The Future Concept Management Anorexia With Immunology Intervention

The Future Concept Management Anorexia By Immunology Intervention

Widodo Judarwanto. Picky Eaters & Grow Up Clinic, Jakarta Indonesia

Anorexia nervosa is a serious eating disorder characterized by extreme weight loss and abnormalities of the neuroendocrine and immune systems. To determine the potential role of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and transforming growth factor-beta (TGF-beta) in anorexia nervosa, serum concentrations of these cytokines were measured in patients with anorexia nervosa during starvation and after weight gain. Serum IL-6 and TGF-beta concentrations were both significantly elevated during starvation and returned to levels comparable to those of normal-weight controls by the end of therapy. In contrast, serum TNF-alpha levels were undetectable in all patients and controls. Cytokines may play previously unsuspected roles in anorexia nervosa and its complications.

Tumor necrosis factor-alpha (TNF-alpha) is a cytokine with numerous immunological and metabolic activities. To study the role of TNF-alpha on the pathophysiology of anorexia nervosa and its complications, plasma concentrations of TNF-alpha, 2 soluble TNF receptors (sTNF-RI and sTNF-RII), and leptin were measured in 20 female patients with anorexia nervosa (AN) and 20 age-matched normal women (N). Plasma TNF-alpha concentrations in AN were significantly higher than those in N. Although no significant difference was observed in plasma sTNF-RI concentrations between the two groups, plasma sTNF-RII concentrations in AN were significantly higher than those in N. Plasma concentrations of TNF-alpha and sTNF-RII after treatment of 8 anorectic patients were not different from those before treatment, although body fat mass and plasma leptin concentrations significantly increased after treatment. Plasma TNF-alpha concentrations were not related to body fat mass in anorectic patients. These results suggest that the adipose tissue may not be the immediate source of TNF-alpha in anorectic patients and that TNF-alpha may contribute to the pathophysiology of immunological and metabolic abnormalities in anorexia nervosa.

The new immunological model of anorexia and bulimia nervosa will be presented in which the inflammatory cytokines are conceived as the fundamental regulators of body metabolism. This conception differs from the conventional view in which the inflammatory cytokines are perceived primarily as peptide molecules utilized by the immune system to control infection, inflammation and tissue or neuronal damage. Given that the inflammatory cytokines are also fundamental regulators of body metabolism, when they become dysregulated they create physiological chaos which results in the development of a number of autoimmune, metabolic and psychiatric disorders. In this proposed immunological model of anorexia and bulimia nervosa, elevated tumor necrosis factor-alpha features as the primary cause of these conditions. Pathophysiological parallels are drawn between anorexia nervosa and cancer cachexia in terms of the causal role the cytokines, neuropeptides and neurotransmitters play in the manifestation of shared symptoms. These shared symptoms include elevated tumour necrosis factor-alpha, down-regulated interleukin-2 and interleukin-4 and depletion of lean body mass.

Immune changes may occur in patients with anorexia nervosa (AN) or bulimia nervosa (BN), and a role for proinflammatory cytokines has been proposed in the pathogenesis of both disorders. We measured plasma levels of interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha (TNF-alpha), soluble forms of the cytokine receptor proteins gp130 and leukemia inhibitory factor receptor (LIF-R), the anti-inflammatory Clara cell 16-kD protein (CC16), prolactin (PRL), cortisol and 17beta-estradiol in 21 anorexic women, 21 bulimic women and 21 healthy females. As compared to healthy subjects, anorexics exhibited significantly increased plasma levels of gp130 and LIF-R, whereas bulimics had significantly decreased blood concentrations of CC16. No significant differences emerged in the blood levels of the remaining immune parameters. Both patient groups manifested higher plasma levels of cortisol and reduced plasma concentrations of PRL and 17beta-estradiol. In anorexics, a significant negative correlation was found between plasma levels of gp130 or LIF-R and the body mass index. These findings do not support the hypothesis that proinflammatory cytokines may play a pathogenetic role in eating disorders.

