Metabolic and pathophysiological characterization of constitutional thinness

Abstract

Purpose

Constitutional thinness (CT) is characterized by a persistently low body weight in the absence of eating disorders or overt disease. Distinguishing CT from anorexia nervosa (AN) is often challenging, and the metabolic and cardiovascular features of CT remain incompletely defined. The present study investigated nutritional, metabolic, and cardiovascular parameters in women with CT and compared them with those of women with AN and normal-weight healthy controls.

Methods

Data from 7 women with CT were compared with those from 6 women with AN and 6 normal-weight healthy women serving as controls. The resting metabolic rate (RMR) and endothelial function, assessed by flow-mediated dilatation (FMD), were measured.

Results

Body weight, body mass index, fat mass and fat-free mass (FFM) were comparable between the CT and AN groups and significantly lower than those of the control group. Absolute and FFM-normalized RMR values were significantly higher in the CT group (median [IQR]: 1263 [247] kcal/24 h and 29.2 [3.1] kcal/FFM-kg/24 h) than in the AN group (1046 [272] kcal/24 h and 25.4 [2.7] kcal/FFM-kg/24 h; P < 0.001 and P < 0.05, respectively), and did not differ from those observed in controls (1317 [221] kcal/24 h and 29.5 [1.2] kcal/FFM-kg/24 h). Flow-mediated dilatation was significantly lower in both the CT (7.2 [2.7] %) and AN (7.6 [6.2] %) groups compared with controls group (14.0 [9.0]%; P < 0.05).

Conclusion

These findings indicate that RMR differs between CT and AN, with women with CT exhibiting a metabolic profile distinct from that of AN and similar to that of normal-weight controls. Endothelial dysfunction was observed in both CT and AN, suggesting a potential cardiovascular alteration that warrants further investigation.

Introduction

Constitutional thinness (CT) is a clinical entity that remains poorly defined from an etiopathogenetic and clinical perspective. Understanding the mechanisms that allow some individuals to maintain a stable low body weight despite apparently increased caloric intake and the absence of concomitant pathologies that cause weight loss could result in the development of better targeted approaches to body weight management as well as a better understanding of the metabolic aspects that regulate body weight. Notably, although individuals with CT often report hypercaloric dietary intake and may have a sedentary lifestyle, their body weight remains remarkably stable over time. This observation has led to the hypothesis that CT may represent a genetically determined, obesity-resistant phenotype. Some studies [1, 2] have shown that a hypercaloric diet is often ineffective for achieving weight gain in individuals with CT. In response to hypercaloric diets, these individuals appear to develop endocrine and metabolic adaptations, including increased energy expenditure and other mechanisms that are not yet fully elucidated [1]. In addition, modulation of appetite- and metabolism-related gut hormones, such as peptide YY (PYY) and glucagon-like peptide 1 (GLP-1), has been reported [3, 4]. However, while these hormonal alterations have been observed in experimental settings, their causal role in the maintenance of low body weight in CT remains speculative, and the underlying mechanisms have yet to be clearly established.

Diagnostic uncertainty represents another major challenge in the clinical management of CT. Both CT and anorexia nervosa (AN) are characterized by low body weight, commonly defined as a body mass index (BMI) < 18.5 kg/m², and misclassification between the two conditions is frequent in clinical practice. Traditionally, CT has been conceptualized as a metabolic or nutritional condition, whereas AN is classified as a psychiatric disorder according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) [5, 6]. However, this distinction is increasingly recognized as an oversimplification. Growing evidence suggests partial overlap between the two conditions, with shared biological pathways involving metabolic, neuroendocrine, and gut–brain mechanisms, including potential contributions of the gut microbiome [7].

Conversely, the diagnosis of CT is generally made via exclusion. In particular, the diagnostic features of CT, according to available studies in the literature [1, 8–14] for the differential diagnosis of CT from AN, can be summarized as follows: (a) no psychological or eating disorders or other disorders that could explain the low body weight; (b) a desire to gain body weight; (c) unaltered hormones and markers of nutritional status; and (d) the maintenance of a neutral or positive energy balance.

