Journal of Neural Transmission

, Volume 118, Issue 4, pp 571–578 | Cite as

Screening for anorexia nervosa via measurement of serum leptin levels

  • M. Föcker
  • N. Timmesfeld
  • S. Scherag
  • K. Bühren
  • M. Langkamp
  • A. Dempfle
  • E. M. Sheridan
  • M. de Zwaan
  • C. Fleischhaker
  • W. Herzog
  • K. Egberts
  • S. Zipfel
  • B. Herpertz-Dahlmann
  • J. Hebebrand
Biological Child and Adolescent Psychiatry - Original Article

Abstract

Due to their sub-normally low fat mass, leptin levels in patients with acute anorexia nervosa (AN) are well below reference levels for age and sex-matched controls. This hypoleptinemia entails endocrinological and behavioral characteristics observed in AN patients during starvation. We aimed to study the appropriateness of hypoleptinemia as a diagnostic marker for AN by assessing sensitivity, specificity and likelihood ratios for different referral serum leptin levels for predicting anorexia nervosa and healthy leanness. For prediction, we additionally generated a score based on a multivariate logistic model including body mass index (BMI; kg/m²) and leptin level. For this purpose, we measured leptin levels in 74 female patients with acute AN upon admission for inpatient or outpatient treatment. Adolescent and adult patients were recruited according to DSM-IV criteria from two multi-center studies. Additionally, leptin levels were measured in 65 female healthy, lean students. Mean serum leptin level was significantly decreased in patients with AN compared to underweight controls (0.87 ± 0.90 vs. 6.43 ± 3.55 μg/L, p < 0.001). Leptin predicted AN independently of BMI; we confirmed a cutoff value in the range of 2 μg/L as having both high specificity and sensitivity. Hypoleptinemia represents a state marker of acute AN and is useful for a laboratory-based diagnostic screening.

