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Keywords:

  • anorexia nervosa;
  • diffusion capacity;
  • emphysema;
  • malnutrition;
  • pulmonary function tests

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Data analysis
  6. Results
  7. Discussion
  8. Acknowledgements
  9. References

Abstract.  Pieters T, Boland B, Beguin C, Veriter C, Stanescu D, Frans A, Lambert M (Cliniques, Universitaires Saint-Luc, Brussels, Belgium). Lung function study and diffusion capacity in anorexia nervosa. J Intern Med 2000; 248: 137–142.

Study objectives. In humans, malnutrition alters the respiratory system in different ways. It impairs the ventilatory drive, decreases respiratory muscle strength and reduces immune competence. In addition, typical emphysema-like changes were demonstrated in starved animals. The presence of emphysema has never been demonstrated in starved humans. Our objective was to investigate whether pulmonary emphysema occurs in anorexia nervosa by means of a pulmonary function study.

Population and method. We examined 24 women aged between 14 and 38 years (nine smokers). We studied the lung function including lung volumes, ventilatory capacity, maximal respiratory pressures and transfer factor, as well as PaO2.

Results. All respiratory tests were within normal limits with the exception of decreased maximal inspiratory (59% of predicted values) and expiratory pressures (35%), and increased residual volume (162%). Diffusion capacity (98.1 ± 16.2%) and transfer coefficient (98.4 ± 16.2%) were also normal. The diffusion coefficient was lower in current smokers than in those who had never smoked (P < 0.01), a difference similar to that calculated from existing reference values for transfer factor for smokers and nonsmokers.

Conclusion. In anorexia nervosa, pulmonary function tests are within normal limits with the exception of maximal pressures and residual volume. Diffusion capacity is not decreased. The present results within the limitations of the used method are not compatible with the hypothesis of starvation-induced pulmonary emphysema.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Data analysis
  6. Results
  7. Discussion
  8. Acknowledgements
  9. References

Malnutrition has several adverse effects on the respiratory system. It impairs the ventilatory drive, decreases respiratory muscle strength and reduces immune competence in humans [1–3]. Extreme malnutrition has been shown to induce emphysema-like morphological changes in animals. Studies on starved rats have shown emphysema-like alterations similar to those observed in naturally occurring or enzyme-induced emphysema [4–7]. Moreover, starvation worsens elastase-induced emphysema in rats [8]. Elastic recoil pressure at any lung volume is lower in starved than in control rats.

In humans, there are some arguments for suggesting alterations to lung structure during starvation and under-nourishment. Emphysema has been reported in autopsy studies performed on the malnourished people from the Warsaw Ghetto, including young individuals [9]. Furthermore, in chronic obstructive pulmonary disease (COPD) patients, where a reduction in diffusing capacity for carbon monoxide and weight loss are associated separately with respiratory-related mortality, diffusion indices were more severely disturbed in patients who had suffered weight loss [10 11]. Nevertheless, the causal relationship between weight loss and emphysema has not been demonstrated.

Anorexia nervosa is an eating disorder occurring mostly amongst adolescents and young women. It leads to profound weight loss associated with severe but reversible impairment of the diaphragmatic function [12]. Spirometric and arterial blood gases values are almost in the normal range. However, diffusion indices have never been studied. Thus, the presence of emphysema-like changes has, as far as we know, not yet been explored in this disease. Isolated cases of pneumomediastinum and subcutaneous emphysema after coughing, vomiting or strenuous exercise have been reported, suggesting a loss of lung tissue elastic properties [13 14].

In this paper we have investigated whether pulmonary emphysema occurs in anorexia nervosa, by measuring the diffusion capacity for carbon monoxide, which is amongst the best respiratory function parameters correlated with histological and radiological emphysema [15–17].

Materials and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Data analysis
  6. Results
  7. Discussion
  8. Acknowledgements
  9. References

Twenty-four consecutive anorexic women were prospectively recruited by two of us (BB and ML) from the outpatient or inpatient clinic. All patients met the diagnostic criteria of The American Psychiatric Association for anorexia nervosa [18]. Eight patients were hospitalized for nutritional support at the time of the study. Fifteen patients were amenorrheic, the other nine were taking oral contraceptives. None had symptoms or a history of pulmonary disease. Nine patients were current smokers. For reasons of comparison of smokers and nonsmokers, four patients were excluded from the nonsmoker group, in order to obtain similar groups of age and height.