The cardiovascular implications of CT also remain unclear. While low body weight might intuitively be considered protective, excessive or imbalanced energy intake—regardless of its effect on body weight—could still promote atherogenic processes. Giannini et al. [15] reported increased oxidative stress and endothelial dysfunction in children and adolescents with CT. However, it remains uncertain whether these alterations are primarily driven by growth- and developmental factors or whether they persist into adulthood, potentially conferring long-term cardiovascular risk. To date, no studies have directly compared cardiovascular and metabolic profiles of adult women with CT to those of women with AN.

In the present study, we compared women with CT to women with AN and to normal-weight healthy controls in order to evaluate metabolic and cardiovascular characteristics and to contribute to a more precise clinical and pathophysiological definition of CT.

Methods

Participants

Participants who were diagnosed with CT or AN at the Clinical Nutrition, Obesity, and Metabolic Diseases Unit of the University Hospital Policlinico “P. Giaccone” in Palermo (Italy) between November 2018 and June 2020 were included in this study. A dedicated team of doctors and dieticians performed all nutritional evaluations. Some of the data collected were compared with those of a healthy normal-weight control group that consisted of age- and sex-matched individuals. Participants with CT were selected among individuals who reported that they wished to increase their body weight and were unable to do so despite routine normal- or high-calorie food intake. Additional inclusion criteria for participants with CT were female sex, age 18–35 years, BMI < 18.5 kg/m² from pubertal age, stable body weight within the past 2 months, regular dietary habits consisting of at least 3 main meals per day, and a dietary intake of at least 28 kcal/kg of body weight, on the basis of the FFQ validated for the local population. The exclusion criteria for CT were: smoking > 5 cigarettes/day; occurrence of primary or secondary amenorrhea; malignancies; diagnosis of systemic or organ-related diseases, including those that cause malabsorption, hyperthyroidism or hypothyroidism; diagnosis of eating disorders assessed through psychological testing and psychiatric evaluation; and pregnancy. The inclusion criteria for participants with AN were female sex, age 18–35 years, BMI < 18.5 kg/m², and a diagnosis of AN. The exclusion criteria for participants in the AN group were smoking > 5 cigarettes/day; diagnosis of malignancies; diagnosis of systemic or organ-related diseases, including those that cause malabsorption, hyperthyroidism or hypothyroidism; and pregnancy.

A psychiatric specialist interview was performed to determine the presence of an eating disorder, with particular attention to AN, and dedicated tests, such as the Eating Disorders Inventory-3 (EDI-3) [16], the Beck Depression Inventory (BDI-II) [17], the Toronto Structured Interview for Alexithymia (TSIA) [18], and the Somatic Inkblot Series (SIS) [19], were administered.

The institutional ethics committee (“Palermo 1” of the Policlinico “P. Giaccone” University Hospital, 10 September 2018, ref: 08/2018) approved the study protocol, and each participant signed an approved informed consent form.

Anthropometric and clinical measurements

Body composition was estimated as fat mass (FM, percentage of body weight) and fat-free mass (FFM, kg) using bioelectrical impedance analysis (BIA), as previously described [20] [BIA-101 Anniversary, Akern Srl, Florence, Italy], to obtain body resistance (R; ohm), reactance (Xc, ohm), and phase angle [PA degrees 5 arctan (Xc/R) 3 (180/p)]. The use of crude BIA measures, such as the phase angle (PA), has received increased attention, as these may be plausible indicators of intra- and extracellular hydration and nutritional status [21]. The body circumference was measured at the umbilicus (waist circumference) and at the most prominent buttock level (hip circumference). The waist-to-hip ratio (WHR) was used as an indirect index of body fat distribution. The volumes of the abdominal visceral and subcutaneous adipose tissues was also measured by means of high-resolution B-mode ultrasound (Envisor G5; Philips, US) [22]. Transverse scans were obtained 5 cm above the umbilicus along the xipho-umbilical line. A 10-MHz linear probe was used to measure the distance between the cutis and the conjunction of rectus muscles at the linea alba (cutis-rectis thickness; CR) as a measure of subcutaneous fat. A 3.5-MHz convex probe was used to measure the distance between the linea alba and the anterior wall of the abdominal aorta (rectis-aorta thickness, or RA) as a measure of visceral abdominal fat. The RA-to-CR ratio (RA/CR) is also considered an indirect measure of body fat distribution. Muscle strength was measured with a hand grip test using a hydraulic hand dynamometer (model no. SH5001; Jamar, Saehan, Republic of Korea). The participants were instructed to perform a maximal isometric contraction. The test was repeated within 15 to 20 s for each hand, and the average value (kg) of the three tests was used for the analysis [23]. Habitual dietary intake was assessed using a validated food frequency questionnaire (FFQ) specifically designed for the local population [24]. The participants were required to report their typical dietary habits over the previous year, including their meal patterns and food choices. Data from the FFQ were analyzed to determine overall dietary characteristics. Habitual physical activity level was investigated using a specific questionnaire validated for the local population that describes 4 levels (very low = 1, low = 2, moderate = 3, high = 4) of physical activity [25].

