David H. Ingbar
The respiratory system and the thyroid gland are interrelated in several major ways. First, the thyroid is in proximity to the trachea. Second, both systems are functionally linked to cellular oxidative metabolism, and each contributes to determining the steady-state levels of carbon dioxide and tissue oxygen. Third, thyroid hormones probably play an important role in the development of the lung. This chapter briefly summarizes current knowledge about the biochemical interactions of thyroid hormones with the lungs and considers the ways in which the respiratory system is affected in thyrotoxicosis. Other conditions in which abnormalities of both the thyroid gland and the respiratory system coexist are reviewed.
BIOCHEMISTRY OF THYROID HORMONES IN THE LUNG
Relatively little is known about the mechanisms of thyroid hormone action in the lung. Thyroxine (T4) and triiodothyronine (T3) are small molecules that should be accessible to the lung in proportion to their free serum concentrations. The intracellular compartment of the rat lung has a high concentration of T3relative to T4 (lung:plasma ratios of 2.6 and 0.04, respectively) (1,2). The liver and kidney have similar intracellular concentrations of T3, but they contain relatively more T4 (ratios of 0.5). Replacement therapy with T3 or T4 in hypothyroid rats results in lung tissue T3 levels that are low relative to plasma T3 or T4levels (3).
The relatively high T3:T4 ratio in the lung could result from rapid conversion of T4 to T3 in rat lung tissue. However, while there is agreement that there is less type I 5′-deiodination of iodothyronine in rat lung than in liver or kidney, whether this activity is high or low is debatable (3,4,5). Lung deiodinase activity increased postnatally and was not increased further by corticosterone (5).
Alternatively, the lung could contain a large number of high-affinity binding sites for T3. High-affinity nuclear receptors for T3 are present in nuclei from mixtures of lung cells (5,6,7) and from L-2 and A-549 cell lines (8), which supposedly derive from rat and human type II alveolar pneumocytes, respectively. The characteristics of the lung nuclear T3 receptors are similar to those in many other organ systems. Gonzales and Ballard (6,7) demonstrated T3 receptors in the lungs of human fetuses and fetal and adult rabbits, with increasing amounts during gestation. Using alveolar epithelial cell lines, organ culture systems, and in vivo autoradiography, T3 bound to the alveolar type II cell nuclei more than to the perinuclear or lamellar body regions, whereas little T4 was bound (8,9,10,11). Whether other lung cell types also express high-affinity T3-binding sites is not certain.
FUNCTIONAL EFFECTS OF THYROID HORMONES ON THE LUNG
The localization of nuclear T3 binding in type II alveolar epithelial cells agrees with other evidence discussed in Chapter 54, suggesting that thyroid hormones play a role in type II cell development and in surfactant synthesis in the fetus. Adult rats made thyrotoxic with exogenous T4 show increased size of their type II cells, greater diameter and number of lamellar bodies, and increased surfactant secretion; phospholipid composition is normal (12). Similar changes occur in fetal rats within 2 days after the intraamniotic injection of high doses of T4 at day 18 of gestation. This effect is promoted by hydrocortisone and is partially blocked by metyrapone (13). Rats made hypothyroid from day 18 of gestation display decreases in lung weight; protein synthesis; and lung content of DNA, protein, and β-adrenergic receptors (14). Thyrotropin-releasing hormone (TRH) can promote lung maturation (15). Mice homozygous for a mutation of the thyrotropin receptor have delayed fetal lung maturation (16). Maternal TRH administration markedly stimulated mouse fetal lung maturation (17), but this effect did not require the TSH receptor (18). Intraamniotic T3 injection improved neonatal pulmonary function in preterm lambs, with better oxygenation and lung mechanics (19). Thus, in almost all experimental studies, thyroid hormones promote maturation of lung structure and of the surfactant system. The mechanisms of these effects are uncertain and probably are complex. For example, T3 depresses the levels of insulin-like growth factor I receptor1, an important regulator of lung growth (20). There likely is synergism between T3 and glucocorticoids in promoting lung development (21,22). Similarly, synergies between thyroid hormone and the β-adrenergic system during development may indirectly influence lung development, including effects on the number of β-adrenergic receptors (23,24). In contrast, data are scant on the functional role of T3 in the adult lung, but two recent studies demonstrate a potential role for T3 in clearance of alveolar edema fluid. Systemic T3 treatment of rats for 2 days doubled the rate of alveolar fluid clearance (25), and T3 at either physiologic or pharmacologic doses stimulated alveolar epithelial cell Na+,K+-ATPase, a key enzyme required for solute and fluid resorption (26).
Several transcription factors are important for the development of both the lung and the thyroid gland. Thyroid transcription factor-1 (TTF-1) (also known as Nkx2.1) is a homeobox gene selectively expressed in these organs during early development. It activates the expression of tissue-specific genes and is essential for morphogenesis (27,28,29,30). In the thyroid, TTF-1 is a positive regulator of thyroglobulin and thyroperoxidase gene transcription. In the developing rat lung, TTF-1 is expressed early in the lung bud and airway epithelium; later, it is expressed in type II cells. Transcription of lung epithelium-specific genes (surfactant apoproteins A, B, and C and Clara cell secretory protein) and other early transcription factors (hepatic nuclear factor 3) is increased by TTF-1 (31). Although TTF-1 is normally present in type II cells perinatally, it is largely absent in the infant respiratory distress syndrome and bronchopulmonary dysplasia (32). Mice with genetic deficiency of TTF-1 have dysmorphic rudiments of thyroid and lung (33). A newborn infant with thyroid dysfunction and respiratory failure associated with heterozygous deletion of the TTF-1 gene has been described (34). The localization of TTF-1 and normal lung development are altered by ectopic expression of the Tbx4 gene, a T-box transcription factor that may act through fibroblast growth factor-10 (35).