Pulmonary function tests were performed using standard techniques. Residual volume was determined by the 7-min helium dilution technique (Pulmonet III, Sensormedics, Bilthoven, The Netherlands). The single breath diffusion capacity for carbon monoxide was measured in duplicate after a seated rest period of 30 min (Morgan Benchmark Transfer Test, Rainham, Kent, England). The mean value is reported (the difference in the mean values of the first and second DCO measurements was 3% on the average), expressed as diffusion capacity (DCO); this was also calculated per litre alveolar volume, measured by the helium dilution during the 10-s apnea of the DCO test (diffusion coefficient; KCO). Values were given corrected for carboxyhaemoglobin (HbCO) and haemoglobin (Hb) [19]. Maximum inspiratory and expiratory pressures (PImax and PEmax) were obtained according to Black and Hyatt [20]. Maximum expiratory pressure was measured by asking subjects to inhale to total lung capacity and to make a maximum expiratory effort sustained for 3 s in an aneroid pressure gauge with a small air leak. Maximum inspiratory pressure was measured by asking subjects to exhale to residual volume and to make a maximum inspiratory effort. Maximum inspiratory and expiratory pressures were recorded three times and best values are reported. Blood gases were measured in seated patients after a rest period of 10 min. A stepwise exercise was then performed until exhaustion and arterial blood gases were again measured.

For adult subjects (age ≥18 years), the predicted values for spirometric data were those of Jouasset [21], and the predicted values of diffusion indices were those of Salorinne [22]. For girls younger than 18 years, references values were those of Dickman et al. [23] for spirometry data and those of Rosenthal et al. [24] for diffusion indices. For smokers and nonsmokers, we compared the calculated values of DCO with those calculated from the reference equations of Miller et al. [25], Van Ganse et al. [26] and Hall et al. [27], using the mean values of our patients. Predicted values are those from normal weight subjects, as respiratory function equations do not take weight into account.

Written informed consent was obtained. The study has been approved by the Commission d’Ethique Biomédicale Hospitalo-Facultaire.

Data analysis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Data analysis
  6. Results
  7. Discussion
  8. Acknowledgements
  9. References

The results were expressed as mean, median, standard deviation and range. Because the data were not normally distributed, the Wilcoxon test was used for comparison between smokers and nonsmokers. The calculation was performed with SAS software. A P-value of less than 0.05 was considered statistically significant.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Data analysis
  6. Results
  7. Discussion
  8. Acknowledgements
  9. References

Mean (±SD) age was 21.3 ± 6.8 years (range 14–38 years; median 18.5 years). Nine patients were younger than 18 years. Body mass index was 14.3 ± 1.8 kg m–2; body mass index of the eight hospitalized patients for nutritional support was not significantly different from that of the 16 ambulatory patients. Severe denutrition (body mass index < 15 kg m–2) was present in 12 patients (50%). The median duration of anorexia nervosa was 24.5 months and the median duration of anorexia nervosa with a body mass index <15 kg m–2 was 4.5 months. No patient had deficiency in serum protein (7.2 ± 0.9 g dL–1), albumin (4.9 ± 0.7 g dL–1) or α1-antitrypsine (87.4 ± 15.4% of a local reference sample of 1000 persons). Anemia (Hb < 12 g dL–1) was present in six patients (25%), all values being higher than 10 g dL–1. Mean beta-carotene was increased (270 ± 134 µg dL–1, normal range 100–200 µg dL–1) and both serum total triiodothyronine (63.4 ± 28.5 ng dL–1, normal range 90–200 µg dL–1) and somatomedin-C (0.4 ± 0.1 U mL–1, normal range 0.4–2 U mL–1) were decreased, as classically founded in anorexia nervosa.

Pulmonary function tests were normal with the exception of residual volume and residual volume/total lung capacity, which were high, and maximal respiratory pressures, which were low (Table 1). After correction for haemoglobin and carboxyhaemoglobin, DCO was not different between hospitalized and outpatient subjects (21.9 ± 2.9 vs. 24.8±3.9 mL mmHg–1 min–1). We found that body mass index was significantly correlated with vital capacity (VC) (r = 0.43; P < 0.05), and that duration of anorexia was inversely correlated with total lung capacity (r = –0.47; P < 0.05) and positively correlated to maximum inspiratory pressure (r = 0.60; P < 0.01). Arterial blood gases at rest and after a stepwise exercise (mean 106 W, median 120 W; range 20–200 W) were normal in all patients.