Indirect calorimetry

The resting metabolic rate (RMR) was determined using the indirect calorimetry method, as previously described [26], and a ventilated hood system (Quark RMR; Cosmed, Rome, Italy). The device was equipped with an infrared analyzer for carbon dioxide measurement (VCO2) and a zirconium cell analyzer for oxygen measurement (VO2). The analyzers were calibrated before each test using gases with a known percentage of oxygen and carbon dioxide. The data were obtained from approximately 30–60 min of stable measurements, and the average intrasubject variability in the RMR was 3.9%. The RMR was calculated using the Weir equation [27] and was expressed both in absolute terms (kcal/24 h) and normalized to the FFM value (kcal/kg-FFM • 24 h). The respiratory quotient (RQ; VCO2/VO2), an indirect measure of both carbohydrate and lipid oxidation, was obtained. With respect to the substrate oxidation measurement [28], the urea nitrogen excreted in the urine over the last 12 h is assumed to be derived from protein oxidation; the grams of oxidized proteins were obtained by multiplying the amount (g) of ureic nitrogen by 6.25. Since the quantity of O₂ necessary to oxidize one gram of protein and the amount of CO₂ produced are known, the nonprotein RQ (NPRQ) was obtained by subtracting these estimated volumes from the measured volumes; thus, this value reflected only the relative proportions of lipid and carbohydrate oxidation.

Endothelial function

The flow-mediated dilatation (FMD) of the brachial artery was assessed as a measure of endothelial function using a high-resolution ultrasound linear probe (10 MHz, Sonoline G50 Philips, US), as previously described [29]. Briefly, a sphygmomanometer, cuffed at 220–250 mmHg 2 cm below the antecubital fossa, induces reactive hyperemia by occluding the artery for 300 s. Real-time computed video analysis of B-mode ultrasound images (FMD Studio; Institute of Physiology CNR; Pisa, Italy) recorded variations in brachial artery diameter. The baseline vessel size was determined as the mean of measurements obtained during the first minute. FMD was calculated as the maximum percentage increase in brachial artery diameter over the baseline. Endothelium-independent dilatation was assessed after the administration of 300 µg sublingual glyceryl–trinitrate (GTN). All flow-mediated dilation and glyceryl trinitrate dilatation assessments were performed by the same operator; ultrasound images were video recorded and analyzed by a trained reader. The intra-observer coefficient of variation for flow-mediated dilation was 2.9% in our laboratory.

Laboratory exams

Fasting blood samples were collected from all participants after an overnight fast of at least 8 h. Fasting plasma glucose (FPG), total cholesterol, high-density lipoprotein cholesterol (HDL-c), triglyceride (Tg), uric acid, and creatinine concentrations were measured using standard clinical chemistry methods (Glucosio HK UV; Colesterolo tot. Mod P/D; Colesterolo HDL gen 3 mod P/917; Trigliceridi; Acido urico MOD P/917; Creatinina enzimatica; Roche Diagnostics; Monza, Italy). Serum low-density lipoprotein cholesterol (LDL-c) concentrations were calculated using Friedewald’s formula, and HOMA-I values were calculated as described by Matthews et al. [30].

