Asbestos and the Lung

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Asbestos and the Lung* Marc M. Dunn, M.D.

PATIENT PRESENTATION

A

,,'hite man presented "rith the complaint of etfortInduced dyspnea. He also mentioned the presence of minimal pedal edema. At the time of evaluation he had fine crackles on lung auscultation. They "rere present in mid- to late inspiration over the left chest and the lower half of the right chest. A right ventricular heave was noted and accentuated pulmonic valve closure sound was also heard. The digits of his hands were clubbed. Pulmonary function tests showed a restrictive pattern ,,'ith generalized reductions in lung volumes. The diffusing capacity for carbon monoxide (Oro) "'as 50 percent of predicted. His Pa0 2 was 70 mm Hg and PaCO 2 ,,'as 24 mm Hg. Pleural calcifications and interstitial infiltrates were noted on the chest radiograph. The patient had been working in the "shingle and flex board" division of a major asbestos manufacturing corporation for 18 years. The diagnosis of pulmonary asbestosis was made based upon his clinical presentation and epidemiologic history. He retired shortly after the initial examination, but his symptoms progressed over the next five years until he died of respiratory failure. ~-year-old

DISCUSSION

We might begin our discussion by wondering why we should be interested in asbestos-related lung disorders at all since asbestos use has markedly diminished in recent years. There are two reasons why asbestos related lung disorders remain important. First, pulmonary diseases due to asbestos exposure, including asbestosis, bronchogenic carcinoma, benign pleural effusion, and mesothelioma remain common despite the marked reduction in the use of this fiber. The latency period of greater than 20 years, from first exposure to disease, for most asbestos-related disorders ensures their continued presence for the forseeable future. In addition, asbestosis and asbestosinduced bronchogenic carcinoma are pathologically similar to other fibrotic and malignant pulmonary disorders. Insights into the pathogenesis of these asbestos-related disorders may also aid in the understanding of other lung disorders. The magnitude of the industrial use of asbestos has *From the Division of Pulmonary Medicine, Department of Internal Medicine, Northwestern University Medical School Veterans MeAdministration Lakeside Medical Center, and Northwe~tern morial Hospital, Chicago. Presented at Internal Medicine Grand Rounds, Northwestern University Medical School, Chicago. 1304

been enormous. Desirable industrial features of the asbestos fiber include high tensile strength, resistance to corrosive destruction, and resistance to high temperatures. These features, in combination with its low cost, ensured its widespread use before the adverse health implications of asbestos were recognized. Over 30 million tons of asbestos have been mined since 1900 and over 30 million people have been exposed to asbestos over this period of time. The occupations at particular risk include those in which milling, mining, and handling of the asbestos fiber occurs. 1.2 The asbestos-related pulmonary disorders to be discussed here include asbestosis, bronchogenic carcinoma, benign pleural diseases including effusions and plaque, and mesothelioma. I will briefly describe clinical features associated with these disorders, as well as selected features of their proposed pathogenesis. Asbestosis

Asbestosis refers to the fibrotic lung disease resulting from significant inhaled asbestos exposure. The diagnosis is usually made clinically and is dependent on exposure history, the presence of dyspnea on exertion, and crackles on auscultation. Small, irregular opacities are usually demonstrated on the chest roentgenogram, particularly in the lower two thirds of the lung fields. A restrictive pattern is seen on pulmonary function testing. 1,2 There are no pathognomonic clinical, roentgenologic, or physiologic findings found with asbestosis. The most common symptoms and signs are dyspnea, inspiratory crackles, and cough (Table 1). The presence of clubbing is diagnostically useful, but is inconstantly found. Radiologic findings are also nonspecific (Table 2). Small irregular opacities involving the lower lung fields are commonly noted. In the absence of an exposure history, asbestosis may be difficult to distinguish clinically or radiographically from other pulmonary fibrotic disorders. Pleural changes, "shaggy" heart or diaphragm, or rounded atelectasis, when present, point towards the diagnosis of asbestosis. Asbestos and the Lung (Marc M. Dunn)

Table 3- Bronchoalveolar lAvage in A8be.toaia Potienta

Table l-A8batolil: Clinical Finding. Symptom/Sign Dyspnea Crackles Cough Sputum Chest pain Clubbing