Table 1.  Pulmonary function tests, diffusion and blood gases values in the 24 patients with anorexia nervosa
 Mean ± SD% of predicted values
  1. To convert into ISU, multiply by 0.133 for PaO2 or PaCO2; and by 0.335 for DCO and KCO. RV = residual volume; TLC = total lung capacity; Pimax = Maximum inspiratory pressure; Pemax = Maximum expiratory pressure. aOutside predicted values. bPredicted values from Sorbini et al. [40]. cPredicted values from Hertle et al. [41].

VC (l)3.2 ± 0.785.1 ± 13.4
FEV1 (l)2.9 ± 0.691.8 ± 13.6
FEV1/VC90 ± 5108 ± 7
TLC (l)4.9 ± 0.7101.9 ± 12.6
RV (l)1.7 ± 0.5a162.2 ± 47.1
RV/TLC (%)34 ± 8a161 ± 37.1
PImax (mbar)–45 ± 10a59 ± 13
PEmax (mbar)51 ± 10a35 ± 7
DCO (ml mmHg–1 min–1)24.2 ± 4.098.1 ± 19.8
KCO (mmHg–1 min–1)5.3 ± 0.998.4 ± 16.2
PaO2 rest (mmHg)103.4 ± 7.994.5b
PaO2 end exercise114 ± 7.8 
PaCO2 rest (mmHg)37.4 ± 3.735.4c
PaCO2 end exercise34.5 ± 3.5 

The mean smoking history was 4.1 pack-years (median 2.5; range 1.5–17). Spirometric data were not statistically different between smokers and nonsmokers. However, there was a statistical difference in DCO (absolute and percentage of predicted values) between smokers and nonsmokers (P < 0.01), with a mean difference in DCO of 4 mL mmHg–1 min–1 (24% for predicted values). Such a difference was also observed when DCO was calculated from other reference equations using height, age and gender, but not weight or body mass index (Table 2).

Table 2.  Comparison of predicted diffusion capacity (ml mmHg–1 min–1) between nonsmokers and smokers according to different equations
 Rosenthal [24] Salorinne [22]aVan Ganse et al. [26]Hall et al. [27]Miller et al. [25]
  1. To convert into ISU, multiply by 0.335. aRosenthal's equation was used for adolescents (<18 years) and Salorinne's equation for adults.

Nonsmokers26.524.535.126.8
Smokers22.423.024.722.2
Mean difference 4.0 1.510.4 4.5
Difference15% 6%30%17%

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Data analysis
  6. Results
  7. Discussion
  8. Acknowledgements
  9. References

Anorexia nervosa is an eating disorder in which malnutrition is a major feature, leading to various biological anomalies. Besides psychological and anthropometric diagnostic criteria, normal levels of serum protein and albumin associated with elevated serum β-carotene levels and a low-T3 are frequent findings. The low serum somatomedin-C levels also reflects malnutrition. Our group of anorexic patients presented these features.

Severe malnutrition alters the visco-elastic properties of animal lungs [28]. Collagen and elastin contents of the lungs have been shown to be affected more severely, by food deprivation over only 4 weeks, in young rats, than in older ones [29]. Under drastic caloric restriction resulting in weight loss, there is a decrease in tissue elastic recoil in both young and adult rats [6 8 11]. Morphologically, in adult food-deprived rats, enlargement of air spaces, particularly at subpleural areas of the lung, with minimal degree of alveolar wall destruction has been demonstrated [30]. Interalveolar septa of starved rats were thin and irregular, and interalveolar pores were larger and more numerous than those seen in fed rats. Elastic fibers in the interstitium were shorter, irregular and fewer in number [4 6 31]. These features have led to the concept of nutritional emphysema [6]. However, in humans, there is only one old study which has analysed emphysema-like changes in malnourished men. Emphysema was observed in 50 lungs out of 370 autopsies performed on victims of the Warsaw Ghetto [9]. The changes were present mostly in young adults. Histological description were not precise so it is not possible to ascertain whether the encountered changes meet the ATS Statement for emphysema [32].