The importance of active ion transport in resorption of alveolar fluid from the lung has received considerable recent attention (36), and it occurs through coordinated action of alveolar epithelial sodium channels and sodium pump. Rats treated with T3 for two days had major increases in alveolar fluid resorption, and the increase was not blocked by propranolol (25). Since T3 stimulates Na+,K+-ATPase activity in many cell types, the impact of T3 on alveolar type II cell Na,K-ATPase recently was determined. T3 rapidly increased Na,K-ATPase activity through a nontranscriptional pathway involving translocation of sodium pump protein to the plasma membrane (26). These data suggest that thyroid status may help determine alveolar fluid clearance and raise the possibility of a therapeutic role for thyroid hormone in the lung.
In summary, thyroid hormones promote maturation of the lung and of the type II pneumocyte-surfactant system and, in adult lung, likely stimulate the alveolar fluid clearance system. There is little information as to whether other aspects of lung structure or function are altered in thyrotoxicosis, but other effects are likely. For example, exogenous T3 decreases secretion of glycosaminoglycans by cultured human skin fibroblasts (37); thyroid hormones might influence the nature of the extracellular matrix in the lung through changes in glycosaminoglycans, proteoglycans, elastin, and collagen.
THE LUNGS IN THYROTOXICOSIS
Dyspnea on exertion is a common complaint in thyrotoxic patients, but its cause remains unclear and probably varies from one patient to another. Proposed explanations include respiratory muscle weakness, high-output left heart failure causing an engorged pulmonary capillary bed, increased ventilatory drive to breathe, increased airway resistance, diminished lung compliance, and tracheal compression by an enlarged thyroid gland.
Despite the high incidence of Graves' disease, there are no large, detailed studies of the effects of thyrotoxicosis on the lung. The results of the available small studies frequently conflict with one another and confuse the overall picture. Table 32.1 summarizes the spectrum of respiratory changes that occur in thyrotoxicosis.
TABLE 32.1. RESPIRATORY CHANGES IN THYROTOXICOSIS
Increased oxygen consumption
Increased carbon dioxide production
Increased minute ventilation
Decreased vital capacity
Decreased diffusing capacity for carbon monoxide
Decreased lung compliance
Respiratory muscle weakness
Increased ventilatory response to hypercapnia
Increased ventilatory response to hypoxia
High-output congestive left ventricular failure
Pulmonary artery dilation and hypertension
The increased metabolic rate stresses the lungs, necessitating a higher rate of gas exchange to accommodate the increased oxygen consumption and carbon dioxide production. Although normal persons can accomplish this easily, a patient who has thyrotoxicosis and an underlying lung disease may not be able to meet the demand for increased gas exchange.
LUNG VOLUMES AND FLOW RATES
Early in the twentieth century Peabody and Wentworth (38) were interested in thyrotoxicosis as a cause of dyspnea; two of their seven patients with thyrotoxicosis had decreased vital capacity (VC). Using only clinical signs and symptoms as markers of congestive heart failure (CHF), however, Lemon and Moersch (39) found that a decreased VC correlated only with “cardiac decompensation” and not with either the basal metabolic rate (BMR) or the severity of the thyrotoxic symptoms. Other early studies found an inverse correlation between the VC and the BMR (40). Despite several studies of the lung volumes in the subsequent 80 years, little more is known.
Because pulmonary function testing included analysis of the subdivisions of lung volume, one older study noted that one quarter of patients had decreased residual volume (RV), VC, and total lung capacity (TLC), with normal arterial blood gas (ABG) results and diffusing capacity for carbon monoxide (41). In 12 patients and 12 normal subjects, no differences were found in the mean baseline VC, TLC, RV, static compliance, or pressure-volume curves; but after treatment, the VC and TLC increased significantly in eight patients. Airway resistance and flow rates were normal in all studies (42). Studies of the subdivisions of lung volumes present a confusing picture (42,43,44,45,46,47), with frequent decreases of VC that increases in response to treatment, but inconsistent changes in the other lung volumes. These heterogeneous findings may reflect the presence of other underlying lung diseases in some patients; a more likely alternative is that thyrotoxicosis causes several types of changes in the lungs, all of which do not occur in the same patient. For example, respiratory muscle weakness resulting from chronic thyrotoxic myopathy probably occurs only in some patients.
ABG partial pressures and the oxygen and carbon dioxide–hemoglobin dissociation curves usually are normal (43). Mixed venous oxygen saturation typically increases because the elevation in cardiac output is greater than the increased oxygen consumption. Although the total amount of oxygen extracted by the peripheral tissues is increased, the efficiency of oxygen extraction is decreased. Diffusing capacity of the lung for carbon dioxide (DLCO) at rest may be normal (42,43,47) or low (48), but usually it is lower than expected for the high cardiac output. With exercise, the DLCO usually increases, but to a lesser extent than normal—or it may even decline. The reason for this decreased efficiency of gas exchange with exercise is not clear, but there may be disturbances in the alveolar capillary wall or in the recruitment of reserve capillaries.