Frequency (%) 70-100 95

70 40-60 30-50 20-80

However, these findings are not common. A decreased diffusing capacity is frequently the first abnormality found on pulmonary function tests. A restrictive pattern then develops as the disease worsens. There has been a question for some time whether asbestos can produce a purely obstructive pattern. This possibility seems unlikely when concomitant smoking effects are eliminated. On the other hand, there is pathologic and physiologic evidence for small airways dysfunction as an early event in asbestosis. 3 ,4 Pathologically, asbestosis can be subdivided into early and late pulmonary alterations. Early changes are characterized by peribronchiolar macrophage infiltration and fibrosis. Later, diffuse interstitial inHammation and fibrosis are present which may be indistinguishable from idiopathic pulmonary fibrosis. Fibrosis is generally associated with greater than 1 million asbestos fibers per gram of lung tissue. The presence of asbestos bodies in lung tissue is suggestive of significant asbestos exposure, but is not diagnostic of asbestosis. Asbestos bodies are fibers which are coated with hemosiderin and glycoprotein and are formed by the alveolar macrophage after phagoctyosis. They are 2 to 5 f.Lm in diameter and 20 to 50 f.Lm in length. There is no clear threshold number of asbestos bodies associated with asbestosis. 5,6 Theories of the pathogenesis of asbestosis should take into account the early pathologic findings, as well as recently described phenomena noted from bronchoalveolar lavage studies. For example, increased neutrophils or lymphocytes have been described in the bronchoalveolar lavage Huid of patients with asbestosis (Table 3). Increased neutrophils have also been associated with crackles, and decreased Pa02 , Dco, or FVC. Thus, the presence of neutrophils is Table 2-Btuliographic Finding. in A8beaton. Irregular opacities Honeycombing Kerley B lines Distribution: Lower Lower + middle Pleural changes S~he~ord~phm~

50% 33%

Increased neutrophils Increased lymphocytes

75%

35% 35% 35% 30% 50% 5%

associated with clinical findings common in asbestosis. Asbestos bodies may also be found in bronchoalveolar lavage. As has been noted, this merely points to asbestos exposure, but is not diagnostic of asbestosis. Information from bronchoalveolar lavage and pathologic findings have provoked investigation into asbestos induced biochemical and cellular alterations which might help explain the pathogenesis ofasbestos-related pulmonary disease. Biochemical changes which occur with asbestos exposure include the activation of complement which results in the generation of C5a, a potent chemoattractant for macrophages and PMN. 7,8 Asbestos also directly causes lipid peroxidation. 9 These lipid peroxides may be toxic to cells, or when formed within a cell membrane, result in alterations of function. Asbestos also induces increased BAL fibronectin levels when instilled into the lung. 10 Fibronectin is chemotactic for fibroblasts and serves as an attachment and growth factor for these cells. When macrophages are incubated with asbestos in vitro, they elaborate the alveolar macrophage-derived growth factor for fibroblasts (AMDGF), a chemotactic factor for macrophages, and a chemotactic factor for neutrophils which is probably leukotriene B".11,12 When fibroblasts encounter asbestos, collagen production increases. Thus, the interaction of asbestos with components of the pulmonary milieu results in inHammation, cytotoxicity and fibrosis. There is growing evidence for a prominent role for oxygen radicals in asbestos induced injury. First, asbestos can be phagocytosed by and is toxic to epithelial cells in tissue explants. This effect was probably mediated through oxygen radical production. 13,14 Furthermore, alveolar macrophages and PMN appear to have a role in asbestosis and both are potent producers of oxygen radicals. Phagocytosis of asbestos by these cells may stimulate oxidant release. Furthermore, iron, an intrinsic component of the asbestos fiber, catalyzes the production of the hydroxyl radical (OH+), an extremely potent oxygen radical, through the modified Haber-Weiss reaction:* O 2 -. + Fe3 +-.()1l + Fe2 + Fell+ + H 20 11""'OH·+ Fe3 +OHH10 2 + Asbestos-Fell+-.()H·+ Asbestos-Fe3 +

This reaction has been demonstrated and deferroxamine, an iron chelator, prevents asbestos-induced hydroxyl radical formation. In vivo verification of this

