Background: Nontoxic goiters can cause extrathoracic upper airway obstruction and, if large, may extend into the thorax, causing intrathoracic airway obstruction. Although patients with goiter often report orthopnea, there are few studies on postural changes in respiratory function in these subjects.
Purpose: The aim of this study was to investigate the postural changes in respiratory function and the presence of flow limitation (FL) and orthopnea in patients with nontoxic goiter.
Methods: In 32 patients with nontoxic goiter, respiratory function was studied in seated and supine position. Expiratory FL was assessed with the negative expiratory pressure method. Goiter-trachea radiologic relationships were arbitrarily classified as follows: grade 1, no evidence of tracheal deviation; grade 2, tracheal deviation present in lateral and/or anteroposterior plane but with tracheal compression < 20%; and grade 3, tracheal deviation present with compression > 20%. Subgroups were considered according to this classification and occurrence of orthopnea and FL.
Results: In all three groups of patients, the average maximal expiratory flow at 50% of FVC/maximal inspiratory flow at 50% of FVC ratios were > 1.1, suggesting the presence of upper airway obstruction. Grade 3 patients had a significantly lower expiratory reserve volume and maximal expiratory flow at 25% of FVC and higher airway resistance and 3-point FL score than patients with grade 1 and grade 2. The prevalence of orthopnea was highest in patients with grade 3 (75%, as compared to 18% in the grade 1 group). In patients with orthopnea, the prevalence of intrathoracic goiter was also higher (78%, vs 21% in patients without orthopnea).
Conclusion: There is a high prevalence of orthopnea in patients with goiter, especially when the location is intrathoracic and causes a reduction of end-expiratory lung volume and flow reserve in the tidal volume range, promoting FL especially in supine position. Obesity is a factor that increases the risk of orthopnea in patients with goiter.
Key words: flow limitation; goiter; lung function; negative expiratory pressure; obesity; orthopnea; postural changes
Abbreviations: BMI = body mass index; DLCO = diffusing capacity of the lung for carbon monoxide; EL = elastance of the lungs; Ers = elastance of respiratory system. ERS = European Respiratory Society. ERV = expiratory reserve volume; EW = elastance of the chest wall; FL = flow limitation; FRC = functional residual capacity; IC = inspiratory capacity; ME[F.sub.50] = maximal expiratory flow at 25% of FVC; ME[F.sub.50] = maximal expiratory flow at 50% of EVC; MI[F.sub.50] = maximal inspiratory flow at 50% of FVC; NEP = negative expiratory pressure; PEF = peak expiratory flow. Raw = airway resistance; RawE = expiratory airway resistance; RawI = inspiratory airway resistance; RV = residual volume; TLC = total lung capacity; VG = intrathoracic volume of the goiter; Vr = relaxation volume of respiratory system; WI = inspiratory work of breathing
Nontoxic goiters can cause extrathoracic upper airway obstruction and, if large, may extend into the thorax, causing intrathoracic upper airway obstruction as well. (1-6) Correlation between radiologic indexes and routine spirometric parameters of upper airway obstruction is poor. (1,6) Although patients with goiter often report orthopnea, the nature of this phenomenon has not been studied in detail. Orthopnea implies that the inspiratory work is substantially greater in the supine position than in the upright position. (7-9) There are two mechanisms that can cause this phenomenon: (1) to the extent that goiter causes upper airway obstruction, an increase in airway resistance (Raw) is axiomatic, and orthopnea may simply reflect a greater increase in Raw, and hence in resistive inspiratory work, in supine position; and (2) intrathoracic goiters occupy space in the thoracic cavity and, similar to obesity, (7,10) the expiratory reserve volume (ERV) should be reduced with a concurrent increase of Raw. Furthermore, because maximal expiratory flow rates decrease with decreasing lung volume, the reduction of EBV promotes tidal expiratory flow limitation (FL). (9,11,12) Tidal FL in turn promotes dynamic hyperinflation with concurrent intrinsic positive end-expiratory pressure, which acts as an inspiratory threshold load and causes additional inspiratory work. (9) This, as well as the increase in resistive work, is especially important in the supine position because the ERV is normally smaller when supine than when sitting. (7,12) Thus, our hypotheses are that patients with goiter and orthopnea should exhibit a decrease in EBV, and an increase in Raw and tidal expiratory FL, particularly in the supine position. (12,13) Accordingly, in the present study on 32 patients with euthyroid goiter, we assess lung function, Raw, and FL, and their association with orthopnea.