LUNG COMPLIANCE AND RESPIRATORY MUSCLE WEAKNESS
Airway resistance, lung compliance, and respiratory muscle function determine the volumes of gas moved into or out of the lung. Airway resistance is normal in thyrotoxic patients. Some patients presumably have chronic thyrotoxic myopathy that involves the diaphragm, but simultaneous changes in intrinsic lung compliance also may occur. Lung compliance could be altered by changes in the elastic properties (connective tissue) or by vascular engorgement. Compliance usually is determined from the static pressure–volume curve of the lung, with measurement of intrathoracic pressure using an esophageal balloon manometer. The maximal inspiratory pressure (Pimax) at RV, maximal expiratory pressure (Pemax) at TLC, maximal transdiaphragmatic pressure, and maximal voluntary minute ventilation (MVV) yield information about maximal respiratory muscle power. Even with these techniques, it is difficult to separate patients with pure respiratory muscle weakness from patients who have only decreased lung compliance. For example, almost all of 13 thyrotoxic patients had decreased lung compliance and decreased Pimax and Pemax, and in all of them, these parameters improved significantly after therapy (41). These findings have been confirmed in some studies (46), but not in others (47). Most patients whose lung compliance improved with treatment also had increases in VC, but TLC did not increase as expected if muscle function had improved.
Most thyrotoxic patients who complain of exertional dyspnea have diminished proximal muscle strength (48). In half the patients with proximal muscle weakness, Pimax improved significantly after 6 weeks of therapy. The mean values of Pimax and Pemax were decreased in many thyrotoxic patients (42,43,45,47,49,50). Static lung compliance and elastic recoil were normal and did not improve with treatment. In the only study that directly measured transdiaphragmatic pressures of thyrotoxic patients with proximal muscle weakness and decreased Pimax and Pemax, transdiaphragmatic pressure was decreased in only one of the four patients, but all four patients had significantly increased transdiaphragmatic pressure after treatment that correlated with improvements in Pimax, Pemax, VC, and proximal muscle strength (49). In another study, the Pimax and Pemax were decreased in 5 and 8 of 14 patients, respectively (44). Significant increases in both values after correction of the thyrotoxicosis were typical. Structural and functional changes in the costal and crural parts of the diaphragm occurred in thyrotoxic dogs, evidenced by decreased transdiaphragmatic pressures and twitch shortening accompanied by vacuolization and loss of diaphragm muscle fibers (51).
The biochemical basis of these changes in respiratory muscle function is not understood. The thyrotoxic rat diaphragm has depressed glycolytic, tricarboxylic acid cycle, and fatty acid oxidative activity (50). The change in lung compliance could be due to altered lung extracellular matrix, but vascular engorgement is an unlikely cause because the DLCO is not increased as in other high cardiac output or capillary engorgement conditions, such as asthma or mild CHF.
In summary, chronic thyrotoxic myopathy affects the diaphragm and other respiratory muscles in up to half of thyrotoxic patients, causing loss of maximal respiratory muscle power. Involvement of the diaphragm must be inferred from physiologic tests because of the lack of specific pathologic or electromyographic hallmarks of chronic thyrotoxic myopathy. Easy fatigue also may cause exertional dyspnea. Whether chronic thyrotoxic myopathy of the diaphragm also predisposes to fatigue is unknown, and a shift in the high-low-power spectrum of the diaphragmatic electromyogram should be examined in future studies. Rarely, myasthenia gravis associated with thyrotoxicosis causes respiratory muscle weakness and easy fatigue.
The increased oxygen consumption and carbon dioxide production of thyrotoxicosis lead to a homeostatic increase in minute ventilation. Thyrotoxicosis may affect the central regulatory response to a blood gas perturbation. Ventilatory response or drive is measured as the increase of minute ventilation, transdiaphragmatic pressure (Pdi), or mouth occlusion pressure (P0.1) while breathing either hyperoxic hypercapnic (HCVR) or hypoxic isocapnic (HVR) gas mixtures (52). The Pdi and P0.1 more directly reflect neural output and are not as confounded by the presence of other lung disease.
Using a carbon dioxide rebreathing method of assessing HCVR, two studies of a total of 27 patients showed increased responses to carbon dioxide (53,54) (Fig. 32.1), although this was not true in another study (52). The effect of thyrotoxicosis on the HCVR was not mediated by catecholamines, since it was unaffected by propranolol (54) (Fig. 32.2). Hypoxic ventilatory response normally increases with exercise and fever in proportion to the elevation of the metabolism (55). Zwillich and co-workers found a significant increase of the HVR in 13 thyrotoxic patients, correlated with the increase in BMR (54) (Figs. 32.1 and 32.2) and unaffected by propranolol. A study using P0.1 as the output confirmed the increases in HVR and HCVR in 15 hyperthyroid patients (56).
