Edited by: Jacques Epelbaum, Université Paris Descartes, France
Reviewed by: Bruno Bonaz, Centre Hospitalier Universitaire de Grenoble, France; Per Sodersten, Karolinska Institutet, Sweden
†Bruno Estour, Bogdan Galusca and Natacha Germain have contributed equally to this work.
This article was submitted to Neuroendocrine Science, a section of the journal Frontiers in Endocrinology.
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Clinical and biological aspects of restrictive anorexia nervosa (R-AN) are well documented. More than 10,000 articles since 1911 and more than 600 in 2013 have addressed R-AN psychiatric, somatic, and biological aspects. Genetic background, ineffectiveness of appetite regulating hormones on refeeding process, bone loss, and place of amenorrhea in the definition are widely discussed and reviewed. Oppositely, constitutional thinness (CT) is an almost unknown entity. Only 32 articles have been published on this topic since 1953. Similar symptoms associating low body mass index, low fat, and bone mass are reported in both CT and R-AN subjects. Conversely, menses are preserved in CT women and almost the entire hormonal profile is normal, except for leptin and PYY. The aim of the present review is to alert the clinician on the confusing clinical presentation of these two situations, a potential source of misdiagnosis, especially since R-AN definition has changed in DSM5.
In a young population of women, between 15 and 30 years old, a low body mass index (BMI) associated with apparent healthy state suggests that the diagnosis of anorexia nervosa (AN). For the same age range, other etiologies of starvation are associated with specific symptoms leading to obvious diagnosis of blood or oncologic pathologies, digestive absorption disorders.
Although restrictive anorexia nervosa (R-AN) definition reported in the “diagnostic and statistical manual of mental disorders” (DSM) is in perpetual evolution, diagnosis remains easy for an experienced clinician. The last issue, DSM5, was published in 2013 (
In a similar population of women, a low BMI associated with apparent healthy state could also suggests that the diagnosis of a not yet well-known entity called constitutional thinness (CT). This natural and physiological low BMI (<18.5 kg/m2) state is associated with preserved menses (without contraceptive treatment) and reproductive function leading to constitutional thin families. CT prevalence is unknown in the developed world. These subjects want to gain weight and often consult in this perspective. We recently showed that they failed to gain weight in a controlled overfeeding study (
Thinness is defined by the World Health Organization which specified three levels of underweight for BMI <18.5 kg/m2 (
This review summarizes the main features opposing R-AN and CT including nutritional markers, bone loss physiology, appetite regulating hormones, and how the DSM5 definition can lead to misdiagnoses between those two etiologies of thinness. The results published by our group come from a large cohort of more than 600 R-AN and 100 CT.
Hormonal abnormalities data about R-AN reported so far in literature are commonly accepted and have been showed and published many times by different teams. Most of them are undernutrition markers such as low free-T3 (
Anorexia nervosa is associated with well-known hypothalamus–pituitary–peripheral axis changes/disturbances such as “pseudo-Cushing syndrome” and hypogonadism. Indeed, the excess of the hypothalamic–pituitary–adrenal (HPA) axis activity includes high CRF (
Restrictive anorexia nervosa amenorrhea, the only somatic trait in the DSM IV classification, is the consequence of blunted HPG axis associating low estradiol (
Oppositely, normal HPA axis activity suggested by normal six-point (8, 12, 16, 20, 24, 04 h) circadian levels of cortisol was found in CT subjects matched for BMI and gender. Functional HPG axis was also attested by normal LH, FSH, estradiol, and free testosterone plasma level without oral contraception, and preserved fertility (
The alteration of bone quality in AN, a consequence to undernutrition and hormonal abnormalities, is widely accepted. Loss of bone density, correlated with the duration of low BMI (
Bone loss with 44% of osteopenia is also found in 20 years old CT subjects (
While low food intake characterizes R-AN subjects, equilibrated energy balance was noticed in CT (
In CT, ghrelin and obestatin are in a normal range (
Studies on anorexic appetite regulating hormones as PYY and GLP-1 in AN present with conflicting results (
For the same, low BMI, anorectic behavior, and adaptive appetite regulating hormone characterizes R-AN patients and distinguishes them from CT patients.
Finally, genetic pathophysiologic role in AN was proposed throughout polymorphism gene studies (
This review focused on biological differences between R-AN and CT. As CT display specific clinical features and normal hormonal parameters, the misdiagnosis between CT and R-AN is no longer permitted. A very thin girl who claims a normal diet should be heard and not considered as a “liar” AN patient. A biological assessment including leptin, free-T3, and IGF-1 is proposed in order to avoid a misdiagnosis.
This review also focused on conflicting literature data reported in R-AN. Because of the clinical or biological heterogeneity of patients selected for the studies, publications results cannot always be compared and could explained the conflicting data. Therefore, straight and objective classification also called “phenotyping” is required in clinical research in order to obtain better comparable symptoms. For example, the definition shift between DSM IV and DSM5 changes the developing risk of AN, double in a dancer population (
In conclusion, CT represents a well-defined real state of low BMI associating a real weight gain desire, normal nutritional markers except for a mild decreased leptin, a constitutive appetite regulating hormone profile, the presence of menses in young women and low bone mass. While CT diagnosis is still poorly known, the new DSM5 AN definition proposing only psychological traits and no organic symptom is warring. In line with mentioned somatic differences, we advocate complementary biological markers in AN definition in order to avoid the misdiagnosis between AN and CT.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The authors would like to thank Prof. Lang for his psychiatric perspective on this issue.