MATERIALS AND METHODS
A cross-sectional study was carried out on 32 consecutive outpatients (12 male) with nontoxic goiter. The diagnosis was made at the Endocrinology Unit, San Luigi Gonzaga Hospital, Orbassano, Turin, Italy, by ultrasonography and/or nuclear imaging of the thyroid, and by measuring thyrotropin, free tri-iodothyronin, and free thyroxin concentrations. A classification of goiter based on clinical examination has been provided by Thillu (14) for the World Health Organization; for this study, only patients with palpable and visible goiter at neck extension (classified as grade 1B or greater according to World Health Organization) were considered. Patients with a history of chronic cardiopulmonary disease were excluded. The radiographs of the trachea were obtained in standing subjects in the anteroposterior and lateral planes. Based on these radiographs, goiter was classified as intrathoracic if the inferior part extended below the upper limit of the sternum.
The goiter-trachea relationship was independently evaluated by two physicians and arbitrarily classified as follows: grade 1, no evidence of tracheal deviation; grade 2, tracheal deviation present in lateral and/or anteroposterior plane but with tracheal compression < 20% (/e, the ratio of the tracheal diameter at the point of maximal compression to that above the upper limit of the goiter was > 0.8); grade 3, tracheal deviation present with compression > 20%. Based on these grades, the patients were assigned to three subgroups, as shown in Table 1. Table 1 also provides the anthropometric characteristics and the site of goiter relative to the trachea. Eight patients had a body mass index (BMI) > 30. Five patients were current smokers, and 11 patients were ex-smokers.
Pulmonary Function Tests
Each patient underwent in the same morning a complete spirometric study in the sitting position. Using a whole-body plethysmograph (Autobox 2800; SensorMedics; Yorba Linda, CA), the inspiratory Raw (RawI), expiratory Raw (RawE) and total Raw were measured at a panting frequency < 1 Hz. Maximal expiratory and inspiratory flow-volume loops were assessed according to the European Respiratory Society (ERS) guidelines. (15) Diffusion capacity of the lung for carbon monoxide (DLCO) was measured and corrected for hemoglobin, carboxyhemoglobin, and altitude above sea level with a Biomedin water-sealed spirometer (Padua, Italy), using helium for alveolar volume measurement according to ERS guidelines. Predicted values by the ERS were used for all parameters (15) except Raw, which was computed according to Peslin (16) (1.4 cm [H.sub.2]O/L/s and 1.5 cm [H.sub.2]O/L/s for male and female subjects, respectively).
Tidal FL was assessed with the negative expiratory pressure (NEP) technique. (12) An NEP of -5 cm [H.sub.2]O was applied with the Direc/NEP System 200A (Raytech Instruments; Vancouver, Canada) 0.2 s after the onset of tidal expiration. Flow-volume curves obtained without and with NEP were superimposed; patients in whom the expiratory flow with NEP did not exceed the reference flow in part or over the whole tidal expiration were considered flow limited. The degree of FL was assessed in terms of a 3-point FL score, (9) where 0 = no FL in both supine and seated positions, 1 = FL when in supine position but not seated; and 2 = FL in both supine and seated positions.
Before the spirometric study, the occurrence of orthopnea was assessed by asking each patient the following question: "Do you feel more breathless when you are lying supine than when you are seated?" (9) Based on the answer, the patients were classified in two groups: patients who reported orthopnea, and patients who did not report orthopnea.
Data are presented as means [+ or -] SD. Correlation coefficients of orthopnea with respiratory parameters were obtained with the Spearman ([rho]) nonparametric test. One-way analysis of variance was performed between the different groups of patients, and post hoc analysis with the Scheffe test applied if significant differences were found with analysis of variance. Differences between groups were analyzed with unpaired t test; changes from seated to supine positions were analyzed with paired t test. The 3-point FL score and 3-point goiter effect on the trachea were expressed as categorical variables. The statistical analysis was performed using statistical software (SPSS Statistical Package; SPSS; Chicago, IL).