FIGURE 32.1. Mean ventilatory responses (dotted lines) to hypoxia (A) and hypercapnia (B) of 13 thyrotoxic patients are contrasted to the mean responses of 44 normal persons (solid lines). Both the hypoxic and the hypercapnic responses are significantly greater in the thyrotoxic group. (From Zwillich CW, Matthay M, Potts DE, et al. Thyrotoxicosis: comparison of the effects of thyroid ablation and beta adrenergic blockage on metabolic rate and ventilatory control. J Clin Endocrinol Metab 1978;46:495, with permission.)
FIGURE 32.2. Effects of treatment with iodine-131 (A) and propranolol (B) on the mean ventilatory response to hypercapnia of 13 patients with thyrotoxicosis. Pretreatment responses (solid lines) and posttreatment responses (dotted lines) to hypercapnia. Radioactive iodine, but not propranolol, significantly diminished the hypercapnic ventilatory response. (From Zwillich CW, Matthay M, Potts DE, et al. Thyrotoxicosis: comparision of effects of thyroid ablation and beta adrenergic blockage on metabolic rate and ventilatory control. J Clin Endocrinol Metab 1978;46: 496, with permission.)
In summary, both the HCVR and the HVR are increased in most thyrotoxic patients, likely contributing to dyspnea. This effect is independent of the β-adrenergic effects of catecholamines. It is not clear whether thyroid hormones affect the peripheral chemoreceptors or the medullary respiratory center. When superimposed on underlying lung disease, thyrotoxicosis can worsen dyspnea and might cause frank respiratory failure.
Thyrotoxicosis typically increases the resting heart rate, cardiac output, respiratory rate, and minute ventilation (57). The normal increases in these variables during exercise are magnified in thyrotoxic patients (41,43,45,47,58). The amount of oxygen consumed to perform any workload is increased. Although the rate of the increase in oxygen consumption with increasing work is normal (59) (Fig. 32.3), both the minute ventilation and the cardiac output for a given level of oxygen consumption are elevated at all levels of oxygen consumption (Fig. 32.4). The efficiency of oxygen extraction and utilization are decreased (60). The minute ventilation and P0.1 may be elevated disproportionately for the carbon dioxide production rate (42), possibly because of a rapid, shallow breathing pattern with more wasted dead space ventilation (61) and consistent with a more than compensatory increase in ventilatory drive. Ventilatory drive, expressed as the ratio of P0.1 to PaCO2, increased proportionally with the T3 level, and β-blockade decreased the ventilatory drive in the individuals with the highest T3 levels. In one study, the anaerobic threshold was lower than predicted, but it was not clear whether this was due to poorer oxygen extraction by the peripheral tissues, greater lactate production, or both.
FIGURE 32.3. Oxygen consumption of 19 thyrotoxic patients at increasing workloads of bicycle exercise is shown. Most of the men (left panel) and women (right panel) had increased oxygen consumption at all workloads; the slope of the increase, however, was the same in the thyrotoxic patients as in the normal subjects. (From Massey DG, Becklake MR, McKenzie JM, et al. Circulatory and ventilatory response to exercise in thyrotoxicosis. N Engl J Med 1967; 276:1107, with permission.)
FIGURE 32.4. Cardiac output and minute ventilation responses to increasing oxygen consumption during exercise for patients with thyrotoxicosis. These are contrasted with the normal responses (heavy lines). The 95% confidence interval for the normal response is shown by the broken lines. (Data for cardiac output response are from Bishop JM, Donald KW, Wade OL. Circulatory dynamics at rest and on exercise in the hyperkinetic states. Clin Sci1956;14:329; data for the minute ventilation response are from Bishop et al. and Stein M, Kimbel P, Johnson RL. Pulmonary function in hyperthyroidism. J Clin Invest 1961; 40348.) Both the cardiac output and the minute ventilation are higher than normal at all levels of oxygen consumption. (From data synthesized and plotted by Massey DG, Becklake MR, McKenzie J, Bates DV. Circulatory and ventilatory response to exercise in thyrotoxicosis. N Engl J Med 1967;276:1106.)
Thyrotoxic patients may be limited predominantly by their cardiac (62,63) or pulmonary systems. None of 15 patients achieved 80% of their predicted maximal oxygen uptake, and only 7 patients exceeded 80% of their predicted maximal heart rates (42). Because both organ systems are affected, cardiac limitation probably predominates in the absence of other lung disease or severe respiratory muscle weakness (63). With treatment, the maximal work performed usually increased significantly; surprisingly, however, the subjective sense of dyspnea and maximal oxygen uptake achieved during exercise testing did not improve in two studies (42,47), even with increases in maximal respiratory muscle pressures.
Pulmonary artery pressures of thyrotoxic patients may increase more than usual with exercise (58), but how often this occurs is uncertain. Exercise normally decreases the mixed venous oxygen saturation and the dead space:tidal volume ratio (61) the converse occurs in thyrotoxicosis (40). The DLCO of some patients decreases with exercise, especially at higher workloads (48). The elevated cardiac output may shorten capillary transit times and prevent complete gas equilibration. However, oxygen desaturation with exercise has not been reported. The normal respiratory exchange ratio suggests that oxidative phosphorylation is not uncoupled.