*Weitzman, Arch Biochem Biophys 1984; 228:373, CHEST I 95 I 6 I JUNE. 1989

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phenomenon and its prevention might lead to new therapeutic approaches towards asbestosis. There are clearly many possible pathophysiologic mechanisms that may interact to produce asbestosis. Further work is necessary to determine which factors are most prominent. There is no specific treatment for asbestosis despite our improved understanding of its pathogenesis. Steroids are not recommended. Measures to stop smoking are suggested in order to avoid concomitant chronic obstructive disease. Furthermore, asbestos exposure and smoking are synergistic in the promotion of bronchogenic carcinoma. The prognosis for established asbestosis has improved despite the lack of effective therap~ This is probably related to the decrease in exposure in the last several decades. An increase in the incidence of bronchogenic carcinoma has occurred concomitant with the increased survival ofpatients with asbestosis, however, and it is necessary to maintain a high level of suspicion for this neoplasm. 1.3 Presently, the best measures are aimed at prevention. Decreasing asbestos exposure will minimize the risks of asbestosis, as well as other asbestos related lung disease. Effective smoke cessation will result in a decreased risk of bronchogenic carcinoma in individual patients. Bronchogenic Carcinoma

As the prognosis for asbestosis has improved, the incidence of bronchogenic carcinoma has increased. There is nothing to distinguish asbestos related tumors from bronchogenic carcinoma seen in cigarette smokers unexposed to asbestos with the exception that they are more commonly located in a peripheral and basilar location. As with most other asbestos related disorders, there is a greater than 20-year latency between exposure and disease. It is well known that cigarette smoking and asbestos exposure behave synergistically in the pathogenesis of bronchogenic carcinoma. The relative risk of developing carcinoma in those with asbestos exposure is two to three times that of the general population. Smokers have a tenfold excess risk and the combination of smoking and asbestos exposure increases the risk 6O-fold. 6 The histologic subtypes of tumor are the same in the smokers and asbestos exposed.15 ,16 Thus, asbestos exposure may result in an increase in the magnitude of the carcinogenic exposure, but not the specific target cells. Recent studies have described a number of ways in which asbestos may be involved in the pathogenesis of bronchogenic carcinoma. Before describing this new information, I will digress by outlining a current model of carcinogenesis. In this model a normal cell is acted upon by an initiator which irreversibly alters the cellular genetic material. The initiated cell is then 1308

acted upon by a promoter which stimulates cell division while inhibiting differentiation which results in the production of a tumor cell and then a clone of tumor cells. Asbestos has both initiator and promoter functions. Indirect initiator functions include its ability to absorb carcinogens such as benzopyrene. Asbestos also catalyzes the oxidation of weak to potent carcinogens. The combination of hydrogen peroxide, present in cigarette smoke, and asbestos may induce DNA strand breaks via a hydroxyl radical dependent mechanism. Metaplasia of hamster tracheal cells is an example of the promoter effects of asbestos. 17-20 The diagnostic and therapeutic approach to asbestos-induced bronchogenic carcinoma is the same as usual instances of bronchogenic carcinoma and will not be discussed further here. An extremely high index of suspicion for bronchogenic carcinoma should be maintained when evaluating relevant symptoms in asbestos-exposed persons, particularly those who have smoked cigarettes. Certainly the primacy of urging smoking cessation for prevention of bronchogenic carcinoma in this group is readily apparent. Benign Pleural Disorders

Asbestos-induced benign pleural disorders include effusions and plaques. Asbestos-induced pleural effusions usually occur with a latency of 10 to 20 years following asbestos exposure making this entity one of the earliest asbestos-related disorders to be encountered. They may be unilateral or bilateral and may be recurrent in 30 percent of patients. These effusions are usually asymptomatic, although they are uncommonly associated with fever and leukocytosis. On occasion, the effusion may be blood~ However, with the exception of this feature, there are no other distinguishing findings on thoracocentesis. The diagnosis is made by a history of asbestos exposure, the absence ofother predisposing causes, and spontaneous remission of the effusion. Although there is no particular relationship of these effusions to development of mesothelioma, one quarter to one half do result in pleural fibrosis. 21.22 Pleural plaques are the most common asbestosrelated disorder. They occur with a latency period of 20 to 30 years and are usually asymptomatic. A history of asbestos exposure can be obtained in greater than 80 percent ofpatients with pleural plaques. 1,23 Plaques are present on the posterior aspect ofthe lower parietal pleura or diaphragm on chest roentgenograms and are typically bilateral. The apices and costophrenic angles are spared. Plaques are usually not calcified. Although it is rarely necessary to perform other studies to detect plaques, both oblique chest films and cr scan do have increased yield. 15,24,25 No therapy is required for either disorder and biopsy procedures should be avoided when the presentation is typical. Asbestoe and the Lung (Marc M. Dunn)

Table 4-Me.othelioma: Symptoml History

Presenting (If,)

Final (%)