Tables 1, 2 show the anthropometric, clinical, and baseline respiratory function data for all 32 patients and three subgroups stratified according to the 3-point goiter effect on the trachea. All subgroups included a few obese patients (BMI > 30). Static lung volumes, total lung capacity (TLC), functional residual capacity (FRC), residual volume (RV), as well as FVC were, on average, lower in group C than in groups A and B, though the difference was significant only in the case of ERV between group C and group B (p < 0.05). All dynamic lung function parameters (FE[V.sub.1], peak expiratory flow [PEF], maximal expiratory flow at 50% of FVC [ME[F.sub.50]], and maximal expiratory flow at 25% of FVC [ME[F.sub.25]]) were also, on average, lower in group C than in groups A and B, though the difference was significant only in the case of ME[F.sub.25] (p < 0.05). RawI, RawE, and total Raw were significantly greater (p < 0.01) in group C. Compared to groups A and B, the patients in group C exhibited a significantly lower ERV. While DLCO did not differ among the three groups, the 3-point FL score was significantly greater in group C than group A (p < 0.05). The prevalence of orthopnea was lowest in group A and highest in group C. There was a significant correlation of the 3-point goiter effect on trachea to the 3-point FL score (p = 0.51, p < 0.01) and Raw (p = 0.44, p < 0.05), but not with orthopnea.
Table 3 shows the anthropometric and baseline respiratory function data of the patients stratified according to the 3-point FL score. In patients without FL, the goiter location was in most instances extrathoracic (76%), while the opposite was true in the patients who had FL in both seated and supine positions (17%). The differences between groups in Table 3 were similar to those in Table 2. In this connection, it should be noted that most patients (67%) with an FL score of 2 belonged to group C. Apart from the 3-point goiter effect on trachea, there was also a significant correlation of the 3-point FL score to Raw ([rho] = 0.42, p < 0.02).
Figure 1, left, A, depicts the 3-point FL score of all 32 patients with goiter stratified according to presence or absence of orthopnea; the patients who reported orthopnea had significantly (p = 0.025) higher FL scores than those who did not. Since obesity promotes FL, (7,10) we also explored the relationship between the 3-point FL score and orthopnea by omitting the eight patients with goiter and BMI > ,30. As shown in Figure 1, right, B, the p value decreased (p = 0.056) but was still very close to significance. Among all respiratory variables studied (including the 3-point goiter effect on trachea), only the 3-point FL score correlated significantly with orthopnea.
[FIGURE 1 OMITTED]
The changes in lung function in shifting from seated to supine position in patients with or without orthopnea are shown in Table 4. Patients without orthopnea exhibited a significant decrease in ERV and increase of inspiratory capacity (IC); in subjects with orthopnea, only the decrease in ERV was significant. In both groups of patients, FVC did not change significantly with posture; in the orthopneic group, there was a small but significant decrease of FE[V.sub.1] in the supine position (p < 0.03).
The main finding of the present study is that tidal FL, as reflected by the 3-point FL score, is the strongest risk factor for reported orthopnea in patients with euthyroid goiter, and that this phenomenon is enhanced by concurrent obesity. Orthopnea probably results from increased inspiratory work in supine position due to increased inspiratory resistance, elastance of respiratory system (Ers) and, more importantly, intrinsic positive end-expiratory pressure caused by dynamic hyperinflation.
Goiter is known to promote upper airways obstruction, which should be characterized by a ratio of ME[F.sub.50] to maximal inspiratory flow at 50% of FVC (MI[F.sub.50]) of > 1. (17) In fact, our patients had an ME[F.sub.50]/MI[F.sub.50] ratio of approximately 1.2, independent of the degree of compression of the trachea (Table 2). This observation confirms that the correlation between radiologic indexes of upper airways obstruction and spirometric variables is poor. (1,6)
While FE[V.sub.1] and FVC were within normal limits in the three groups of patients classified according to the 3-point goiter effect on trachea, the values of PEF, ME[F.sub.50], and ME[F.sub.25] tended to be lower than normal, especially in group C. The static lung volumes were within normal limits except for ERV, which in group C was reduced.
On average, Raw was increased above the predicted normal by approximately 30% in group A and group B, and 145% in group C (Table 2). Ill almost all group C patients (88%), the goiter extended into the thorax, and the values of Raw, RawI, and RawE were significantly higher than in group A and group B (p < 0.01). The prevalence of orthopnea was also higher in group C (75%) than in group B (47%) or group A (18%).