EFFECTS OF CARDIAC CHANGES ON THE LUNGS
The lungs may be affected by the cardiac consequences of thyrotoxicosis in two ways (see Chapter 31): high-output cardiac failure or pulmonary artery dilatation, possibly accompanied by pulmonary hypertension. The pulmonary capillary wedge pressure has been normal in most patients studied to date.
The pulmonary artery may appear dilated on plain chest radiography. Physical findings of an accentuated pulmonic second heart sound and a right ventricular heave suggest pulmonary hypertension. Elevation of resting pulmonary artery pressure are common with thyrotoxicosis, and the pressure frequently increases significantly during exercise (58). Most patients reported have had mild pulmonary hypertension, but the elevation may be moderate (64). Resting right ventricular stroke work often is elevated because an increased volume of blood is pumped against a somewhat increased pulmonary vascular resistance. The incidence of severe pulmonary hypertension attributable solely to thyrotoxicosis is not clear. Means-Lerman sign, a scratchy, coarse systolic ejection rub or murmur that is heard best along the left sternal border at the base of the heart, has been attributed either to rubbing of the dilated aorta or pulmonary artery against some other mediastinal structure or to turbulent pulmonary artery blood flow.
OTHER INTERACTIONS OF THE RESPIRATORY SYSTEM AND THYROID GLAND
Systemic processes may affect both the thyroid gland and the respiratory system. Alternatively, abnormalities of one system may affect the actual or apparent function of the other. Table 32.2 outlines these situations.
TABLE 32.2. OTHER INTERACTIONS OF THE RESPIRATORY SYSTEM AND THYROID GLAND
Pulmonary disorders that influence the thyroid
Hypercalcitonemia due to bronchogenic carcinoma
Lung cancer metastatic to the thyroid
Primary pulmonary hypertension
Thyroid disorders that influence the respiratory system
Thyroid carcinoma with lung metastases
Compression of trachea or superior vena cava due to enlarged thyroid
Chronic cough due to thyroiditis
? Increased airway reactivity in asthma
Increased serum angiotensin-converting enzyme in hyperthyroidism
Propylthiouracil-induced pleuritis or pneumonitis
Systemic conditions that affect both the lung and the thyroid
Acute respiratory distress after surgery or molar pregnancy
Associated autoimmune disorders: systemic lupus erythematosus, Sjögren's syndrome, myasthenia gravis
Infections: Pneumocystis carinii or Aspergillus
Langerhans' cell histiocytosis
PULMONARY DISORDERS THAT INFLUENCE THE THYROID
Pulmonary diseases, such as chronic obstructive pulmonary disease (COPD), tuberculosis, and lung cancer, or critical illness can cause several patterns of change in thyroid function tests (see section on nonthyroidal illness in Chapter 11). In one study of patients in the intensive care unit, the degree of suppression of serum TSH responses to TRH correlated with outcome (65). In rats with sepsis, T3 levels decreased markedly over 20 to 30 hours (66). Treatment with exogenous T3 increased their ventilatory drive and lung mechanics, but it did not affect mortality or gas exchange. A controversial, untested suggestion is that TRH be used to treat endocrine disorders associated with critical illness (67).
Medullary carcinoma of the thyroid (MCT) can cause high elevated basal serum levels of calcitonin that increase markedly after pentagastrin administration. Hypercalcitonemia may occur in all pathologic types of bronchogenic carcinoma (68), but it occurs most commonly in small cell carcinoma. Some bronchogenic-carcinoma patients with normal basal calcitonin levels have a supranormal response to pentagastrin stimulation, but to a lesser degree than in MCT. The calcitonin can be produced ectopically by the tumor itself, or it may come from the thyroid gland owing to the presence of a factor secreted by the tumor.
Lung cancer can metastasize to the thyroid gland. Over 25 years at the Mayo Clinic, 5 of 30 cases of metastatic thyroid involvement were from a primary lung cancer (69). Typically, patients presented with a painful, tender thyroid mass, and a lung lesion was found either concurrently or later. Fine-needle aspiration biopsy of the thyroid has demonstrated small cell and squamous cell carcinomas metastatic from the lung (70).
Primary pulmonary hypertension seems to be associated with an increased frequency of thyrotoxicosis (71). This association does not seem to be due to drug therapy with prostacyclin. In some patients treatment of their hyperthyroidism has improved their pulmonary hypertension.
THYROID DISORDERS THAT INFLUENCE THE RESPIRATORY SYSTEM
Thyroid Cancer Metastatic to the Lung
Thyroid diseases other than thyrotoxicosis can affect the respiratory system. Thyroid cancer metastasizes to the lungs in 5% to 20% of cases (72,73), most commonly papillary carcinoma. In patients who die of thyroid cancer, more than 50% have lung metastases (74). The pulmonary metastases usually are asymptomatic, but they may cause dyspnea on exertion. Rarely, these patients present with hemoptysis from airway involvement, Pancoast's syndrome, or polycythemia from hypoxemia attributed to small arteriovenous shunts in the tumor. The chest radiograph may be normal or reveal diffuse miliary opacities that may have stippled calcification because of aggregation of psammoma bodies in the tumor. Less commonly, a smaller number of large nodules are present bilaterally on the chest radiograph. Airway involvement with thyroid carcinoma may be visualized with bronchoscopy, but biopsy usually is needed for diagnosis (75). Bronchial lavage and cytologic examination of the fluid may also reveal metastatic thyroid cancer (75a).