Cytokines and anorexia nervosa.

Recent studies have indicated that the inflammatory cytokines could be implicated in anorexia nervosa and in its complications. To determinate the potential role of interleukins (IL-1, IL-2, IL-4, IL-6, IL-10), interferon (IFN gamma), tumor necrosis factor (TNF-alpha), and transforming growth factor (TGF-beta2) in anorexia nervosa, serum concentrations of these cytokines were measured in patients suffering from anorexia nervosa in comparison to healthy subjects. Twenty-nine anorexic women according to DSM-IV criteria participated in the study. The control group consisted of 20 healthy women without eating disorders, mood disorders, and immunological disorders.

Corcos et al reported that serum IL-2 and TGF-beta2 concentrations were both significantly decreased in anorexic patients, although the other cytokines did not differ significantly between the two groups.

These study results show that in patients with anorexia nervosa, there are lower levels of specific cytokines (especially IL-2 and TGF-beta2). These levels may reflect the combination of impaired nutrition and weight loss, therefore, the dysregulation of these cytokines may contribute in anorexia’s complications. Follow-up studies should examine the effects of parameters such as starvation, psychopathologic factors, and psychoneuroendocrinological perturbation which could affect interplay between cytokines, neuropeptides, and neurotransmitters.

Raymond NC previously reported elevated serum levels of the cytokines interleukin-6 (IL-6) and transforming growth factor-beta (TGF-beta) in patients with anorexia nervosa (AN). He investigated the cellular production of these two cytokines and of interferon-gamma (IFN-gamma), interleukin-1alpha (IL-1alpha), and tumor necrosis factor-alpha (TNF-alpha) in subjects with AN, bulimia nervosa (BN), and obesity as well as in normal-weight control subjects.

Supernatant fluids from isolated peripheral blood mononuclear cells (PBMC) incubated with and without concanavalin A (ConA) were assayed for cytokine concentrations by enzyme-linked immunosorbent assay (ELISA). Significant differences across the four groups were found in the stimulated cellular production of IFN-gamma and IL-6. Stimulated IFN-gamma production was elevated in the AN group compared to controls. IL-6 production was significantly elevated in obese subjects relative to the two normal-weight groups, BN and controls, and tended to be higher in the AN group than in the controls, but not significantly so. IL-1alpha production was greater in obese subjects.

The findings of increased IFN-gamma production and a tendency toward increased IL-6 production (both of which suppress food intake in animals) in individuals who severely restrict food intake suggest a potential role for these cytokines in the pathogenesis of AN. Elevated IL-6 and IL-1alpha production by PBMC in obese individuals requires further investigation to determine if these cytokines contribute to the development or perpetuation of obesity.

Cytokine mRNA expression patterns in the disease course of anorexia nervosa.

Anorexia nervosa (AN) is a serious eating disorder characterized by extreme weight loss and abnormalities of the neuroendocrine and immune systems. Cytokines have been discussed to be involved in the pathomechanisms underlying cachexia. Therefore some study aimed at examining the mRNA expression pattern of tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin-6 (IL-6) and interleukin-10 (IL-10) in whole blood of 11 female AN patients and 10 age and sex matched normal weight control subjects using a sensitive quantitative polymerase chain reaction (PCR) method.

Kahl KG, et al. Reported that found a significant increase in TNF-alpha and IL-6 mRNA expression in anorectic patients at admission when compared to controls. During follow-up, the expression of TNF-alpha mRNA remained significantly higher in formerly anorectic patients while IL-6 mRNA expression decreased. These study interpret the results as suggesting that TNF-alpha may contribute to metabolic abnormalities in anorexia nervosa even after goal BMI is achieved.