Keywords

Anorexia nervosa Hypoleptinemia Leptin threshold Screening State marker 

References

  1. American Psychiatric Association (APA) (1994) Diagnostic and statistical manual of mental disorders, 4th edn. American Psychiatric Association, Washington text revisionGoogle Scholar
  2. Blum WF, Englaro P, Hanitsch S, Juul A, Hertel NT, Muller J, Skakkebaek NE, Heiman ML, Birkett M, Attanasio AM, Kiess W, Rascher W (1997) Plasma leptin levels in healthy children and adolescents: dependence on body mass index, body fat mass, gender, pubertal stage, and testosterone. J Clin Endocrinol Metab 82(9):2904–2910PubMedCrossRefGoogle Scholar
  3. Buyukberber M, Koruk M, Savas MC, Gulsen MT, Pehlivan Y, Deveci R, Sevinc A, Gergerlioglu S (2007) Leptin levels in the differential diagnosis between benign and malignant ascites. World J Gastroenterol 13(3):398–402PubMedGoogle Scholar
  4. Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, Ohannesian JP, Marco CC, McKee LJ, Bauer TL et al (1996) Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 334(5):292–295PubMedCrossRefGoogle Scholar
  5. Estour B, Germain N, Diconne E, Frere D, Cottet-Emard JM, Carrot G, Lang F, Galusca B (2010) Hormonal profile heterogeneity and short-term physical risk in restrictive anorexia nervosa. J Clin Endocrinol Metab 95(5):2203–2210PubMedCrossRefGoogle Scholar
  6. Fichter M, Quadflieg N (2001) The structured interview for anorexic and bulimic disorders for DSM-IV and ICD-10 (SIAB-EX): reliability and validity. Eur Psychiatry 16(1):38–48PubMedCrossRefGoogle Scholar
  7. Fichter MM, Herpertz S, Quadflieg N, Herpertz-Dahlmann B (1998) Structured interview for anorexic and bulimic disorders for DSM-IV and ICD-10: updated (third) revision. Int J Eat Disord 24(3):227–249PubMedCrossRefGoogle Scholar
  8. Fichter MM, Quadflieg N, Georgopoulou E, Xepapadakos F, Fthenakis EW (2005) Time trends in eating disturbances in young Greek migrants. Int J Eat Disord 38(4):310–322PubMedCrossRefGoogle Scholar
  9. Greenhalgh T (1997) How to read a paper. Papers that report diagnostic or screening tests. BMJ 315(7107):540–543PubMedGoogle Scholar
  10. Grinspoon S, Gulick T, Askari H, Landt M, Lee K, Anderson E, Ma Z, Vignati L, Bowsher R, Herzog D, Klibanski A (1996) Serum leptin levels in women with anorexia nervosa. J Clin Endocrinol Metab 81(11):3861–3863PubMedCrossRefGoogle Scholar
  11. Haas V, Onur S, Paul T, Nutzinger DO, Bosy-Westphal A, Hauer M, Brabant G, Klein H, Muller MJ (2005) Leptin and body weight regulation in patients with anorexia nervosa before and during weight recovery. Am J Clin Nutr 81(4):889–896PubMedGoogle Scholar
  12. Haluzik M, Papezova M, Nedvidkova J, Kabrt J (1999) Serum leptin levels in patients with anorexia nervosa before and after partial refeeding, relationships to serum lipids and biochemical nutritional parameters. Physiol Res 48(3):197–202PubMedGoogle Scholar
  13. Hebebrand J, Bulik C (2010) Critical appraisal of the provisional DSM-5 criteria for anorexia nervosa and an alternative proposal. Int J Eat Disord [Epub ahead of print]Google Scholar
  14. Hebebrand J, van der Heyden J, Devos R, Kopp W, Herpertz S, Remschmidt H, Herzog W (1995) Plasma concentrations of obese protein in anorexia nervosa. Lancet 346(8990):1624–1625PubMedCrossRefGoogle Scholar
  15. Hebebrand J, Blum WF, Barth N, Coners H, Englaro P, Juul A, Ziegler A, Warnke A, Rascher W, Remschmidt H (1997) Leptin levels in patients with anorexia nervosa are reduced in the acute stage and elevated upon short-term weight restoration. Mol Psychiatry 2(4):330–334PubMedCrossRefGoogle Scholar
  16. Hebebrand J, Exner C, Hebebrand K, Holtkamp C, Casper RC, Remschmidt H, Herpertz-Dahlmann B, Klingenspor M (2003) Hyperactivity in patients with anorexia nervosa and in semistarved rats: evidence for a pivotal role of hypoleptinemia. Physiol Behav 79(1):25–37PubMedCrossRefGoogle Scholar
  17. Hinney A, Lentes KU, Rosenkranz K, Barth N, Roth H, Ziegler A, Hennighausen K, Coners H, Wurmser H, Jacob K, Romer G, Winnikes U, Mayer H, Herzog W, Lehmkuhl G, Poustka F, Schmidt MH, Blum WF, Pirke KM, Schafer H, Grzeschik KH, Remschmidt H, Hebebrand J (1997) Beta 3-adrenergic-receptor allele distributions in children, adolescents and young adults with obesity, underweight or anorexia nervosa. Int J Obes Relat Metab Disord 21(3):224–230PubMedCrossRefGoogle Scholar