The changes in Raw are consistent with the changes in PEF and MEF. Increased Raw, however, cannot per se explain orthopnea because the correlation between these two variables was not significant. Furthermore, the increased Raw in group C patients cannot explain the concurrent reduction in ERV. Together with upper airways obstruction, however, the latter must have contributed to the marked increase of Raw in group C because Raw increases with decreasing lung volume. (18)
Increased RawE should per se increase ERV because a high resistance impedes expiration and, as a result, inspiration may start before the respiratory system is allowed to reach the elastic equilibrium volume (relaxation volume [VR]) of the respiratory system. (7-10) This is contrary to the present findings. In fact, in our patients with FL score of 2, the ERV was well below the normal limits; also, in the patients with FL scores of 0 and 1, the average values of ERV were at the lower limits of normal (Table 3).
Extension of the goiter into the thorax can cause not only intrathoracic upper airways obstruction but also a decrease in ERV because of space competition between the goiter mass and the intrapulmonary gas. The latter should depend on goiter size, which can vary from 20 to 970 g, (6) and the static elastance of the lungs (EL) and elastance of chest wall (EW). According to Gautier et al, (19) the reduction of Vr can be computed as follows:
[DELTA]Vr = VG/(1 + EL/EW)
where [V.sub.G] is the intrathoracic volume of the goiter. Since in the sitting position the EL/EW ratio is normally equal to 1, (20) it follows that the reduction of Vr caused by a VG of 0.4 L should amount to 0.2 L. This mechanism probably explains in part the reduction of ERV observed in our patients with goiter, especially those with an FL score of 2. It should be noted that the latter patients were very small (Table 3) and hence their ERV should be normally small; as a result, the reduction in ERV caused by a given VG should be proportionately greater than in taller individuals. In addition to size, obesity also contributed to the decrease in ERV in our patients with goiter. In fact, in half of our patients with an FL score of 2 the BMI was > 30.
A reduction in ERV implies that tidal breathing takes place at low lung volume, with concurrent reduction in expiratory flow reserve since maximal expiratory flows decrease progressively with decreasing lung volume. (17) Breathing at low lung volumes is known to promote tidal FL. (7)
Tidal FL was present in 15 of our patients (47%) sitting and/or in supine position. The presence of FL implies that goiter does not cause only upper airways obstruction but also wave-speed expiratory FL in the peripheral airways during tidal breathing. (13) Since tidal FL promotes dynamic hyperinflation, it is likely that in our patients with FL scores of 2 the end-expiratory lung volume was above Vr both sitting and in supine position, while in patients with scores of 1 this should occur only in supine position. (9) Thus in goiter patients, similar to obesity, (10) there are two conflicting mechanisms that govern end-expiratory lung volume: the intrathoracic goiter mass, which tends to decrease end-expiratory lung volume, and FL, which tends to increase it.
In shifting from sitting to supine position, there is normally little or no change in vital capacity, while the ERV is substantially reduced with a concurrent increase of IC. (20) The latter is caused by a reduction of Vr due to gravitational factors. (20) In our patients, the FVC also did not change with posture and the ERV decreased, but only patients without orthopnea exhibited a significant increase of IC in supine position (p < 0.005; Table 4). In patients with FL, the postural reduction of ERV due to gravity (reduced Vr) is partly compensated by FL-induced dynamic hyperinflation. In fact, in patients with severe COPD who presumably had FL seated and/or in supine position, there is in usually little change in FRC when shifting from sitting to supine position. (21,22)
As a result of dynamic hyperinflation and increased work due to intrinsic positive end-expiratory pressure, in all patients with FL the inspiratory work of breathing (WI) should be higher in supine position than when sitting. (7,10) There are, however, additional factors that should increase WI in supine position, namely increased upper airway resistance, (23,24) lower airway resistance, (18) and Ers. (20) Since the postural changes in lower airway resistance and Ers are volume dependent, they should play a more important role in patients with orthopnea in whom the ERV in supine position was lower than in patients without orthopnea (Table 4). In this connection, it should also be noted that in patients with intrathoracic goiter, the gravitational increase of EW in the supine position causes a further decrease of Vr. In fact, according to equation 1, an increase of EW implies a decrease in EL/EW ratio and hence a greater reduction of Vr for a given VG. As a result, similar to obesity, (7) the Vr in some patients with goiter may be located below the residual volume. This involves a further increase of work due to intrinsic positive end-expiratory pressure in supine position, promoting orthopnea. (7) In patients with orthopnea, there was a small though significant (p < 0.03) decrease in FE[V.sub.1] in supine position (Table 4), probably reflecting an increase of upper airway resistance in this position.