Statistical analysis

Statistical analysis was performed using Systat (Windows version 13.0; San Jose, CA, USA). Given the small sample size in each group (n = 6–7), continuous variables are reported as median and interquartile range (IQR). Differences among the three groups were assessed using the Kruskal–Wallis test. When the overall test was significant, post hoc pairwise comparisons were conducted using the Conover–Inman procedure with Holm correction for multiple testing. A two-sided p value < 0.05 was considered statistically significant.

Results

In this study, one woman with AN and one woman in the control group refused to participate in the study. Finally, we recruited 7 women with CT, 6 women with AN and 6 controls. The physical and clinical characteristics of the participants in the three groups are presented in Table 1. Notably, the physical characteristics of the AN and CT groups did not significantly differ. Compared with the control group, both the AN group and the CT group exhibited lower body weights and FMs with less subcutaneous fat. Data related to dietary habits, energy expenditure and basal substrate oxidation are presented in Table 2. The habitual intake of energy and macronutrients did not differ among the three groups.

Table 1.

Physical and clinical characteristics of the women with anorexia nervosa (AN) and constitutional thinness (CT)

	Groups			K-W test P
	Control (n = 6)	AN (n = 6)	CT (n = 7)
Age (years)	30 (2)	23 (6)	28 (5)	0.36
Body weight (kg)	57.0 (7.7)∗, **	47.5 (4.1)	46.4 (5.1)	< 0.05
BMI (kg/m2)	20.8 (2.0)#, ••	17.1 (0.3)	17.9 (0.5)	< 0.005
Body circumferences:
Waist (cm)	80.0 (6.7)•, ••	65.0 (1.5)	66.0 (1.9)	< 0.05
Hip (cm)	95.0 (5.2)•, ∗∗	85.0 (5.0)	88.5 (7.4)	< 0.05
Waist to hip ratio	0.81 (0.08)*, **	0.76 (0.03)	0.75 (0.07)	< 0.05
Bioimpedance analysis:
Resistance (Ohm)	649 (90)	733 (75)	673 (36)	0.12
Reactance (Ohm)	69 (13)	82 (13)	75 (8)	0.28
Phase angle (°)	7.3 (1.2)	6.6 (0.8)	6.4 (0.4)	0.50
Fat mass (%)	21.1 (4.8)*,**	15.0 (1.5)	14.8 (2.7)	< 0.05
Fat free mass (kg)	46.4 (7.5)	40.7 (3.2)	40.1 (2.2)	0.31
Ultrasound thicknesses:
Cutis-rectis (mm)	18 (14)	4 (1)	6 (2)	0.47
Rectis-aorta (mm)	3 (1)	4 (1)	2 (1)	0.06
Hand-grip test (kg)	30 (3)	25 (5)	24 (5)	0.22
Blood concentrations of:
Glucose (mg/dl)	83 (8)	81 (9)	80 (6)	0.68
Cholesterol (mg/dl)	181 (31)	164 (31)	162 (26)	0.60
Triglycerides (mg/dl)	89 (13)	85 (29)	60 (57)	0.63
HDL-c (mg/dl)	67 (16)	54 (9)	66 (32)	0.43
LDL-c (mg/dl)	96 (18)	99 (23)	80 (19)	0.30
Uric acid (mg/dl)	4.1 (0.3)	3.3 (0.5)	3.4 (0.9)	0.14
Insulin (mU/ml)	6.6 (2.7)	5.0 (3)	6.1 (1.7)	0.81
HOMA-I	1.3 (0.8)	0.9 (0.7)	1.2 (0.5)	0.72
C-reactive protein (mg/l)	2.2 (0.9)	0.6 (0.7)	0.4 (0.3)	0.24

Median; interquartile range in parenthesis; KW, Kruskal-Wallis test; Pairwise comparisons: ^*P < 0.05 vs. AN group, ^**P < 0.05 vs. CT group, ^•P < 0.01 vs. AN group, ^••P < 0.01 vs. CT group, ^#P < 0.001 vs. AN group

BMI, body mass index; HDL-c, high-density lipoprotein cholesterol; HOMA-I, homeostatic model assessment index; LDL-c, low-density lipoprotein cholesterol

Table 2.