  18. Hoek HW (2006) Incidence, prevalence and mortality of anorexia nervosa and other eating disorders. Curr Opin Psychiatry 19(4):389–394PubMedCrossRefGoogle Scholar
  19. Holtkamp K, Hebebrand J, Mika C, Grzella I, Heer M, Heussen N, Herpertz-Dahlmann B (2003a) The effect of therapeutically induced weight gain on plasma leptin levels in patients with anorexia nervosa. J Psychiatr Res 37(2):165–169PubMedCrossRefGoogle Scholar
  20. Holtkamp K, Mika C, Grzella I, Heer M, Pak H, Hebebrand J, Herpertz-Dahlmann B (2003b) Reproductive function during weight gain in anorexia nervosa. Leptin represents a metabolic gate to gonadotropin secretion. J Neural Transm 110(4):427–435PubMedCrossRefGoogle Scholar
  21. Köpp W, Blum WF, von Prittwitz S, Ziegler A, Lubbert H, Emons G, Herzog W, Herpertz S, Deter HC, Remschmidt H, Hebebrand J (1997) Low leptin levels predict amenorrhea in underweight and eating disordered females. Mol Psychiatry 2(4):335–340PubMedCrossRefGoogle Scholar
  22. Laxman B, Morris DS, Yu J, Siddiqui J, Cao J, Mehra R, Lonigro RJ, Tsodikov A, Wei JT, Tomlins SA, Chinnaiyan AM (2008) A first-generation multiplex biomarker analysis of urine for the early detection of prostate cancer. Cancer Res 68(3):645–649PubMedCrossRefGoogle Scholar
  23. Machado PP, Machado BC, Goncalves S, Hoek HW (2007) The prevalence of eating disorders not otherwise specified. Int J Eat Disord 40(3):212–217PubMedCrossRefGoogle Scholar
  24. Mantzoros C, Flier JS, Lesem MD, Brewerton TD, Jimerson DC (1997) Cerebrospinal fluid leptin in anorexia nervosa: correlation with nutritional status and potential role in resistance to weight gain. J Clin Endocrinol Metab 82(6):1845–1851PubMedCrossRefGoogle Scholar
  25. Matejek N, Weimann E, Witzel C, Molenkamp G, Schwidergall S, Bohles H (1999) Hypoleptinaemia in patients with anorexia nervosa and in elite gymnasts with anorexia athletica. Int J Sports Med 20(7):451–456PubMedCrossRefGoogle Scholar
  26. Misra M, Miller KK, Almazan C, Ramaswamy K, Aggarwal A, Herzog DB, Neubauer G, Breu J, Klibanski A (2004) 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 89(7):3486–3495PubMedCrossRefGoogle Scholar
  27. Mistry K, Cable G (2003) Meta-analysis of prostate-specific antigen and digital rectal examination as screening tests for prostate carcinoma. J Am Board Fam Pract 16(2):95–101PubMedCrossRefGoogle Scholar
  28. Monteleone P, Martiadis V, Colurcio B, Maj M (2002) Leptin secretion is related to chronicity and severity of the illness in bulimia nervosa. Psychosom Med 64(6):874–879PubMedCrossRefGoogle Scholar
  29. Müller TD, Föcker M, Holtkamp K, Herpertz-Dahlmann B, Hebebrand J (2009) Leptin-mediated neuroendocrine alterations in anorexia nervosa: somatic and behavioral implications. Child Adolesc Psychiatr Clin N Am 18(1):117–129PubMedCrossRefGoogle Scholar
  30. Nakai Y, Hamagaki S, Takagi R, Taniguchi A, Kurimoto F (1999) Plasma concentrations of tumor necrosis factor-alpha (TNF-alpha) and soluble TNF receptors in patients with anorexia nervosa. J Clin Endocrinol Metab 84(4):1226–1228PubMedCrossRefGoogle Scholar
  31. R Development Core Team (2009) R: a language and environment for statistical computing. Computing, Vienna, Austria. ISBN 3-900051-07-0. http://www.R-project.org
  32. Rastam M, Gillberg C, Garton M (1989) Anorexia nervosa in a Swedish urban region. A population-based study. Br J Psychiatry 155:642–646PubMedGoogle Scholar
  33. Robins LN, Wing J, Wittchen HU, Helzer JE, Babor TF, Burke J, Farmer A, Jablenski A, Pickens R, Regier DA et al (1988) The composite international diagnostic interview, an epidemiologic instrument suitable for use in conjunction with different diagnostic systems and in different cultures. Arch Gen Psychiatry 45(12):1069–1077PubMedGoogle Scholar
  34. Rosenbaum M, Goldsmith R, Bloomfield D, Magnano A, Weimer L, Heymsfield S, Gallagher D, Mayer L, Murphy E, Leibel RL (2005) Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight. J Clin Invest 115(12):3579–3586PubMedCrossRefGoogle Scholar
  35. Smiechowska J, Utech A, Taffet G, Hayes T, Marcelli M, Garcia JM (2010) Adipokines in patients with cancer anorexia and cachexia. J Investig Med 58(3):554–559PubMedGoogle Scholar
  36. Stoving RK, Vinten J, Handberg A, Ebbesen EN, Hangaard J, Hansen-Nord M, Kristiansen J, Hagen C (1998) Diurnal variation of the serum leptin concentration in patients with anorexia nervosa. Clin Endocrinol (Oxf) 48(6):761–768CrossRefGoogle Scholar