Pulmonary metastases most commonly occur in younger patients and usually present within 1 to 2 years of diagnosis rather than as a late complication. The metastases may or may not take up iodine, but rarely synthesize thyroid hormone (76). Patients with functioning metastases have a better prognosis than nonfunctioning metastases, especially if the chest radiograph is normal. Radioiodine scans are most likely to reveal pulmonary involvement after surgical removal of the primary tumor and thyroid gland. In some series, half the patients with lung metastases had normal chest radiographic films and diffuse uptake on radioiodine scans (76). Rarely, primary lung tumors, such as adenocarcinoma, or other conditions, such as bronchiectasis, concentrate iodine and are confused with metastatic thyroid cancer. Indium 111-DTPA scanning has moderate sensitivity for detecting thyroid cancer metastases and may be positive even when conventional imaging is normal (77).
The presence of pulmonary metastases does not necessarily mean a poor clinical course. Even without treatment, densities in the chest radiograph may persist without progression for many years (78). Many reports suggest that functional lung metastases disappear in half the patients treated with 131I, but other reports showed lesser responses (79,80). A sudden increase in pulmonary involvement after a long period of stability suggests that the tumor may have undergone an anaplastic change. Documentation by biopsy and more aggressive treatment may be necessary.
Thyroid cancer in the neck or mediastinum can obstruct the trachea by compression or displacement, or it can erode into the trachea or esophagus, causing luminal obstruction or bleeding. Rarely, thyroid carcinomas originate in ectopic thyroid tissue located in the trachea (81). Thyroid carcinoma involves the upper airway in 1% to 6% of cases and causes hemoptysis and vocal cord paralysis more often than does benign thyroid disease (82). Airway invasion may be more common in older men. Lymphoma, in particular, infiltrates the tracheal wall, obstructing the lymphatics and causing laryngeal and subglottic edema. Compression or infiltration of the tracheal wall is more common than intraluminal tumor growth. Only 18 of 2,000 cases of thyroid carcinoma seen at the Mayo Clinic had intraluminal growth of tumor (83). Rarely, thyroid carcinoma develops in substernal or intrathoracic goiters, causing rapid enlargement and compressive symptoms.
Surgical treatment of thyroid carcinoma with laryngotracheal involvement may be complex (84,85,86,87,88,89). The tumor tends to grow along the trachea rather than causing early luminal obstruction. Resection often requires airway reconstruction, such as sleeve tracheal resection, tracheal and cricoid cartilage resection, or more complex procedures. Of 34 patients at Massachusetts General Hospital undergoing resection, three died postoperatively, but only two patients had airway recurrence (86). Patients who cannot be completely resected have a high mortality rate, whereas patients with total resection and external beam irradiation often do well (87). The 5-year prognosis for patients who undergo surgery may be significantly lower only if the tumor involved or expanded the tracheal mucosa as a nodule or ulcerated mass (90). Shave excision of thyroid carcinoma is dangerous because of the high likelihood of recurrence. Massive invasion prohibiting reconstruction, innominate artery invasion, and deep invasion into the mediastinum are considered major contraindications to resection.
Nonmalignant Upper Airway Compression
Enlargement of the thyroid resulting from a variety of nonmalignant conditions, most commonly multinodular goiter, can compress or displace the surrounding structures (Fig. 32.5). Intrathoracic goiters have an incidence of 1 in 5,000 persons and up to 1 in 2,000 in women over age 45 years (91). The vast majority arise in the cervical thyroid and retain an anatomic connection to it and a similar blood supply. Of 144 patients with goiter, airway obstruction on flow volume loops occurred in 31% and was especially common in men (92).
FIGURE 32.5. Posteroanterior (A) and lateral (B) chest radiographs showing a large substernal goiter, which is causing compression and anterolateral displacement of the trachea toward the left chest.
The consequences of thyroid enlargement depend on the location of the enlarged thyroid tissue. In the neck, it can obstruct the trachea or esophagus or compress the superior vena cava or the recurrent laryngeal or cervical sympathetic nerves, resulting in exertional dyspnea, dysphagia, hoarseness, dysphonia, wheezing, stridor, or cough that may be positional (93). Bilateral vocal cord paralysis also can cause respiratory distress and stridor, which may be mistaken for asthma (94), but this occurs much more commonly in malignant thyroid disease. About 15% to 20% of patients are asymptomatic. Sudden onset of stridor occurs in 2% to 3% of these patients, usually because of spontaneous or traumatic hemorrhage within a multinodular goiter. Stridor also may occur immediately after extubation. In some cases, including subacute thyroiditis, it may be difficult to recognize that a thyroid abnormality is causing chronic cough because of a lack of marked thyroid enlargement (95). A markedly enlarged substernal or mediastinal thyroid is one of the rare benign causes of superior vena cava syndrome (96). In toxic multinodular goiter, propylthiouracil (PTU) may increase the size of the goiter and precipitate or worsen superior vena cava obstruction (97). Unilateral or bilateral Horner's sign also may occur with a large intrathoracic goiter that disrupts the cervical sympathetic nerves.
