabolism (19).
Patients with remitted major depression (20) and bulimic patients (21, 22) seem to be sensitive to reduced levels of TRP in the diet. In these patients, an increase in irritability, level of depression, and, among bulimics, binge eating have been observed. Studies of this type are not available for patients with AN, but our findings suggest that in AN patients, because of undernutrition, low levels of TRP intake might be counteracted by physical activity and by lowering energy intake. The inverse relationship between TRP/LNAA and TRP content in the diet seems to confirm this hypothesis. From this viewpoint, excessive exercise and starvation may be considered a form of "self-medication" to counteract the decrease of TRP/LNAA and serotonin synthesis. The relative increase of serotonin synthesis due to higher TRP/LNAA levels might increase compulsive behaviors, such as physical activity, and the obsession with thinness, as measured by the EDI drive for thinness subscale. These findings suggest a possible role of the TRP/LNAA ratio in the maintenance of AN and might help to explain the difficulty of and resistance to nutritional rehabilitation in patients with AN. Clearly, this hypothesis should be verified in longitudinal studies that assess the variations of TRP/LNAA during refeeding. In fact, amino acid levels seem to change after refeeding (23).
Although no patients with major depressive disorders were included in our sample, we found high levels of depressive symptoms as measured by HSCL. This is common in AN (24) and could be due, at least partially, to reduced serotonin activity, which is often observed in underweight anorexic patients (1, 2). However, no correlation was found between TRP/LNAA and the severity of depressive symptoms (Table 2). Our findings seem to show that low TRP availability cannot be considered the only cause of decreased serotonin activity in patients with AN. Other factors, such as the effect of reduced gonadal steroids on 5-HT activity (25), should be considered in future studies. Such factors may explain why relationships between TRP/LNAA and impulsivity, depression, or diagnostic subgroups were not found in previous studies (7). We found no correlation between TRP/LNAA and levels of depression, anxiety, or hostility as measured by the HSCL (Table 2).
Because AN is characterized by various disturbances of endocrine and neuroendocrine function (26), it would be interesting to understand the influences of various hormones on the TRP/LNAA ratio. The effects of insulin are well known: It stimulates uptake of LNAA by skeletal muscle, leading to an increase in TRP/LNAA. The increased levels of corticotropin-releasing hormone found in AN (26) are probably another significant factor. In fact, cortisol may be involved in the activation of skeletal muscle catabolism.
In conclusion, our aim was to study the relationship between TRP/LNAA and nutritional status in AN. Our findings are limited by the small sample size and by the absence of a control group, but they seem to indicate that nutritional status, excessive exercise, and food restriction affect this ratio. The finding of a higher TRP/LNAA ratio in patients with a more severe catabolic status leads us to hypothesize that TRP/LNAA has a role in maintaining the illness and increasing AN patients’ resistance to change. Our findings highlight the need for further research in this field and the importance of integrating nutritional and psychobiological knowledge.
The authors wish to thank Profs. Francesca Brambilla and Walter H. Kaye for their useful advice.
Received for publication August 10, 1999.
Revision received February 4, 2000.
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This article has been cited by other articles:
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  B. J. Cook and H. A. Hausenblas The Role of Exercise Dependence for the Relationship between Exercise Behavior and Eating Pathology: Mediator or Moderator? J Health Psychol, May 1, 2008; 13(4): 495 - 502. [Abstract] [PDF]
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 A. Favaro, L. Caregaro, L. Di Pascoli, F. Brambilla, and P. Santonastaso Total Serum Cholesterol and Suicidality in Anorexia Nervosa Psychosom Med, July 1, 2004; 66(4): 548 - 552. [Abstract] [Full Text] [PDF]
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