The following neuropeptides are dysregulated in both anorexia nervosa and cancer cachexia: vasoactive intestinal peptide, cholecystokinin, corticotropin-releasing factor, neuropeptide Y, peptide YY and beta-endorphin. In addition, in anorexia and bulimia nervosa, secretion of the neurotransmitter serotonin is inhibited while norepinephrine is enhanced. It will be argued that the causal interplay between the cytokines, neuropeptides and neurotransmitters initiates a cascade of biochemical events which may result in either anorexia or bulimia nervosa, or cancer cachexia. The extent to which these inflammatory cytokines, neuropeptides and neurotransmitters are causally efficacious in the pathogenesis of other autoimmune disorders, such as diabetes mellitus and rheumatoid arthritis, will also be addressed.

Interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) induce anorexia, and multiple behavioral and biochemical alterations that mimic those of anorexia nervosa. Reports in the literature, however, contain contrasting data on the pattern of secretion of the three cytokines and on the downstream activities of their receptors and receptor antagonists in anorexia nervosa. We measured plasma concentrations of IL-1beta, IL-6, TNF-alpha, soluble IL-6 receptor (sIL-6-R), soluble TNF-alpha receptors I and II (s-TNF-alpha-R-I and II), and soluble IL-1beta receptor antagonist (s-IL-1beta-R-A) in 14 female patients with anorexia nervosa (nine restricters, five binge/purgers) and in 13 age- and sex-matched healthy control subjects to see whether the circulating cytokine concentrations and the downstream steps of cytokine activity were impaired, and if these alterations were correlated with some aspects of the disease. Concentrations of IL-1beta, IL-6, TNF-alpha, s-TNF-alpha-R-I and -II and sIL-1beta-RA in plasma did not differ significantly in patients with anorexia nervosa compared with control subjects. Concentrations of sIL-6-R were significantly lower in the patients than in the control subjects, but there were no differences between the two sub-types of anorexia nervosa. The etiopathogenetic significance of the sIL-6-R alteration is not clear, but together with recent data in the literature on cytokine function, the finding suggests that an impairment of the pro-inflammatory cytokine pathway might be involved in the development of anorexia nervosa.

References:

  • Pomeroy C, et al. Role of interleukin-6 and transforming growth factor-beta in anorexia nervosa. Biol Psychiatry. 1994 Dec 15;36(12):836-9.
  • Bou Khalil R, et al. Treatment of anorexia nervosa with TNF-α down-regulating agents. Eat Weight Disord. 2011 Dec;16(4):e300.
  • Raymond NC, et al.Cytokine production in patients with anorexia nervosa, bulimia nervosa, and obesity. Int J Eat Disord. 2000 Nov;28(3):293-302.
  • Brambilla F, et al. Plasma concentrations of interleukin-1-beta, interleukin-6 and tumor necrosis factor-alpha, and of their soluble receptors and receptor antagonist in anorexia nervosa. Psychiatry Res. 2001 Sep 20;103(2-3):107-14.
  • Nakai Y, et al. Plasma concentrations of tumor necrosis factor-alpha (TNF-alpha) and soluble TNF receptors in patients with anorexia nervosa. J Clin Endocrinol Metab. 1999 Apr;84(4):1226-8.
  • Holden RJ, et al. The role of tumor necrosis factor-alpha in the pathogenesis of anorexia and bulimia nervosa, cancer cachexia and obesity. Med Hypotheses. 1996 Dec;47(6):423-38.
  • Holden RJ, et al.The role of tumor necrosis factor-alpha in the pathogenesis of anorexia and bulimia nervosa, cancer cachexia and obesity. Med Hypotheses. 1996 Dec;47(6):423-38.
  • Corcos M, et al. Cytokines and anorexia nervosa. Psychosom Med. 2001 May-Jun;63(3):502-4.
  • Kahl KG, et al. Cytokine mRNA expression patterns in the disease course of female adolescents with anorexia nervosa. Psychoneuroendocrinology. 2004 Jan;29(1):13-20.
  • Monteleone P, et al. Immunoendocrine findings in patients with eating disorders. Neuropsychobiology. 1999 Sep;40(3):115-20.

 

 

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