Dietary habits, energy expenditure and basal substrate oxidation in women with anorexia nervosa (AN) and constitutional thinness (CT)

	Groups			K-W test
	Control (n = 6)	AN (n = 6)	CT (n = 7)	P
Habitual intake of:
Energy (kcal/24 h)	1425 (555)	1225 (712)	1571 (226)	0.91
Carbohydrates (% energy intake)	48.1 (14.1)	47.6 (19)	55.0 (14.9)	0.73
Lipids (% energy intake)	32.2 (7.1)	30.7 (16.1)	25.2 (13.3)	0.91
Proteins (% energy intake)	19.7 (6.9)	21.7 (6.3)	19.8 (2.5)	0.56
Proteins (g/24 h)	70 (7)	72.8 (35)	74.9 (19)	0.99
Physical activity (score)	3.0 (0.8)	2.0 (1.5)	2.0 (1.0)	0.15
Resting metabolic rate:
kcal/24 h	1317 (221) #	1046 (272)	1263 (247)#	< 0.05
kcal/(kg FFM•24 h)	29.5 (1.2) •	25.4 (2.7)	29.2 (3.1) •	< 0.05
Basal substrate oxidation:
NPRQ	0.74 (0.05)	0.80 (0.04)	0.73 (0.08)	0.08
Carbohydrates (%)	16.6 (12.3)	26.5 (32.2)	8.5 (16.1)	0.20
Lipids (%)	55.5 (5.0)	56.9 (24.1)	64.6 (10.1)	0.26
Proteins (%)	27.9 (7.2)	22.0 (11.5)	23.3 (8.7)	0.36

Median, interquartile range in parenthesis; KW, Kruskal-Wallis test; Pairwise comparisons: ^•P < 0.05 vs. AN group, ^#P < 0.001 vs. AN group

FFM, fat-free mass; NPRQ, nonprotein respiratory quotient

Both the absolute and FFM-normalized RMR values of the AN group were significantly lower than those of the CT group and the control group. The FMD and GTN data are presented in Fig. 1. Compared with those in the control group (median value 14.0%; IQR 9.0%) participants in the AN (median value 7.6%; IQR 6.2%) and CT (median value 7.2%; IQR 2.7%) groups had lower FMD values (Kruskal-Wallis test: P < 0.05). The GTN was not significantly different among the three groups (Kruskal-Wallis test: P = 0.60).

Fig. 1.

Endothelial function assessed by flow-mediated and glyceryl-trinitrate–mediated dilation across control, anorexia nervosa, and constitutional thinness groups. Endothelial function was assessed as flow-mediated dilation (FMD) and endothelium-independent dilation following the administration of 300 μg sublingual glyceryl trinitrate (GTN) of the brachial artery in the control (C), anorexia nervosa (AN), and constitutional thinness (CT) groups. Bars represent median values and error bars indicate the interquartile range (25th–75th percentiles). Group comparisons were performed using the Kruskal–Wallis test followed by Conover–Inman post hoc analysis with Holm correction

Discussion

The results of this study suggest that women with CT are psychologically and clinically healthy. Therefore, the assessment of anthropometric and psychological parameters might be sufficient to allow it to be differentially diagnosed with eating disorders that also cause thinness. We did not observe clear evidence of high energy expenditure that would explain the thinness seen in the context of high habitual caloric intake. However, some data support this possibility. First, both the absolute and FFM-normalized RMRs were significantly greater in the CT group than in the AN group, but the values in the CT group were comparable to those of the control group. These findings are consistent with the possibility that in women with AN, caloric restriction, and consequently a negative energy balance, promote a reduction in energy expenditure that favors energy conservation, maintains energy balance, and slows weight loss [31]. Therefore, in women with CT, the value of the RMR was normal since these women did not experience a reduction in habitual caloric intake. These findings indicate that resting metabolic rate normalized for fat-free mass differs between constitutional thinness and anorexia nervosa. Although not intended as a diagnostic tool and despite partial overlap of individual values, this parameter may represent a physiological feature that contributes to distinguishing these two conditions when interpreted in conjunction with clinical assessment. Additionally, compared with the control group, the CT group maintained a significantly lower body weight despite a similar resting metabolic rate, suggesting a reduced energetic efficiency in these individuals. Although data concerning energy expenditure in constitutional thinness are scarce, this observation is consistent with the hypothesis of a condition characterized by increased energy dissipation [32–34]. However, resting metabolic rate represents only one, albeit the major, component of total daily energy expenditure. Therefore, total energy expenditure may not be fully captured by resting metabolic rate alone. In this regard, although structured physical activity levels did not differ between groups in the present study, non-exercise activity thermogenesis (NEAT), which includes spontaneous and unintentional movements such as fidgeting or postural adjustments, was not specifically assessed and may have been underestimated. Increased NEAT could therefore contribute to higher total energy expenditure in individuals with constitutional thinness and help explain the discrepancy between stable low body weight and apparently normal energy intake. Other components of daily energy expenditure not investigated in this study, including postprandial thermogenesis, may also play a role. These observations align with a recent review [35] indicating that constitutional thinness represents a distinct phenotype with unique energy regulation profiles and metabolic features that challenge traditional concepts of energy balance. Nevertheless, these considerations remain speculative and require confirmation in future studies.