If the thyroid enlargement is at the level of the narrow thoracic inlet, compression of the trachea or esophagus is particularly likely, even with relatively small goiters. Elevating the arms or flexing the neck may raise the retroclavicular goiter into the inlet and aggravate the compression, which has been termed the “thyroid cork” (98). Thoracic inlet compression results in decreased venous return, increased jugular venous pressure, facial plethora, dysphonia, hoarseness, dizziness, and shortness of breath. Precipitation of these findings by raising the arms is defined as Pemberton's sign (99). In contrast to the superior vena cava syndrome, there is no venous dilatation over the chest wall because the obstruction is not central.
Tracheal obstruction can have severe consequences, such as difficulty with intubation or rapid airway obstruction after extubation. Stridor and recognizable upper airway obstruction occur only with loss of 75% or more of the trachea's cross-sectional area. Tracheomalacia may result from long-standing pressure on the trachea and may worsen after surgical tracheotomy. A sudden increase in the size of the thyroid mass, as with hemorrhage, can acutely obstruct the trachea, causing respiratory arrest (100).
Forty-three of 269 patients (16%) with enlarged thyroid glands had symptoms of obstruction to breathing or swallowing (101). Of the 5% of these patients with exertional dyspnea, most had tracheal deviation and hoarseness, but the degree of tracheal displacement was independent of the degree of compression (102). Intraluminal involvement, vocal cord paralysis, or hemoptysis did not always indicate malignant disease. Although the goiters frequently extended into the superior mediastinum and were visible on chest radiographs as a superior mediastinal mass, sternotomy usually was not required for surgical removal. In another series, 45 of 300 patients (15%) undergoing thyroidectomy had tracheal compression from benign thyroid disease (103). Four patients presented with acute upper airway obstruction requiring intubation, and four patients developed life-threatening obstruction while hospitalized. About half of 20 consecutive nonsurgical patients with euthyroid benign goiters, on careful questioning, had exertional dyspnea, and 80% had abnormalities of pulmonary function tests or tracheal tomography (104).
With airway obstruction, the peaks of the flow volume loop are cut off and flattened. Extrathoracic obstruction primarily diminishes inspiratory airflow, whereas intrathoracic obstruction predominantly affects expiratory airflow (105). Spirometric changes indicative of upper airway obstruction include decreased peak flow rates, a forced inspiratory flow measured at 50% of VC that is less than 100 L per minute, a ratio of forced inspiratory to forced expiratory flow rates measured at 50% of VC that is greater than 1, and a ratio of forced expiratory volume in 1 second to peak expiratory flow that is greater than 10 L/min. The inspiratory–expiratory flow volume loop is probably the most sensitive test, particularly if the test is performed with the patient in the supine position (106). A neural network algorithm based on the flow volume loop was 88% sensitive and 94% specific in detecting airway obstruction from goiter and was more accurate than specialist interpretation (107). Although chest radiography and ultrasonography predict retrosternal extension of goiter, they do not predict upper airway obstruction.
Tracheal tomography and computed tomography (CT) delineate the extent of luminal narrowing and may help plan airway and surgical management. A barium swallow can determine whether the esophagus also is compressed or deviated, as is true in up to one third of patients. Fluoroscopy can identify a pulsatile mass, indicating the presence of an aortic aneurysm rather than thyroid tissue. A radioactive iodine scan can confirm that a mediastinal mass takes up iodine and is likely to be thyroid tissue; a negative scan does not exclude the possibility that it is nonfunctioning thyroid tissue, but it must be done before CT scanning with iodinated contrast. Bronchoscopy or esophagoscopy may be necessary to ensure that primary cancer of one of these organs is not coexisting with a goiter.
About 10% of anterior mediastinal masses are mediastinal thyroid tissue. Overall, 5% of mediastinal tumors prove to be intrathoracic goiters. Suggestive CT features include anatomic continuity with the cervical thyroid, focal calcifications, high CT number (>70 HU), and a prolonged increase in CT number after iodinated intravenous contrast material (>100 HU) (108). Less commonly, mediastinal goiters occur in other parts of the mediastinum. Radionuclide scanning after administration of 123I or 131I may confirm this diagnosis.
Surgical treatment of a large substernal goiter with airway compression can be difficult (72,100). Most intrathoracic goiters should be removed because of the risk for sudden enlargement, unless the patient is in a high-risk group for surgical complications. Such goiters usually can be removed using a standard cervical collar incision, but sometimes a sternotomy or a thoracotomy is required. A combined surgical approach often is necessary for posterior mediastinal goiters. Tracheostomy should be avoided, if possible, unless laryngeal edema is present. Intubation should be attempted only in life-threatening situations or at the time of definitive surgery, after the diagnostic workup is otherwise complete. Surgery usually is recommended for goiters that cause peak inspiratory flow rates of 1.5 L per second or less. Peak and midinspiratory flow rates often double after removal of large goiters with significant tracheal obstruction. Two patients with hypercapnia preoperatively became normocapnic after removal of the goiter. Substernal goiters can recur in as many as 20% of postoperative patients. Until recently, there was reluctance to treat patients with large multinodular goiters and compressive symptoms with 131I, but one study of 21 patients demonstrated objective improvement in tracheal luminal size and tracheal deviation (109).