In normal subjects, WI is higher when in supine position than when sitting because of Ers and resistance of respiratory system, (18,20,25) but there is no orthopnea. This implies that in order to report orthopnea, the increase in WI in supine position must be substantial. However, orthopnea is commonly present in patients with COPD, (9) chronic heart failure, (8) and gross obesity (7,10); in all instances, its main determinant is tidal FL. In the present investigation, there was also a significant correlation between orthopnea and the 3-point FL score. Although tidal FL was the main risk factor for orthopnea in our patients with goiter, other factors must have contributed to increased WI in the supine position, namely increased EW (20) and increased Raw. (18) Indeed, three patients (two were not obese) who claimed orthopnea did not have FL (Fig 1, left, A). All three subjects, however, had markedly increased Raw (> 2.3 cm [H.sub.2]O/L/s). Thus, other factors besides dynamic hyperinflation and intrinsic positive end-expiratory pressure may cause or worsen dyspnea in recumbency in patients with goiter.
It is unlikely that upper airway obstruction played an important role in the genesis of orthopnea in our patients. In fact, the ME[F.sub.50]/MI[F.sub.50] ratio did not correlate significantly with orthopnea and, if any, the impairment of maximal expiratory flows (PEF, FE[V.sub.1], ME[F.sub.50], and ME[F.sub.25]) was mild. However, upper airway obstruction may play a role in limiting exercise performance, though this has yet not been studied in patients with goiter.
Our patients with goiter included eight subjects with BMI > 30 (range, 32 to 42). Since obesity per se promotes FL and orthopnea, (7,10) this aspect has to be discussed in relation to our patients. In 46 massively obese subjects (BMI > 40), there was a high prevalence of orthopnea (44% of subjects) and FL (59% of patients with FL in supine position and 22% both seated and in supine position). (7) In another study, tidal FL in supine position was also observed in eight massively obese subjects (10); however, only one of our patients was massively obese (BMI of 42). Therefore, it is unlikely that obesity per se was the cause of FL and orthopnea in most of our obese patients with goiter. A more likely hypothesis is that obesity and the intrathoracic goiter mass both contributed to reducing ERV, leading to FL and orthopnea.
Tidal FL has been shown to be an important risk factor for orthopnea in patients with COPD, (9) chronic heart failure, (8) and massive obesity. (7,10) The present results indicate that the same mechanism plays a dominant role in the genesis of orthopnea in patients with euthyroid goiters; therefore, goiters can cause not only upper airway obstruction, as previously thought, but also FL in the lower airways due to the reduction in end-expiratory lung volume caused by the intrathoracic goiter mass.
An increase in the ME[F.sub.50]/MI[F.sub.50] ratio was found in most of our goiter patients. This index of upper airway obstruction, however, was independent of the radiologic assessment of goiter location and degree of tracheal compression, and did not correlate significantly with the degree of orthopnea.
In conclusion, our results indicate the following: (1) in patients with euthyroid goiter, there is a high prevalence of orthopnea, especially when the goiter is intrathoracic and promotes tidal FL; (2) tidal FL is due to impingement of the goiter mass into the thorax, resulting in decreased ERV and expiratory flow reserve and increased Raw; (3) obesity enhances FL and orthopnea in patients with goiter; and (4) upper airway obstruction in patients with goiter appears to be relatively mild since the maximal flows are relatively well preserved.
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* From Fisiopatologia Respiratoria (Drs. Torchio Gulotta Perboni, Guglielmo, and Ciacco), Ospedale San Luigi Gonzaga, Orbassano, Turin, Italy; Dipartimento di Scienze Cliniche e Biologiche (Dr. Orlandi), Universita di Torino, Orbassano, Turin, Italy; and Meakins-Christies Laboratories (Dr. Milic-Emili), McGill University, Montreal, PQ, Canada.
Manuscript received June 11, 2002; revision accepted December 9, 2002.
Correspondence to: Roberto Torchio, MD, Fisiopatologia Respiratoria, Ospedale S. Luigi Gonzaga, I-10043 Orbassano, Torino, Italy; e-mail: email@example.com
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