The assessment of habitual dietary intake in individuals with anorexia nervosa represents a major methodological challenge, as no currently available approach can provide fully accurate or unbiased estimates in this population. Self-reported tools, including food frequency questionnaires, are particularly prone to recall and reporting bias in individuals with eating disorders. However, in the absence of more reliable alternatives for the evaluation of habitual intake, a food frequency questionnaire validated for our geographical area was used in the present study. The similar reported energy intake observed across groups is therefore unlikely to reflect true equivalence in dietary intake and should be interpreted with caution. Nevertheless, it is noteworthy that the constitutional thinness group reported a habitual energy intake comparable to that of the control group. Although this finding should not be overinterpreted given the limitations of dietary self-report, it is consistent with the study hypothesis and may suggest the presence of metabolic or physiological mechanisms allowing constitutional thinness women to maintain a significantly lower body weight despite an apparently similar energy intake. It should also be noted that, although not an inclusion criterion, all patients with anorexia nervosa who participated in the study were of the restricting subtype, which may partially limit heterogeneity but does not eliminate the intrinsic limitations of dietary self-report in this condition.

The present study cannot provide direct insights into the pathophysiological mechanisms underlying constitutional thinness. Among the proposed hypotheses, an increased contribution of brown or beige adipose tissue has been suggested. However, in the absence of direct imaging or functional assessment in the present study, the role of brown adipose tissue should be considered speculative and mainly supported by previous literature. A small PET study reported an association between brown adipose tissue expansion and higher resting metabolic rate in women with constitutional thinness [32], and brown adipose tissue has been shown to be inversely associated with body mass index and potentially protective against obesity [36, 37]. Nonetheless, further studies are required to clarify the relative contribution of these mechanisms.

Furthermore, an interesting finding, despite not statistically significant, is that women with CT oxidize more fatty acids under basal conditions; these data are in agreement with the possibility that the CT group may have had a negative energy balance in the presence of adequate energy intake. On the contrary, even if not statistically significant, we found that compared with women in the control group, women in the CT group tended to habitually consume a lower quantity of fats and a higher quantity of carbohydrates. Therefore, a negative balance between fat intake and fat oxidation occurs, which is a characteristic that is in line with the condition of leanness [38]. Similarly, Ling et al. demonstrated that adipocytes from individuals with CT are smaller in size than adipocytes from normal-weight individuals and that the mitochondria in those with CT exhibit more intense activity and more marked lipid oxidation activity compared with mitochondria in controls, which was also confirmed through indirect calorimetry [39].

Epidemiological evidence indicates an increased mortality risk even in BMI classes indicative of thinness. In line with this observation, we found that, compared with the control group, both CT and AN were characterized by endothelial dysfunction, as demonstrated by significantly lower FMD values, despite preserved endothelium-independent vasodilation, as assessed by GTN. Endothelial dysfunction represents a key early event in the development of atherosclerosis [40], and FMD is considered the reference non-invasive method for the in vivo assessment of endothelial function in humans [41]. Several studies have shown that reduced FMD is associated with increased cardiovascular events and reduced survival [42–44]. Therefore, the presence of impaired endothelial function in women with constitutional thinness suggests the possibility of an increased cardiovascular risk and highlights the need for careful clinical evaluation and long-term follow-up in this population. However, these findings should not be interpreted as sufficient to define constitutional thinness as a disease requiring treatment, but rather as evidence of a physiological alteration that may have relevant clinical implications and deserves further investigation.