Thyrotoxicosis and Asthma
Thyrotoxicosis has been said to worsen airway hyperreactivity in patients with asthma, based on several case reports and a study of five patients with severe intractable asthma who became responsive to therapy after several days of antithyroid treatment with PTU (110,111,112,113). In a small study, exogenous T3given chronically to asthmatics decreased their symptoms and increased their peak flow rates (114); however, peak flow measurement is highly variable and significantly effort dependent. In contrast, normal subjects who were made thyrotoxic with exogenous T3 and challenged with methacholine inhalation did not increase their airway resistance (115). Nonasthmatic thyrotoxic patients did not have bronchoconstriction after histamine challenge or a change in response after becoming euthyroid (116). Mild asthmatics with T3-induced thyrotoxicosis also did not have a change in methacholine-induced bronchospasm, pulmonary function tests, or exercise capacity (117). To confuse the subject further, thyrotoxicosis decreased bronchial reactivity to carbachol provocation in 8 of 11 patients studied before and after treatment (118). Acute hypothyroidism caused by thyroidectomy for cancer was associated with increased bronchial reactivity to carbachol in 11 patients without pulmonary disease (119).
In summary, most data do not support a consistent relationship between thyroid function and bronchial reactivity. It remains unclear whether or not hyperthyroidism and asthma are associated more frequently than expected based on their individual prevalence.
Airway obstruction (asthma or COPD) and thyrotoxicosis interact in other ways. For example, β-blockers may worsen airway obstruction. Theophylline metabolism can be accelerated up to fourfold in patients with thyrotoxicosis because of increased hepatic metabolism by the cytochrome P450 system (120,121). Theophylline can increase serum T4 concentrations, at least transiently, in adults and children (122).
Serum angiotensin-converting enzyme activity, once considered a diagnostic test for sarcoidosis, may be elevated in many granulomatous diseases, diabetes mellitus, and thyrotoxicosis (123). PTU can cause eosinophilic pleuritis or diffuse interstitial pneumonitis (124,125). The latter was documented by lung biopsies of two patients with dyspnea, a productive cough, and restrictive pulmonary function tests within 1 to 3 months after beginning PTU therapy. The pulmonary findings resolved rapidly after discontinuation of PTU. Antineutrophilic cytoplasmic antibody (ANCA) may occur in patients taking PTU (rarely methimazole) and occasionally results in ANCA-vasculitis, including alveolar hemorrhage (125a). Finally, Hashimoto's thyroiditis may be associated with an increase in the frequency of bronchogenic carcinoma, especially adenocarcinoma (126).
SYSTEMIC CONDITIONS THAT AFFECT BOTH LUNG AND THYROID
A variety of systemic conditions can affect both the lung and the thyroid. In the past, children with cystic fibrosis (CF) often were treated with potassium iodide as an expectorant. The goitrogenic effects of chronic iodide therapy led to a high incidence of goiter and hypothyroidism (127,128). In older studies, children with CF had lower than normal serum T4 levels and high T3/T4 ratios with an increased serum TSH response to TRH (129), suggesting subclinical hypothyroidism, but these studies did not control for the effects of malnutrition or exocrine pancreatic deficiency.
Iodinated glycerol previously was used to increase clearance of mucus and for symptomatic treatment of COPD, and may cause thyrotoxicosis or hypothyroidism (130,131); consequently, iodine was removed from this medication. Chronic iodine therapy can cause pulmonary edema (132).
Cigarette smoking can alter thyroid function tests subtly; however, the changes are not clinically important in most people. Discontinuation of smoking may lead to decreases in serum T4 and rT3 levels, a small increase in the serum TSH level, and no change in the serum T3 level (133). In contrast, in another study, heavy smokers had lower serum T4 and T3 levels compared with light smokers and control subjects (134). Other measures of thyroid function did not differ among the three groups. The pyridine components of cigarette smoke or higher serum thiocyanate concentrations in smokers may have a mild antithyroid effect. Smoking also is associated with a higher prevalence of ophthalmopathy in patients with Graves' disease (135,136,137) and nontoxic goiter, and it may increase the serum TSH further in subclinical hypothyroidism or impair the peripheral action of thyroid hormone (138). Nicotine per se is probably not the cause of the smoking-induced changes in thyroid function (139).
Systemic autoimmune disorders may involve the lung and often are associated with thyroid disease. Examples include Sj□gren's syndrome, systemic lupus erythematosus, and rheumatoid arthritis. Myasthenia gravis occurs in 0.1% of patients with Graves' disease, which is a 30-fold increase over the prevalence in the general population. Pulmonary manifestations can include thymoma, aspiration resulting from bulbar involvement, and respiratory muscle weakness leading to respiratory failure.
Other systemic diseases can involve both the lung and thyroid. Pneumocystis carinii infection of the thyroid has been found in acquired immunodeficiency syndrome (AIDS) patients with enlarged thyroid glands, most of whom were receiving aerosolized pentamidine prophylaxis against P. carinii pneumonia (140). The goiters may or may not be tender, and patients have been thyrotoxic or hypothyroid. Radioactive iodine uptake usually is decreased in the affected region. Aspergillus also may infect the lungs and thyroid. Langerhans' cell granulomatosis may occur in the thyroid gland of patients with or without pulmonary involvement (141,142).
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