Pulmonary function tests have been scarcely studied in anorexia nervosa. The first study of 10 patients reported in 1966 that forced expiratory volume in one second (FEV1) and residual volume were normal whilst vital capacity was decreased to 75% of the predicted values, but residual volume/total lung capacity was increased to about 30% [33]. Blood gases were normal and pulmonary compliance was normal or low. More recently, Lands et al. reported normal spirometric values in nine anorexic adolescents whose physical fitness appeared to be lowered by diminished muscle mass and/or muscular dysfunction [34]. Diaphragmatic strength in another study of 15 anorexic women was markedly impaired but improved after refeeding [12]. Spirometric, residual volume, and arterial blood gases values were within the normal range. Our study confirms, on a greater number of patients, that spirometry is almost normal and that respiratory muscle function is clearly impaired in anorexia nervosa. Similar findings were made in a group of 16 cachectic, mostly cancer patients, who had normal total lung capacity and residual volume [3]. These muscle dysfunctions are different from those seen in patients with polymyositis or other proximal myopathies [35], who present low VC and total lung capacity (62 and 66% of the predicted values, respectively), with loss of strength evenly distributed amongst inspiratory and expiratory muscles. In our study, maximum expiratory pressure was much more altered than maximum inspiratory pressure. This probably accounted for the elevation of residual volume. We have no explanation for why maximum inspiratory pressure and not maximum expiratory pressure is correlated to duration of anorexia nervosa. Despite muscle weakness, our patients with anorexia nervosa were not short of breath and their blood gases values were not modified after exercise.

Currently, emphysema can be best detected by radiological and diffusion indices. Diffusion indices are the most sensitive lung function indices for the detection of pulmonary emphysema [15–17 36]. In humans, diffusion correlates significantly with emphysema scores on excised lobes, postmortem lungs or high resolution computed tomography (r = 0.86; P = 0.001) [17]. In starved adult rats, DCO and KCO have been shown to be 52% and 28%, respectively, significantly lower when compared to age-matched fed animals (4). We report in this paper, the first study of diffusing capacity in anorexia nervosa. In anorexic patients, after correction for haemoglobin and carboxyhaemoglobin, we did not observe any decrease in diffusing capacity expressed as a percentage of predicted values for either DCO or KCO. We are aware of only one report on a single case of a 25-year old woman with anorexia nervosa in whom KCO was also normal and remained unchanged after refeeding [1]. Furthermore, a normal FEV1/VC ratio practically excludes the presence of pulmonary emphysema in our subjects. The explanation for normal values in our subjects may lie in the composition of the diets. In contrast to conditions that are principally protein-deficient malnutrition, i.e. marasmus, exudative enteropathy or starvation, protein or vitamin deficiency is not a cardinal feature in anorexia nervosa. Indeed, Kerr and Riley have demonstrated that protein restriction is the major dietary factor contributing to nutritional-induced emphysema in rats [6]. Based on normal values of serum proteins, none of our anorexics were protein deficient. In a recent study of other patients with anorexia nervosa followed in our hospital, the lean tissue mass, reflecting protein and collagen content, measured by dual energy X-ray absorptiometry, was decreased by only 19% whilst the fat mass was reduced by 84% in comparison with controls [37]. By contrast, one third of the autopsied cases from the Warsaw Ghetto showed generalized oedema, suggesting a diminution of oncotic pressure following protein depletion [9].

We also investigated whether emphysema can be detected in anorexic women whose lungs have been injured by smoking. In humans, emphysema is considered to be a consequence of an inbalance between elastase and antielastase action, favoured by smoking. The difference in DCO between smokers and nonsmokers appears very soon in life, as observed in women aged of 15–29 years, the age range of our patients [38]. A great proportion of the difference in DCO in young people is not secondary to structural changes that need time to develop, but is due to a vascular effect as suggested by partial reversibility of DCO after smoking cessation [38 39]. In our study, smoking was recent and moderate (4 pack-year). Smoking anorexic women had a significantly lower DCO than the nonsmokers. The mean difference in DCO was, however, comparable to the difference calculated from reference equations for smoking and nonsmoking women of normal weight [25–27], indicating that the observed difference was not due to malnutrition. Surprisingly, it seems that, according to the equations, the calculated difference between smokers and nonsmokers is quite variable.

In summary, our data, according to the results of lung function tests including diffusion indices, do not support the hypothesis that anorexia nervosa leads to emphysema, even in smokers. This could be explained by the non protein-deficient malnutrition, characteristic of anorexia nervosa, or to the relatively short duration of starvation in our rather young patients. Further pulmonary studies are still necessary and should compare chronic anorexia nervosa with protein deficient diseases.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Data analysis
  6. Results
  7. Discussion
  8. Acknowledgements
  9. References

We are indebted to Professor DO Rodenstein for reviewing the manuscript.

References

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  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Data analysis
  6. Results
  7. Discussion
  8. Acknowledgements
  9. References
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Received 2 November 1999; revision received 15 March 2000; accepted 4 April 2000