Different mechanisms may underlie endothelial dysfunction in constitutional thinness and anorexia nervosa. In constitutional thinness, excessive substrate oxidation may promote oxidative stress, potentially contributing to endothelial and metabolic stress, whereas in anorexia nervosa, antioxidant deficiencies may play a predominant role.

This study has several limitations, but the main limitation is likely the small sample size. However, the incidence of well-defined cases of CT is relatively low, and therefore, it is difficult to include a substantial number of case studies. Furthermore, the inclusion of individuals with anorexia nervosa in studies similar to this one is difficult. However, the merits of this study are that it considered multiple nutritional, metabolic, and cardiovascular aspects in the same subjects and compared cases of CT with difficult-to-interpret conditions such as anorexia nervosa. Only well-coordinated multicenter studies will be able to obtain data from larger case series. Another limitation of this study is the use of BIA to assess body composition. Bioelectrical impedance analysis is widely used for the assessment of body composition; however, its validity in very lean populations deserves consideration. Previous studies have shown that BIA tends to underestimate fat-free mass in individuals with low body mass index, while overestimating it in subjects with higher BMI, likely due to alterations in hydration status and body geometry [45]. Importantly, this potential source of systematic error is unlikely to explain the present findings regarding resting metabolic rate normalized for fat-free mass (RMR/FFM). Indeed, the anorexia nervosa and constitutional thinness groups were characterized by comparable BMI values; therefore, any BIA-related bias would be expected to affect both groups in a similar manner. Despite this, RMR normalized for fat-free mass was significantly different between the two groups, suggesting that the observed difference is unlikely to be attributable solely to measurement-related bias and may reflect a genuine difference in resting metabolic rate between the two conditions. Nevertheless, confirmation of these findings using reference techniques such as dual-energy X-ray absorptiometry would be desirable in future studies.

In conclusion, the results of this study support the hypothesis that individuals with CT exhibit a distinct energy regulation profile, particularly when compared with individuals with AN. Endothelial dysfunction seems to characterize individuals with CT or AN. Further studies are necessary to confirm these observations and to better understand the mechanisms responsible for the energy dissipating condition in CT.

Abbreviations

AN

Anorexia nervosa

BIA

Bioelectrical impedance analysis

BMI

Body mass index

CR

Cutis-rectis thickness

CT

Constitutional thinness

FFM

Fat-free mass

FM

Fat mass

FFQ

Food frequency questionnaire

FMD

Flow-mediated dilatation

FPG

Fasting plasma glucose

GTN

Glyceryl–trinitrate

HDL

High-density lipoprotein

LDL

Low-density lipoprotein

NPRQ

Nonprotein respiratory quotient

PA

Phase angle

RA

Rectis-aorta thickness

RMR

Resting metabolic rate

TG

Triglyceride

WHR

Waist-to-hip ratio

Author contributions

Silvio Buscemi and Carola Buscemi were responsible for data statistics and writing article. Cristiana Randazzo, Anna Maria Barile, Silvia Ferro, Piero Colombrita, Roberta Caruso, Martina Lombardo performed metabolic and nutritional measurements and collected the data. Rosa Lo Baido and Sabina La Grutta performed psychiatric evaluations. Cristiana Randazzo, Rosa Lo Baido, Sabina La Grutta, Serena Cangemi and Aurora Ligotino contributed to the revision of the manuscript. Silvio Buscemi and Carola Buscemi provided resources and designed the study. All authors contributed to the article and approved the submitted version.

Funding

Open access funding provided by Università degli Studi di Palermo within the CRUI-CARE Agreement. This research received no external funds.

Data availability

The datasets generated during this study are available from the corresponding author upon reasonable request for 2 years following the date of publication.

Declarations

Competing Interests

The authors declare that they have received no competing interests.