Chest pain Dyspnea Cough Weight loss

35 15

60

90

05

70 35

Mesothelioma Mesothelioma is the other tumor associated with asbestos exposure. There are differences between the association of this tumor with asbestos exposure and the association of asbestos with bronchogenic carcinoma. As with bronchogenic carcinoma, there is an increased risk with high exposure. However, mesotheliomas also occur following minimal asbestos exposure and there is no association of this tumor with cigarette smoking. Patients with mesothelioma are usually more than 50 years old and the tumor appears with a latency period of 20 years or more. Eighty percent of mesotheliomas are pleural. Twenty percent are peritoneal.26-29 The clinical presentation of mesothelioma is nonspecific (Table 4). Chest pain is found in 60 percent of patients, but other findings occur in less than one half of the patients. The presence of chest pain may help distinguish mesothelioma from benign pleural effusion. Physical examination may lead the clinician to suspect the diagnosis of mesothelioma, but findings remain nonspecific. An examination consistent with pleural effusion is found in 80 percent of patients. Other findings include clubbing, displaced abdominal contents due to a large effusion, local adenopathy or a "frozen" chest, which represents fibrosis and fixation of the hemithorax. These findings are uncommon.26-29 The radiographic findings found with mesothelioma may be more striking. Pleural effusion is most commonly found. However, other findings may suggest the malignant nature of the effusion. For example, irregular pleural thickening may be noted above the pleural fluid. Nodularity or thickening of the pleura may be seen following thoracocentesis. Crowding of the ribs, an elevated hemidiaphragm or a shift of the mediastinum to the ipsilateral hemithorax may suggest the fibrosis and volume loss seen with this tumor. Rib destruction is also seen rarely. 26,30 The initial diagnostic procedure in the patient with mesothelioma is thoracocentesis. The pleural fluid is exudative, straw-colored in 50 percent of patients, and serosanguinous in less than one third of patients. The fluid has a tendency to reaccumulate following its cytologiremoval by thoracocentesis. Unfortunatel~ cally malignant cells are found in less than 20 percent of patients and the diagnosis of mesothelioma is made in less than 5 percent of patients. The diagnosis of

mesothelioma, then, usually requires a thoracotomy for sufficient histologic material. Features consistent with the diagnosis include the absence of other primary tumors capable of serosal spread, the tendency for superficial spread, and specimens showing epithelial or mesenchymal cells.31 The pathogenesis of mesothelioma is incompletely understood, although physical, rather than biochemical, characteristics of the asbestos fiber have been implicated. Long, thin fibers have the greatest carcinogenic potential. They may be capable ofpenetrating from central airway to the peripheral lung and pleura. It is unclear whether ongoing inHammation is important for the pathogenesis of mesothelioma as with asbestosis.32,33 The prognosis for mesothelioma is, in general, very poor. Survival for greater than three years from the time of diagnosis is unusual. Favorable prognostic signs include age less than 65 years, an epithelial cell type, and pleural origin. However, even with all three favorable signs present, patients survive for less than two years. There has been no consistently effective therapy short of complete surgical removal, a rare event. I have discussed asbestos-induced pulmonary disorders and, in particular newer pathogenic aspects. Although many of these disorders will eventually be eliminated, they serve as models of other fibrotic and malignant pulmonary disorders. In addition, lessons learned from the asbestos story should be kept in mind as we develop new fibers to replace it. QUESTIONS AND ANSWERS

Question: Are there any clues as to how oxygen radicals induce irreversible molecular changes within cells? Dr. Dunn: A number of events occur subsequent to fatal oxidant exposure to cells, including depletion of intracellular glutathione, elevation of intracellular calcium, depletion of NAD, and single strand DNA breaks. It is likely that these events are related to cell death. Question: How can one exclude the diagnosis of mesothelioma in the patient presenting with a pleural effusion, history of asbestos exposure and no other clear etiology of the effusion? Dr. Dunn: Benign pleural effusions characteristically appear earlier following asbestos exposure than mesotheliomas, are usually painless, and usually do not recur. Mesotheliomas may also present with distinctive roentgenologic features, as already discussed. If thoracocentesis is performed, the chest roentgenogram following the procedure may show a residual pleural based mass if mesothelioma is present. Question: Does pleural biopsy give additional information following thoracocentesis? Dr. Dunn: It may increase the sensitivity of diagnosis CHEST I 95 I 6 I JUNE, 1989

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of malignanc)': However, the frequency with which the specific diagnosis of mesothelioma is made is only minimally improved. REFERENCES

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Asbestos and the Lung (Marc M. Dunn)