Anorexia nervosa is the most common life-threatening condition of all psychiatric disorders. Although physical signs of extracellular volume depletion and plasma volume concentration are often studied in anorexia nervosa, few studies have focused on adipocytokines and glucose balance.
Anorexia nervosa is associated with altered carbohydrate and lipid metabolism, multiple endocrine perturbations, and other dysfunctions (1). Although studies regarding insulin sensitivity in anorexia nervosa have had rather contradictory results, some have found increased insulin sensitivity (1,2), and others have postulated decreased or unchanged insulin sensitivity (3,4).
Many experimental and clinical studies have shown that the adipose tissue–derived hormone leptin is a key player in the regulation of food intake and energy balance. In addition to leptin, several other adipose tissue–derived hormones with suggested roles in the regulation of energy metabolism and insulin sensitivity have been discovered recently. Although most studies have focused on changes in endocrine function of adipocytes in obesity, adipose tissue also plays an important role in patients with malnutrition and decreased body fat content: serum leptin levels are severely suppressed in patients with both protein-energy malnutrition and anorexia nervosa (2).
We hypothesized that impaired ghrelin/leptin secretion in anorexia nervosa may be involved in the pathogenesis of this eating disorder. To examine this hypothesis and to further investigate the role of ghrelin in regulating energy homeostasis, we analyzed serial changes in circulating ghrelin and leptin in a patient with anorexia nervosa and examined a possible correlation of these hormones with nutritional status before and after weight gain.
Plasma levels of leptin and ghrelin were measured by a commercial kit, the Human Leptin Assay Kit-IBL (IBL, Gunma, Japan) and the Desacyl-Ghrelin Enzyme-Linked ImmunoSorbent Assay Kit (Mitsubishi Kagaku Iatron, Tokyo, Japan), respectively. Plasma insulin was also measured by a commercial kit, the Cobas System (Roche Diagnostics, Tokyo, Japan). Peripheral insulin resistance was determined by homeostasis model assessment (HOMA-R) according to this formula: fasting plasma insulin (microinternational units per milliliter) × fasting plasma glucose (milligrams/deciliter)/405.
The patient was a 12-year-old girl who had received a diagnosis of restricting anorexia nervosa of 6 months duration. Her body weight, height, and body mass index were 29 kg, 155 cm, and 12.0 kg/m2, respectively. She was admitted to our hospital because of emaciation. On physical examination, her temperature was 36.5°C. Decreased skin turgor, dryness of the oral mucosa membranes, and hypotension (90/48 mmHg) were evident on admission. Her heart rate was 113 beats/minute, and her respiratory rate was 24/minute. She showed confusion and sunken eyes. Her consciousness level was stupor (Japan Coma Scale 30-R). She had urinary incontinence.
The pertinent laboratory findings were as follows: serum sodium 136 mEq/L, potassium 4.0 mEq/L, chloride 91 mEq/L, red blood cells 531 × 104/μL, hemoglobin 15.4 g/dL, hematocrit 46%, white blood cells 4700/μL, platelets 18.6 × 104/μL, C-reactive protein 0.68 mg/dL, total protein 8.1 g/dL, albumin 5.9 g/dL, aspartate aminotransferase 28 U/L, alanine aminotransferase 37 U/L, glucose 79 mg/dL.
From these findings, the diagnosis of moderate dehydration and malnutrition due to anorexia nervosa was made. Fluid and electrolyte replacement therapy in the acute phase, followed by both nutritional and mental support, resulted in clinical improvement. She could make conversation on the 20th day of admission (Fig. 1). During hospitalization she gained 5.0 kg (body mass index = 14.1 kg/m2 at discharge).
We measured fasting plasma levels of ghrelin, leptin, and insulin with glucose and observed a mirror image correlation between plasma leptin and ghrelin level:plasma leptin level was negatively related to plasma ghrelin level. In addition, these levels surged without cyclic secretion during the observational period. HOMA-R was increased at admission, indicating insulin resistance before treatment, although it decreased after treatment (Fig. 1).
Our patient with anorexia nervosa demonstrated an evident negative correlation of the plasma levels between leptin and ghrelin, as shown in Figure 1. Although leptin is considered to be a key player in the regulation of food intake and energy balance, ghrelin, another adipose tissue–derived hormone, plays some roles in the regulation of energy metabolism and insulin sensitivity. In fact, plasma levels of ghrelin showed a negative correlation with body mass index and were significantly higher in bulimia nervosa patients than in control individuals (5). Thus, ghrelin antagonizes leptin action, which suggests the existence of negative feedback systems, and may regulate feeding behavior and energy metabolism in the central nervous system (6).
Our patient also showed insulin resistance on admission, followed by improvement after nutritional rehabilitation. Insulin secretion in response to blood glucose level is closely affiliated with body weight and eating behavior and may change during nutritional rehabilitation. Inasmuch as anorexia nervosa is associated with many endocrinological and metabolic disturbances, increased insulin resistance in malnourished and hyperactive patients with anorexia nervosa may have multiple causes.
It is well known that plasma leptin correlates inversely with plasma ghrelin. We first reported a mirror image of leptin and ghrelin, which were surged, in a patient with anorexia nervosa. It is speculated that the alteration in both nutritional status and eating pattern may induce aberrant secretions of ghrelin and leptin, characterized by a surged pattern and resulting in increasing insulin resistance and forming a vicious circle in the progression of anorexia nervosa. A limitation of this report is that it is a case report, and therefore the observations need future investigation.
From our findings and previous reports, we conclude that the dysregulation in controlling the secretions of ghrelin and leptin may be related to the pathophysiology of anorexia nervosa.
The authors thank Drs A. Araki, S. Taniuchi, and J. Suzukawa for fruitful discussions.
1. Delporte ML, Brichard SM, Hermans MP, et al
. Hyperadiponectinaemia in anorexia nervosa. Clin Endocrinol 2003; 58:22–29.
2. Misra M, Miller KK, Almazan C, et al
. Hormonal and body composition predictors of soluble leptin receptor, leptin and free leptin index in adolescent girls with anorexia nervosa and controls and relation to insulin sensitivity. J Clin Endocrinol Metab 2004; 89:3486–3495.
3. Castillo M, Scheen A, Lefebre PJ, et al
. Insulin-stimulated glucose disposal is not increased in anorexia nervosa. J Clin Endocrinol Metab 1985; 60:311–314.
4. Pannacciulli N, Vettor R, Milan G, et al
. Anorexia nervosa is characterized by increased adiponectin plasma levels and reduced nonoxidative glucose metabolism. J Clin Endocrinol Metab 2003; 88:1748–1752.
5. Tanaka M, Naruo T, Muranaga T, et al
. Increased fasting plasma ghrelin levels in patients with bulimia nervosa. Eur J Endocrinol 2002; 146:R1–R3.
6. Nakazato M, Murakami N, Date Y, et al
. A role for ghrelin in the central regulation of feeding. Nature 2001; 409:194–198.