  37. Takahashi M, Terashima M, Takagane A, Oyama K, Fujiwara H, Wakabayashi G (2009) Ghrelin and leptin levels in cachectic patients with cancer of the digestive organs. Int J Clin Oncol 14(4):315–320PubMedCrossRefGoogle Scholar
  38. Thornton C, Russell J, Hudson J (1998) Does the Composite International Diagnostic Interview underdiagnose the eating disorders? Int J Eat Disord 23(3):341–345PubMedCrossRefGoogle Scholar
  39. Tolle V, Kadem M, Bluet-Pajot MT, Frere D, Foulon C, Bossu C, Dardennes R, Mounier C, Zizzari P, Lang F, Epelbaum J, Estour B (2003) Balance in ghrelin and leptin plasma levels in anorexia nervosa patients and constitutionally thin women. J Clin Endocrinol Metab 88(1):109–116PubMedCrossRefGoogle Scholar
  40. Vaisman N, Hahn T, Karov Y, Sigler E, Barak Y, Barak V (2004) Changes in cytokine production and impaired hematopoiesis in patients with anorexia nervosa: the effect of refeeding. Cytokine 26(6):255–261PubMedCrossRefGoogle Scholar
  41. von Prittwitz S, Blum WF, Ziegler A, Scharmann S, Remschmidt H, Hebebrand J (1997) Restrained eating is associated with low leptin levels in underweight females. Mol Psychiatry 2(5):420–422CrossRefGoogle Scholar
  42. Wabitsch M, Ballauff A, Holl R, Blum WF, Heinze E, Remschmidt H, Hebebrand J (2001) Serum leptin, gonadotropin, and testosterone concentrations in male patients with anorexia nervosa during weight gain. J Clin Endocrinol Metab 86(7):2982–2988PubMedCrossRefGoogle Scholar
  43. Welt CK, Chan JL, Bullen J, Murphy R, Smith P, DePaoli AM, Karalis A, Mantzoros CS (2004) Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med 351(10):987–997PubMedCrossRefGoogle Scholar
  44. Wild B, Friederich HC, Gross G, Teufel M, Herzog W, Giel KE, de Zwaan M, Schauenburg H, Schade-Brittinger C, Schafer H, Zipfel S (2009) The ANTOP study: focal psychodynamic psychotherapy, cognitive-behavioural therapy, and treatment-as-usual in outpatients with anorexia nervosa—a randomized controlled trial. Trials 10:23PubMedCrossRefGoogle Scholar
  45. Wilson J, Jungner G (1968) Principles and practice of screening for disease. World Health Organisation, Geneva. http://whqlibdoc.who.int/php/WHO_PHP_34.pdf
  46. Wittchen HU (1994) Reliability and validity studies of the WHO—Composite International Diagnostic Interview (CIDI): a critical review. J Psychiatr Res 28(1):57–84PubMedCrossRefGoogle Scholar
  47. Wittchen HU, Nelson CB, Lachner G (1998) Prevalence of mental disorders and psychosocial impairments in adolescents and young adults. Psychol Med 28(1):109–126PubMedCrossRefGoogle Scholar
  48. Wolter H, Schneider N, Pfeiffer E, Lehmkuhl U (2009) Diagnostic crossover from obesity to atypical anorexia nervosa—a case report. Obes Facts 2(1):52–53PubMedCrossRefGoogle Scholar
  49. World Health Organization (WHO) (1990) Composite international diagnostic interview (CIDI). World Health Organization, GenevaGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • M. Föcker
    • 1
  • N. Timmesfeld
    • 2
  • S. Scherag
    • 1
  • K. Bühren
    • 3
  • M. Langkamp
    • 4
  • A. Dempfle
    • 2
  • E. M. Sheridan
    • 5
  • M. de Zwaan
    • 6
  • C. Fleischhaker
    • 7
  • W. Herzog
    • 8
  • K. Egberts
    • 9
  • S. Zipfel
    • 10
  • B. Herpertz-Dahlmann
    • 3
  • J. Hebebrand
    • 1
  1. 1.Department of Child and Adolescent Psychiatry and PsychotherapyUniversity of Duisburg-EssenEssenGermany
  2. 2.Institute of Medical Biometry and EpidemiologyPhilipps-UniversityMarburgGermany
  3. 3.Department of Child and Adolescent Psychiatry and PsychotherapyRWTH Aachen UniversityAachenGermany
  4. 4.MediagnostReutlingenGermany
  5. 5.The Zucker Hillside Hospital, Psychiatry ResearchGlen OaksUSA
  6. 6.Department of Psychosomatic Medicine and PsychotherapyUniversity Hospital of ErlangenErlangenGermany
  7. 7.Department of Child and Adolescent Psychiatry and PsychotherapyUniversity of FreiburgFreiburgGermany
  8. 8.Department of Psychosomatic and General Internal Medicine, Centre for Psychosocial MedicineUniversity Hospital HeidelbergHeidelbergGermany
  9. 9.Department of Child and Adolescent Psychiatry and PsychotherapyUniversity of WürzburgWürzburgGermany
  10. 10.Department of Psychosomatic Medicine and PsychotherapyMedical University Hospital Tübingen, University TübingenTübingenGermany

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